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22727329 | 24,383,348 | Developing a measure of eating attitudes and behaviours in cystic fibrosis | Eating disorders or disturbed eating attitudes and behaviours (EABs) may contribute to poor nutritional status in Cystic Fibrosis (CF). Existing measures of disturbed EABs can have different meanings in this population and do not assess CF-related EABs. A self-report measure of EABs in CF was developed to highlight areas of eating disturbance. The content validity of a draft measure was evaluated via expert evaluation and literature review and an amended measure piloted with 8 CF patients using cognitive interviewing. A further amended measure was administered to 155 CF patients (11-62 years) attending CF clinics. Principal components analyses revealed a three-factor structure ('Desire for thinness and weight loss', 'Disturbed EABs', and 'Appetite') with good internal consistencies for subscales and the 21-item whole measure. The measure looks promising as a tool to highlight EAB disturbance in CF. Further work will establish its construct validity and clarify interpretation of subscales. | Gold Standard | clinical characteristics or disease pathology | 0 |
22727716 | 3,031,846 | Pulmonary arterial hypertension in a patient with hereditary hemorrhagic telangiectasia | Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by the triad of epistaxis, telangiectasia and vascular malformations. Pulmonary vascular complications associated with this disease include pulmonary arteriovenous malformations (AVM) and, less frequently, pulmonary hypertension (PH). We report the case of a patient who presented multiple pulmonary AVM and PH probably due to HHT. Embolization was carried out on one of the AVM and the patient received specific pulmonary arterial hypertension treatment with an endothelin receptor antagonist. We also described the patient's functional and hemodynamic improvement after almost 3 years of follow-up. | Gold Standard | therapeutics in the clinic | 3 |
22729251 | 12,561,072 | Monitoring the autonomic nervous activity as the objective evaluation of music therapy for severely and multiply disabled children | Severely and multiply disabled children (SMDC) are frequently affected in more than one area of development, resulting in multiple disabilities. The aim of the study was to evaluate the efficacy of music therapy in SMDC using monitoring changes in the autonomic nervous system, by the frequency domain analysis of heart rate variability. We studied six patients with SMDC (3 patients with cerebral palsy, 1 patient with posttraumatic syndrome after head injury, 1 patient with herpes encephalitis sequelae, and 1 patient with Lennox-Gastaut syndrome characterized by frequent seizures, developmental delay and psychological and behavioral problems), aged 18-26 (mean 22.5 ± 3.5). By frequency domain method using electrocardiography, we measured the high frequency (HF; with a frequency ranging from 0.15 to 0.4 Hz), which represents parasympathetic activity, the low frequency/high frequency ratio, which represents sympathetic activity between the sympathetic and parasympathetic activities, and heart rate. A music therapist performed therapy to all patients through the piano playing for 50 min. We monitored each study participant for 150 min before therapy, 50 min during therapy, and 10 min after therapy. Interestingly, four of 6 patients showed significantly lower HF components during music therapy than before therapy, suggesting that these four patients might react to music therapy through the suppression of parasympathetic nervous activities. Thus, music therapy can suppress parasympathetic nervous activities in some patients with SMDC. The monitoring changes in the autonomic nervous activities could be a powerful tool for the objective evaluation of music therapy in patients with SMDC. | Gold Standard | therapeutics in the clinic | 3 |
22737832 | 43,483,678 | Rupture of the main pulmonary trunk in a woman with severe pulmonary artery hypertension and hereditary hemorrhagic telangiectasia | Spontaneous rupture of the main pulmonary trunk is a very uncommon complication of severe pulmonary hypertension. The condition manifests as sudden death or cardiogenic shock usually diagnosed postmortem. We report the case of a 65-year-old-women with severe pulmonary hypertension and hereditary hemorrhagic telangiectasia, among other diseases, evaluated due to severe epistaxis. Initial evaluation was performed and during observation, the patient developed sudden cardiac death. Autopsy revealed rupture of the main pulmonary trunk as the cause of death. | Gold Standard | clinical characteristics or disease pathology | 0 |
22744870 | 206,330,858 | 42-year-old patient with portal hypertension - case 6/2012 | A 42-year-old woman was referred with a bleeding in the upper gastrointestin**al tract, varices in the fundus of the stomach and portal hypertension of unknown primary. Ultrasound examinations showed splenomegaly as well as portal hypertension. Blood examinations revealed low levels of haemoglobin**. CT imaging showed multiple arteriovenous malformations with arterioportal shunts within the liver which led to a volume-induced portal hypertension. The genetic analysis revealed no mutations in the activin receptor-like kinase (ALK) 1 or endoglin genes. The patient was clinically diagnosed with hereditary hemorrhagic teleangiectasia, also known as Osler-Weber-Rendu disease. Because of the multiple arterioportal shunts within the liver and the resulting portal hypertension with live-threatening gastrointestinal bleeding, the only therapeutic option for the patient is liver transplantation. Therefore, an application for a standard exception was made at Eurotransplant and the patient is going to be liver transplantated within the next months. Osler-Weber-Rendu disease is an autosomal dominant hereditary disease which leads to arteriovenous malformations and which can affect different organ systems. The course of the disease can be rather benign, but it can also lead to live-threatening complications requiring fast interventions. | Gold Standard | therapeutics in the clinic | 3 |
22746027 | 31,158,160 | Anesthetic management of extracorporeal shock wave lithotripsy: case reports of four young patients with epilepsy | Four young patients, including a 7-year-old girl with Aicardi syndrome, an 11-year-old boy with Lennox-Gastaut syndrome, a 22-year-old man with epilepsy due to childhood encephalitis, and a 17-year-old girl with Rett syndrome, were scheduled to undergo extracorporeal shock wave lithotripsy (ESWL) for urolithiasis. Epilepsy in all of the patients was well controlled by medication. Series of ESWL treatment were safely performed under general anesthesia with tracheal intubation. We recommend that maintenance of anesthesia be performed by sevoflurane and nitrous oxide, which can increase threshold of epileptic stroke, and controlled ventilation with a muscle relaxant should be performed to prevent lung or renal injury by the shock wave of ESWL. | Gold Standard | therapeutics in the clinic | 3 |
22747891 | 9,131,662 | Frequency of fungi in respiratory samples from Turkish cystic fibrosis patients | An increased isolation of fungi from the respiratory tract of patients with cystic fibrosis (CF) has been reported. The prevalence of different fungi in CF patients from Turkey is not known. Our aim was to determine the frequency of fungi in the respiratory tract of Turkish CF patients. We investigated a total of 184 samples from 48 patients. Samples were inoculated on Medium B+ and CHROMagar Candida. Candida albicans was the predominant yeast isolated [30 patients (62.5%)], followed by C. parapsilosis [6 (12.5%)] and C. dubliniensis 5 (10.4%). Aspergillus fumigatus was the most common filamentous fungus [5 (10.4%)] and non-fumigatus Aspergillus species were isolated from four (8.3%) patients. Staphylococcus aureus was the most frequently detected bacterium in C. albicans positive samples (53.57%). A. fumigatus and Pseudomonas aeruginosa or S. aureus were detected together in 75% of A. fumigatus positive samples each. No statistically significant relationship was detected between growth of yeast and moulds and age, gender, the use of inhaled corticosteroids or tobramycin. No significant correlation was found between the isolation of C. albicans, A. fumigatus and P. aeruginosa, Stenotrophomonas maltophilia or S. aureus, and the isolation of C. albicans and Haemophilus influenzae. Other factors which may be responsible for the increased isolation of fungi in CF need to be investigated. | Gold Standard | clinical characteristics or disease pathology | 0 |
22780580 | 25,584,020 | Dramatic weight loss with rufinamide | Rufinamide (RUF) is a novel antiepileptic drug considered as second-line therapy in the treatment of Lennox-Gastaut syndrome. Treatment-emergent adverse events (AEs) have consisted mainly of drowsiness, irritability, vomiting, and loss of appetite. RUF is considered as a "weight-neutral" drug. We found clinically significant weight loss in 7 of 15 consecutive adult patients (47%; 3 male, 4 female, aged 18-31 years) treated with RUF as add-on therapy (800-2,400 mg/day: 23.5-57.1 mg/kg/day). The body mass index (BMI) decreased by 7.3-18.7%. Two patients were obese class I before RUF. Five patients (71%) were underweight before RUF (mild in one case, moderate in two cases, and severe in two cases). Four of these patients stopped RUF because of this adverse effect. RUF was recommenced in two patients using a lower and slower dosing strategy; one patient showed improvement in seizure control and no weight loss but RUF was re-stopped in the second patient because of continued weight loss. Despite of weight loss, RUF was continued in two other patients because it reduced seizure activity. We primarily related weight loss to reduced food intake, that is, loss of appetite and nausea, although in two patients no obvious loss of appetite was reported. RUF can cause clinically significant weight loss in adult patients, even at low dose. This AE can affect patients who are already underweight. There is a possibility that lower starting doses and slower escalation might minimize weight loss, but further information is required to determine whether this is the case. | Gold Standard | therapeutics in the clinic | 3 |
22781769 | 44,568,428 | Clinical features and screening of ACVRL1 gene in II hereditary hemorrhagic telangiectasia | To analyze the clinical features and pathogenic gene of the patients with hereditary hemorrhagic telangiectasia (HHT). The clinical features of 3 HHT families were collected. And the patients were diagnosed according to clinical diagnostic analyzed criteria of HHT, the ACVRL1 gene screened and the conservation of mutation protein. Three probands and 1 patient were diagnostic for HHT and 2 patients were suspected. In family I, there was a missense mutation of ACVRL1 gene in c.287A > G on 2 patients, leading to the transferal of amino acids from Asn to Ser at 96(th) place. In family II, there was a missense mutation of c.1271C > T on ACVRL1 in 2 patients, leading to the transfer of amino acids from Pro to Leu at 424(th) place. In family III, there was a deletion mutation of c.147delC on ACVRL1 so as to produce only the former 53 amino acids of ALK1 protein. Through an analysis of multi-species conservation, the mutations were conserved between multiple species. By querying the National Center for Biotechnology Information (NCBI) database, we confirmed that the mutation was not of a single nucleotide polymorphism (SNP). The genetic screening of HHT patients may identify their virulence gene. And genetic screening of their offspring is helpful for the early diagnosis and prevention before disease onset. | Gold Standard | disease mechanism | 2 |
22849993 | 24,160,977 | Migraine with aura and recurrent vertigo attacks in a patient with hereditary hemorrhagic telangiectasia | Hereditary hemorrhagic telangiectasia (HHT) is characterized by systemic vascular diseases mainly shown as arterio-visnous fistula (AVF). Here, we presented a 29-year-old woman with HHT complicated with migraine with aura (MWA) and vertigo. At the age of twelve years, she developed migraine with visual aura. At that time, migraine attacks were seen three times a year. At the age of 29 years, she also developed speech disturbance as migraine aura. At the ages of 20 and 29 years, she repeatedly suffered from positional vertigo attacks for a month. Physical examination revealed dilation of the capillary vessels at tongue, soft palate, and nasal mucosa and AVFs were located in the upper cervical cord, parietal lobe, and bilateral lungs. These clinical findings were consistent with the diagnostic criteria of HHT. Embolization of pulmonary AVF decreased the frequency of migraine attacks during 2-year follow-up after the embolization. The frequency of migraine in patients with HHT is higher than that of general population as well as the prevalence of vertigo. Therefore, MWA and vertigo presented in the patient with HHT suggests that there is a common pathological mechanism of dysfunction of endothelial cells and R-L shunt, among HHT, MWA, and vertigo. | Gold Standard | clinical characteristics or disease pathology | 0 |
22859374 | 35,985,162 | Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through TYK2/STAT6 pathway | Goblet cell hyperplasia (GCH) and mucous hypersecretion are common pathological features of chronic pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Despite numerous studies, the molecular basis for this condition remains elusive. Gab2 is a member of the Dos/Gab subfamily scaffolding molecules and plays important roles in regulating growth, differentiation, and inflammation. We found that an elevated level of Gab2 correlates with up-regulated mucus in airway epithelia from patients with lung cancer or COPD, suggesting the potential involvement of Gab2 in pathological lesions in lungs. Knockdown of Gab2 in human airway epithelial cells in vitro decreases IL-13-induced expression of mucin genes. To address the in vivo role of Gab2 in lungs, Gab2-knockout (Gab2(-/-)) mice were sensitized and challenged with ovalbumin (OVA). Further analysis of lungs in an OVA-induced allergy model suggested that GCH and mucus production are remarkably reduced in Gab2(-/-) mice. Mechanistically, Gab2 positively regulates IL-13-induced activation of TYK2/STAT6 by decreasing SOCS3-mediated degradation of TYK2. Together, we define a novel role for Gab2 in mediating mucin gene expression and GCH; these findings have important implications for the pathogenesis and therapy of airway inflammatory diseases. | Gold Standard | disease mechanism | 2 |
22875690 | 206,330,947 | Polymicrobial brain abscess in hereditary haemorrhagic telangiectasia (Osler's disease) | A 38-year-old woman who suffered from migraine was admitted because of severe, worsening headache for 24 hours (dissimilar to the previous migraine attacks), with impaired vision and weakness of the right arm. Mild hemiparesis and expressive aphasia indicated an intracranial tumor. Cranial computed tomography revealed a focal lesion with a diameter of 2.5 cm in the left frontoparietal lobe, with signs of intracranial hypertension, indicating cerebral metastasis or an abscess. Magnetic resonance imaging confirmed the diagnosis of a brain abscess. An urgent craniotomy was performed and the abscess was evacuated. An empirical antibiotic combination with chloramphenicole and metronidazole (switched to cefotaxime because of thrombocytopenia) was initiated. Cultivation of pus revealed Streptococcus constellatus, Aggregatibacter aphrophilus and Fusobacterium spp. Within the first two weeks of treatment progession of the abscess was noted, therefore a second craniotomy with debridement was performed. An elective CT-angio scan revealed several arteriovenous malformations in the caudal segments of both lungs which were embolized without complications. Only retrospectively, cutaneous teleangiectasias were recognized. At present, the patient and her direct relatives are submitted to genetical screening for Osler's disease. In patients with brain abscesses of unknown origin and with a history of repeated epistaxis and/or gastrointestinal bleeding, Osler's disease (hereditary hemorrhagic telangiectasia) should be considered and pulmonary arteriovenous malformations excluded. Physicians should search for cutaneous or mucous teleangiectasias. Family screening and long-term follow-up according to international guidelines is recommended. | Gold Standard | clinical characteristics or disease pathology | 0 |
22888088 | 37,370,406 | RPGR mutations might cause reduced orientation of respiratory cilia | RPGR gene encodes retinitis pigmentosa guanosine triphosphatase regulator protein, mutations of which cause 70% of the X-linked retinitis pigmentosa (XLRP) cases. Rarely, RPGR mutations can also cause primary ciliary dyskinesia (PCD), a multisystem disorder characterized by recurrent respiratory tract infections, sinusitis, bronchiectasis, and male subfertility. Two patients with PCD\_RP and their relatives were analyzed using DNA sequencing, transmission electron microscopy (TEM), immunofluorescence (IF), photometry, and high-speed videomicroscopy. The Polish patient carried a previously known c.154G>A substitution (p.Gly52Arg) in exon 2 (known to affect splicing); the mutation was co-segregating with the XLRP symptoms in his family. The c.824 G>T mutation (p. Gly275Val) in the Australian patient was a de novo mutation. In both patients, TEM and IF did not reveal any changes in the respiratory cilia structure. However, following ciliogenesis in vitro, in contrast to the ciliary beat frequency, the ciliary beat coordination in the spheroids from the Polish proband and his relatives carrying the c.154G>A mutation was reduced. Analysis of the ciliary alignment indicated severely disturbed orientation of cilia. Therefore, we confirm that defects in the RPGR protein may contribute to syndromic PCD. Lack of ultrastructural defects in respiratory cilia of the probands, the reduced ciliary orientation and the decreased coordination of the ciliary bundles observed in the Polish patient suggested that the RPGR protein may play a role in the establishment of the proper respiratory cilia orientation. | Gold Standard | disease mechanism | 2 |
22890535 | 523,962 | Kartagener's syndrome--anaesthetic considerations for ENT surgery | Kartagener's syndrome is a rare autosomal recessive disorder presenting a triad of sinusitis, bronchicetasis and situs inversus with dextrocardia. It occurs in 50% of patients with situs inversus. The most important anesthetic implications of Kartegener's syndrome surgery are assessement of pulmonary and cardiac structure and function. We present a case of 43-year-old woman with chronic rhinosinusitis with polyps and bilateral sectetory otitis media. The chest radiograph and CT scans showed dextrocardia and situs inversus with chronic bronchitis without bronchiectasis. Spirometry showed forced expiratory volume in one second (FEV1) of 2.66 L and forced vital capacity (FVC) of 3.62 L. Electroechography showed no cardiac abnormalities with 55-60% of EF. The anesthetic implications of Kartagener's syndrome are varied. The regional or general anesthesia might be involved with sinus surgery, ear surgery, pulmonary surgery, infertility or abdominal and cardiac surgery. The main anesthetic considerations among patients with Kartagener's syndrome are related to the pulmonary function which include preoperative respiratory infections due to bronchiectasis. We should also monitor potentially occluded congenital heart diseases. Kartagener's syndrome is a rare disease and when the patient need an operation we have to consider surgery with regional or general anesthesia. The general anesthesia would be safe after complete preanaesthetic examination of the patient. The ECG, chest CT scans, spirometry and echocardiography are mandatory before the operation. | Gold Standard | therapeutics in the clinic | 3 |
22898134 | 2,021,088 | Neutrophil necrosis and annexin 1 degradation associated with airway inflammation in lung transplant recipients with cystic fibrosis | Neutrophils sequestered in lower respiratory tract secretions in the inflamed lung may undergo apoptosis and/or necrosis and release toxic cellular contents that can injure airways or parenchyma. This study examined the viability of neutrophils retrieved from the proximal airways of lung transplant recipients with bacterial tracheobronchitis. Integrity and stability of intracellular proteins in neutrophils from proximal airways and peripheral blood from lung transplant recipients with bacterial tracheobronchitis were analyzed via Western blot analysis and determination of neutrophil viability by morphologic appearance and flow cytometry. Neutrophils in tracheobronchial secretions from lung transplant recipients with cystic fibrosis who had normal chest radiographic imaging but bronchoscopic evidence of purulent tracheobronchitis post-transplant were necrotic and associated with degradation of intracellular protein annexin 1. The neutrophil influx was compartmentalized to large airways and not detected in peripheral bronchoalveolar airspaces sampled via bronchoalveolar lavage. Peripheral blood neutrophils from healthy subjects cultured in vitro demonstrated that annexin 1 degradation, particularly to a 33 kDa annexin 1 breakdown product (A1-BP), was associated with neutrophil necrosis, but not apoptosis. Although annexin 1 degradation was not specific to neutrophil necrosis, it was a sensitive marker of intracellular protein degradation associated with neutrophil necrosis. Annexin 1 degradation to 33 kDa A1-BP was not observed in peripheral blood neutrophils from healthy subjects, but annexin 1 appeared to be degraded in peripheral blood neutrophils of lung transplant recipients despite a normal morphologic appearance of these cells. Neutrophils were necrotic from the proximal airways of lung transplant recipients with bacterial tracheobronchitis, and this process may begin when neutrophils are still in the systemic circulation prior to sequestration in inflamed airways. Annexin 1 degradation to 33 kDa A1-BP may be useful as a sensitive marker to detect neutrophil necrosis. | Gold Standard | disease mechanism | 2 |
22921514 | 283,375 | Lennox-Gastaut syndrome in south Iran: electro-clinical manifestations | Lennox-Gastaut syndrome (LGS) is an uncommon epileptic encephalopathy. In this study, we tried to determine the clinical and EEG characteristics of patients with LGS in south Iran. In this retrospective study, all patients with a clinical diagnosis of LGS were recruited at the outpatient epilepsy clinic at Shiraz University of Medical Sciences from 2008 through 2012. Age, gender, age at seizure onset, seizure type(s), epilepsy risk factors, EEG and imaging findings of all patients were registered routinely. During the study period, 2500 patients with epilepsy were registered at our epilepsy clinic. One-hundred and thirty-five patients (5.4%) were diagnosed as having LGS. Age of onset (mean±standard deviation) was 3.2±3.8 years. In 14 (10.4%) patients, age of onset was above 8 years. Eighty-three patients (61.5%) were male and 52 (38.5%) were female. The most common seizure type was tonic, followed by generalized tonic-clonic and myoclonic seizures. The most common EEG finding was slow spike-wave complexes. The most common abnormal MRI finding was brain atrophy. LGS is an uncommon epileptic encephalopathy characterized by multiple seizure types, a specific electroencephalographic pattern and psychomotor retardation, beginning in childhood. However, variants of this classical triad including atypical EEG findings, normal psychomotor function, and late-onset disease could be seen in some patients. These atypical findings in a patient with typical history for LGS should not deter from the correct diagnosis. The mainstay for making a correct syndromic diagnosis is a detailed clinical history. | Gold Standard | clinical characteristics or disease pathology | 0 |
22928917 | 2,797,990 | Co action of CFTR and AQP1 increases permeability of peritoneal epithelial cells on estrogen-induced ovarian hyper stimulation syndrome | Ovarian hyper stimulation syndrome (OHSS) is an iatrogenic complication associated with fertility drugs. It is characterized by increased vascular permeability and substantial fluid shift with accumulation in the body cavity. The pathogenesis of OHSS remains obscure, and no definitive treatments are currently available. Using western blot and short-circuit current (Isc) techniques, we investigate the potential coactions of analysis in cystic fibrosis transmembrane conductance regulator (CFTR) and aquaporin 1 (AQP1) on the hyper permeability of body cavity peritoneal epithelial cells in the pathogenesis of OHSS. The rats develop OHSS symptoms, with the up regulation of both CFTR and AQP1 expression and enhanced CFTR channel activity in peritoneal epithelial cells, can also be mimicked by administration of estrogen, alone in ovariectomized rats. Administration of progesterone suppresses CFTR activity, OHSS symptoms as well as CFTR and AQP1 expression. Besides, AQP1 inhibitor, HgCl(2), can suppress CFTR channel activity. Therefore, antisera against CFTR or AQP1 to OHSS animals may result in alleviation of the symptom. This study confirms the coactions of CFTR and AQP1 play a critical role in the development and progression of increased peritoneal epithelial permeability in severe OHSS. These findings may provide grounds for ameliorating assisted reproduction treatment strategy to reduce the risk of OHSS in in vitro fertilization (IVF). | Gold Standard | disease mechanism | 2 |
22937715 | 89,250,087 | Burkholderia cepacia persistence in patients with mucoviscidosis | Study features of persistence of Burkholderia cepacia in mucoviscidosis patients. In the period from 2008 to 2009, 56 B. cepacia strains isolated from children with mucoviscidosis were obtained. 114 medical histories of children with mucoviscidosis from various age groups were analyzed. The developed algorithm for identification and typing including phenotype and molecular biology methods was used to identify B. cepacia bacteria. Strain genotyping was carried out by RAPD-PCR with random oligonucleotide primer as well as pulse-electrophoresis. Persistence of associations ofmicroogranisms in 59.4% of cases was established to be the feature of persistent infection in mucoviscidosis. The feature of persistence of B. cepacia strains in patients with diagnosis ofmuco-viscidosis mixed form, severe course is persistence in association with Pseudomonas aeruginosa. B. cepacia bacteria that can persist in mucoviscidosis patients are characterized by resistance to many antibiotics. A prolonged (up to 1 year and 5 months) persistence of B. cepacia strains isolated from 1 patient was proven by using microflora monitoring of lower respiratory tract. B. cepacia bacteria may colonize lower respiratory tract of mucoviscidosis patients, persist for a long time and be transmitted between patients. | Gold Standard | clinical characteristics or disease pathology | 0 |
22940655 | 22,757,151 | Pulmonary arteriovenous fistula with Rendu-Osler-Weber disease | A 36-year-old man was admitted to our hospital for examination of a nodular shadow in the left lung. Chest 3-dimensional computed tomography (3D-CT) revealed a pulmonary arteriovenous fistula (PAVF) of 21 mm in diameter composed of the feeding artery (A4) and the draining vein (V4) in the left S4. Abdominal enhanced CT revealed multiple hepatic arteriovenous fistula. Brain CT revealed a cavernous hemangioma in right occipital cerebrum. He had a family history, habitual epistaxis, and oral telangiectasia and was diagnosed as Rendu-Osler-Weber disease (hereditary hemorrhagic telangiectasia:HHT). According to his family history, PAVF was likely to be a risk factor of brain infarction and abscess, and the wedge resection of the lingual lobe was performed to remove PAVF. | Gold Standard | clinical characteristics or disease pathology | 0 |
22966014 | 9,897,692 | Nonintegral stoichiometry in CFTR gating revealed by a pore-lining mutation | Cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette (ABC) protein superfamily. Unlike most other ABC proteins that function as active transporters, CFTR is an ATP-gated chloride channel. The opening of CFTR's gate is associated with ATP-induced dimerization of its two nucleotide-binding domains (NBD1 and NBD2), whereas gate closure is facilitated by ATP hydrolysis-triggered partial separation of the NBDs. This generally held theme of CFTR gating-a strict coupling between the ATP hydrolysis cycle and the gating cycle-is put to the test by our recent finding of a short-lived, post-hydrolytic state that can bind ATP and reenter the ATP-induced original open state. We accidentally found a mutant CFTR channel that exhibits two distinct open conductance states, the smaller O1 state and the larger O2 state. In the presence of ATP, the transition between the two states follows a preferred O1→O2 order, a telltale sign of a violation of microscopic reversibility, hence demanding an external energy input likely from ATP hydrolysis, as such preferred gating transition was abolished in a hydrolysis-deficient mutant. Interestingly, we also observed a considerable amount of opening events that contain more than one O1→O2 transition, indicating that more than one ATP molecule may be hydrolyzed within an opening burst. We thus conclude a nonintegral stoichiometry between the gating cycle and ATP consumption. Our results lead to a six-state gating model conforming to the classical allosteric mechanism: both NBDs and transmembrane domains hold a certain degree of autonomy, whereas the conformational change in one domain will facilitate the conformational change in the other domain. | Gold Standard | disease mechanism | 2 |
22991266 | 22,075,702 | Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations | Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disease with a wide spectrum of vascular malformations (VMs) involving multiple organs. Nine to 16% of patients with HHT harbor brain arteriovenous malformations (AVMs), which can cause intracranial hemorrhage (ICH). Our objective was to study clinical manifestations of brain AVMs in patients with HHT and correlate these with the specific gene mutated. We reviewed records of 171 patients with HHT and brain AVMs. A history of ICH was found in 27% (41/152) patients, with a mean age of 26 ± 18 range, (0-68) years. All of patients with ICH were neurologically asymptomatic prior to ICH. Multiple brain AVMs were found in 23% (170/39) of patients on initial examination. Genetic test results were available in 109 (64%) patients. Mutations in ENG, ACVRL1, and SMAD4 were present in 75 (69%), 18 (17%), and 2 (2%), respectively. A history of ICH was reported in 24% of patients with an ENG mutation and 27% of patients with an ACVRL1 mutation, with a mean age of 26 ± 16 (range, 2-50) and 18 ± 21 (0-48) years, respectively. No statistically significant differences in age at first brain AVM diagnosis, prevalence of ICH history, age at ICH, or other manifestations of brain AVMs were observed among gene groups. In conclusion, no evidence for differences in brain AVM characteristics was observed among HHT gene groups, although we cannot exclude clinically important differences. Larger studies are needed to further guide brain AVM screening decisions in patients with HHT. | Gold Standard | disease mechanism | 2 |
23018639 | 206,913,397 | BMP9 regulates endoglin-dependent chemokine responses in endothelial cells. | BMP9 signaling has been implicated in hereditary hemorrhagic telangiectasia (HHT) and vascular remodeling, acting via the HHT target genes, endoglin and ALK1. This study sought to identify endothelial BMP9-regulated proteins that could affect the HHT phenotype. Gene ontology analysis of cDNA microarray data obtained after BMP9 treatment of primary human endothelial cells indicated regulation of chemokine, adhesion, and inflammation pathways. These responses included the up-regulation of the chemokine CXCL12/SDF1 and down-regulation of its receptor CXCR4. Quantitative mass spectrometry identified additional secreted proteins, including the chemokine CXCL10/IP10. RNA knockdown of endoglin and ALK1 impaired SDF1/CXCR4 regulation by BMP9. Because of the association of SDF1 with ischemia, we analyzed its expression under hypoxia in response to BMP9 in vitro, and during the response to hindlimb ischemia, in endoglin-deficient mice. BMP9 and hypoxia were additive inducers of SDF1 expression. Moreover, the data suggest that endoglin deficiency impaired SDF1 expression in endothelial cells in vivo. Our data implicate BMP9 in regulation of the SDF1/CXCR4 chemokine axis in endothelial cells and point to a role for BMP9 signaling via endoglin in a switch from an SDF1-responsive autocrine phenotype to an SDF1 nonresponsive paracrine state that represses endothelial cell migration and may promote vessel maturation. | Gold Standard | disease mechanism | 2 |
23041289 | 22,780,968 | Magnetoencephalographic analysis of paroxysmal fast activity in patients with epileptic spasms | This study sought to demonstrate the origin and propagation of paroxysmal fast activity (PFA) in patients with epileptic spasms (ESs), using time-frequency analyses of magnetoencephalogram (MEG) PFA recordings. A 204-channel helmet-shaped MEG, with a 600Hz sampling rate, was used to examine PFA in 3 children with ESs. We analyzed MEG recordings of PFA by short-time Fourier transform and the aberrant area or high-power spectrum was superimposed onto reconstructed three-dimensional magnetic resonance images as moving images. One ictal discharge was collected. One child and one adult with PFA due to Lennox-Gastaut syndrome were also examined for comparison. All four PFAs in Patient 1 and five PFAs in Patient 3 were generated from one hemisphere. In Patient 2, four of seven PFAs were generated from one hemisphere and the remaining three were generated from both hemispheres. In Patient 3, one ictal MEG showed ictal discharges that were generated from the same area as the PFA, although the electroencephalogram showed no discharge. In Patients with Lennox-Gastaut syndrome, all 10 PFAs were generated from bilateral hemispheres simultaneously. Short-time Fourier transform analyses of MEG PFA can show the origin and form of propagation of PFA. These results suggest that ESs are representative of focal seizures and the mechanism of PFA is different between ESs and Lennox-Gastaut syndrome. | Gold Standard | clinical characteristics or disease pathology | 0 |
23060444 | 35,478,614 | Regulation of Activation and Processing of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by a Complex Electrostatic Interaction between the Regulatory Domain and Cytoplasmic Loop 3* | Background: NEG2 regulates CFTR gating but the mechanism is unknown. Results: A putative NEG2-CL3 electrostatic attraction, possibly weakened by Arg-764/Arg-766 of the R domain, prohibited CFTR activation. A charge exchange between NEG2 and CL3 caused misprocessing. Conclusion: Electrostatic regulation of CFTR activation and processing may be asymmetric at the CL3-R interface. Significance: The CL3-R interface is optimally designed for multiple regulations of CFTR functions. NEG2, a short C-terminal segment (817–838) of the unique regulatory (R) domain of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, has been reported to regulate CFTR gating in response to cAMP-dependent R domain phosphorylation. The underlying mechanism, however, is unclear. Here, Lys-946 of cytoplasmic loop 3 (CL3) is proposed as counter-ion of Asp-835, Asp-836, or Glu-838 of NEG2 to prevent the channel activation by PKA. Arg-764 or Arg-766 of the Ser-768 phosphorylation site of the R domain is proposed to promote the channel activation possibly by weakening the putative CL3-NEG2 electrostatic attraction. First, not only D835A, D836A, and E838A but also K946A reduced the PKA-dependent CFTR activation. Second, both K946D and D835R/D836R/E838R mutants were activated by ATP and curcumin to a different extent. Third, R764A and R766A mutants enhanced the PKA-dependent activation. However, it is very exciting that D835R/D836R/E838R and K946D/H950D and H950R exhibited normal channel processing and activity whereas D835R/D836R/E838R/K946D/H950D was fractionally misprocessed and silent in response to forskolin. Further, D836R and E838R played a critical role in the asymmetric electrostatic regulation of CFTR processing, and Ser-768 phosphorylation may not be involved. Thus, a complex interfacial interaction among CL3, NEG2, and the Ser-768 phosphorylation site may be responsible for the asymmetric electrostatic regulation of CFTR activation and processing. | Gold Standard | disease mechanism | 2 |
23083943 | 33,801,024 | Effectiveness and tolerability of rufinamide in children and young adults with Lennox-Gastaut syndrome: a single center study in Korea | Rufinamide is a novel antiepileptic drug (AED), which is known to be effective in the treatment of partial seizures and drop attacks in patients with Lennox-Gastaut syndrome (LGS). The aim of this study is to evaluate the efficacy and tolerability of rufinamide in those with LGS. Patients with LGS who had received rufinamide adjunctive therapy were enrolled in this study. We retrospectively reviewed these patient's baseline clinical characteristics, and the reduction of seizure frequency and adverse events after the use of rufinamide. Twenty-three patients (15 males and 8 females, ages 4-22 years) were enrolled in the study. All the patients suffered from daily head drops and tonic seizures despite multiple antiepileptic drugs. After one month of rufinamide, one patient (4.3%) achieved freedom from seizures, ten (43.5%) achieved a ≥50% decrease in seizure frequency. After six months of rufinamide, eight patients (34.8%) maintained a satisfactory response (seizure free in one, and greater than 50% seizure reduction in seven). Adverse events were reported in six (26.0%) patients, which were somnolence in three, aggressive behavior in two, and aggravation of seizure in one patient. Our results suggest that rufinamide is effective and safe in children and young adults with LGS. | Gold Standard | therapeutics in the clinic | 3 |
23090599 | 26,047,689 | Persister cells: molecular mechanisms related to antibiotic tolerance | It is a given that new antibiotics are needed to combat drug-resistant pathogens. However, this is only a part of the need-we actually never had antibiotics capable of eradicating an infection. All pathogens produce a small subpopulation of dormant persister cells that are highly tolerant to killing by antibiotics. Once an antibiotic concentration drops, surviving persisters re-establish the population, causing a relapsing chronic infection. Persisters are especially significant when the pathogen is shielded from the immune system by biofilms, or in sites where the immune components are limited-in the nervous system, the stomach, or inside macrophages.Antibiotic treatment during a prolonged chronic infection of P. aeruginosa in the lungs of patients with cystic fibrosis selects for high-persister (hip) mutants. Similarly, treatment of oral thrush infection selects for hip mutants of C. albicans. These observations suggest a direct causality between persisters and recalcitrance of the disease. It appears that tolerance of persisters plays a leading role in chronic infections, while resistance is the leading cause of recalcitrance to therapy in acute infections. Studies of persister formation in E. coli show that mechanisms of dormancy are highly redundant. Isolation of persisters produced a transcriptome which suggests a dormant phenotype characterized by downregulation of energy-producing and biosynthetic functions. Toxin-antitoxin modules represent a major mechanism of persister formation. The RelE toxin causes dormancy by cleaving mRNA; the HipA toxin inhibits translation by phosphorylating elongation factor Ef-Tu, and the TisB toxin forms a membrane pore, leading to a decrease in pmf and ATP. | Gold Standard | disease mechanism | 2 |
23090737 | 38,333,931 | SMAD4 haploinsufficiency associates with augmented colonic inflammation in select humans and mice | SMAD4 is a common mediator of the TGF-beta signaling pathway. One of the members of this pathway, TGF-beta 1, has an important role in controlling gut inflammation in relation to the continuous stimulation of the intestinal microbiota. SMAD4 haploinsufficiency in humans has been linked to juvenile polyposis hereditary hemorrhagic telangiectasia syndrome (JP/HHT; OMIM#17505). Hematochezia and colonic mucosal inflammation suggestive of inflammatory bowel diseases (IBD) have been reported in JP/HHT. Stimulated by recent experience with two affected pediatric patients presented here, we explored the potential role of Smad4 haploinsufficiency in a murine model of colonic inflammation. Smad4(+/-) mice were maintained on a mixed C57/129SvEv background. Chronic colitis was induced with repeated administration of dextran sulfate sodium (DSS) in drinking water. The colonic mucosal microbiota was interrogated by massively parallel pyrosequencing of the bacterial 16S rRNA gene. 66.7% of Smad4(+/-) mice were sensitive to DSS colitis compared to 14.3% of wild type (Chi-Square p=0.036). The augmented colitis was associated with microbiota separation in the Smad4(+/-) mice. Enterococcus and Enterococcus faecalis specifically was increased in abundance in the colitis-prone animals. Smad4 haploinsufficiency can associate with increased susceptibility to large bowel inflammation in mammals with variable penetrance in association with the colonic mucosal microbiota. These findings may reveal implications not only towards colonic inflammation in the setting of SMAD4 haploinsufficiency, but for colorectal cancer as well. | Gold Standard | disease mechanism | 2 |
23109496 | 205,337,836 | Management of severe epistaxis after Young's procedure: a case report | Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder affecting multiple organ systems, with epistaxis being the most common manifestation. Multiple procedures have been used for the management of epistaxis in the setting of HHT, including closure of the anterior nares via a Young's procedure. While this procedure results in loss of smell and permanent nasal obstruction, proponents note significant improvement in patient symptomatology. Case report. A 70-year-old female with a history of HHT presented to an outside hospital with bleeding into the nasopharynx 2 months after undergoing a modified Young's procedure at an unaffiliated institution. She was transfused with 2 units of packed red blood cells (PRBCs) and transferred to our facility. Due to persistent epistaxis and need for airway protection, the patient was intubated and her throat was packed. She also developed aspiration pneumonia and hypotensive shock requiring vasopressors. Twenty-four hours following bilateral internal maxillary and sphenopalatine artery embolization, she developed significant epistaxis requiring reversal of the Young's procedure on the left and placement of an anterior-posterior pack at the bedside. Upon packing removal several days later in the operating room, she was noted to have significant bleeding that necessitated reversal of the Young's procedure on the right side to obtain adequate exposure and hemostasis. We report a case of significant, life-threatening epistaxis following a modified Young's procedure that requiring multiple transfusions, bilateral embolization, and ultimately reversal of the Young's procedure for control of epistaxis. Although recognized as a potential complication, to our knowledge this is the first report in the English literature of such a case. | Gold Standard | therapeutics in the clinic | 3 |
23140956 | 205,212,208 | Online trapping and enrichment ultra performance liquid chromatography-tandem mass spectrometry method for sensitive measurement of "arginine-asymmetric dimethylarginine cycle" biomarkers in human exhaled breath condensate. | , COPD and cystic fibrosis. To the best of our knowledge, there is no previous report of any analytical method to detect ADMA in EBC. Aim of this work was to develop an online sample trapping and enrichment system, coupled with an UPLC-MS/MS method, for simultaneous quantification of seven metabolites related to "Arginine-ADMA cycle", using the isotopic dilution. Butylated EBC samples were trapped in an online cartridge, washed before and after each injection with cleanup solution to remove matrix components and switched inline into the high pressure analytical column. Multiple reaction monitoring in positive mode was used for analyte quantification by tandem mass spectrometry. Validation studies were performed in EBC to examine accuracy, precision and robustness of the method. For each compound, the calibration curves showed a coefficient of correlation (r(2)) greater than 0.992. Accuracy (%Bias) was <3% except for NMMA and H-Arg (<20%), intra- and inter-assay precision (expressed as CV%) were within ±20% and recovery ranged from 97.1 to 102.8% for all analytes. Inter-day variability analysis on 20 EBC of adult subjects did not demonstrate any significant variation of quantitative data for each metabolite. ADMA and SDMA mean concentrations (μmolL(-1)), measured in EBC samples of asthmatic adolescents are significantly increased (p<0.0001) than in normal controls (0.0040±0.0021 vs. 0.0012±0.0005 and 0.0020±0.0015 vs. 0.0002±0.0001, respectively), as well the ADMA/Tyr (0.34±0.09 vs. 0.12±0.02, p<0.0001) and the SDMA/Tyr ratio (0.10±0.04 vs. 0.015±0.004, p<0.0001). The proposed method features simple specimen preparation, maintenance of an excellent peak shape of all metabolites and reduced matrix effects as well mass spectrometer noise. Moreover, the possibility to perform different cycles of enrichment, using large injection volumes, compensated for the low concentration of analytes contained in EBC, leading to a good analytical sensitivity. Preliminary data obtained from asthmatic and healthy adolescents, demonstrated that the analytical method applied to EBC seems suitable not only for research purposes, but also for clinical routinely analysis. | Gold Standard | clinical characteristics or disease pathology | 0 |
23141144 | 17,120,723 | Long-term safety and efficacy of clobazam for Lennox-Gastaut syndrome: interim results of an open-label extension study | In an ongoing open-label extension (OV-1004), patients with Lennox-Gastaut syndrome who had completed 1 of 2 randomized controlled trials (OV-1002 [Phase II] or OV-1012 [Phase III]) are receiving clobazam at dosages ≤2.0 mg/kg/day (≤80 mg/day). Of 306 eligible patients from OV-1002 or OV-1012, 267 entered the open-label extension. As of the interim date, July 1, 2010, 213 patients (79.8%) had remained in the trial, and 189 had received clobazam for ≥12 months, 128 for ≥18 months, and 94 for ≥24 months. Median percentage decreases in average weekly rates of drop seizures were 71.1% and 91.6% at Months 3 and 24. Mean modal and mean maximum daily dosages were 0.94 mg/kg and 1.22 mg/kg for those who had received clobazam for ≥1 year. The 4 most common adverse events were upper respiratory tract infection (18.4%), fall (14.2%), pneumonia (13.9%), and somnolence (12.7%). Clobazam's adverse event profile was consistent with its profile in controlled trials. | Gold Standard | patient-based therapeutics | 4 |
23143718 | 12,100,244 | Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy | Lacosamide is a US Food and Drug Administration (FDA)-approved antiepileptic drug for patients 17 years or older with partial epilepsy. There are sparse data on children. The objective of our study was to evaluate its efficacy/safety in children with refractory epilepsy. Forty children (mean age 14.3 years) were treated with lacosamide at our institution (adjunctive therapy in 36, monotherapy in 4). Fifteen patients had symptomatic focal epilepsy, 2 had cryptogenic focal epilepsy, 20 had symptomatic generalized epilepsy, and 3 had cryptogenic generalized epilepsy. Two had juvenile myoclonic epilepsy and 5 had Lennox-Gastaut syndrome. Forty-two percent had at least >50% reduction in seizure frequency, and 6 became seizure free. Average dose was 7 mg/kg/d and average follow-up was 9.2 months. Responders had a 76.5% mean decrease in seizures. Fifteen children experienced an adverse reaction and 7 discontinued lacosamide (4: Ineffective, I: insurance denial, 1: tremor, 1: behavior). Lacosamide is effective and well-tolerated in children with refractory epilepsy. | Gold Standard | patient-based therapeutics | 4 |
23168156 | 40,257,046 | The Young's procedure for severe epistaxis from hereditary hemorrhagic telangiectasia | Surgical treatment of epistaxis in hereditary hemorrhagic telangiectasia (HHT) has historically been managed with the laser procedure or the septodermoplasty procedure. For transfusion-dependent patients with severe epistaxis we have been performing the Young's procedure or surgical closure of the nostrils. The objective of this study was to report treatment of severe epistaxis related to HHT with the Young's procedure and assess patient outcome. Patients with severe iron or blood transfusion-dependent epistaxis who underwent a Young's procedure in three otolaryngology HHT centers were reviewed. Patients were evaluated for postoperative epistaxis and subjective outcome. Forty-three patients underwent a Young's procedure for severe epistaxis and were observed for a mean of 34 months. The procedure was well tolerated by all patients and 30 of 36 patients (83%) experienced complete cessation of bleeding after the Young's procedure. Patients had a mean increase in hemoglobin of 4.68 g/dL after the procedure. The average Glasgow Benefit Inventory score after surgery was 43.56. No patients requested a reversal of the procedure. The Young's procedure is a safe and efficacious procedure with complete cessation of epistaxis in most patients with severe epistaxis and HHT. | Gold Standard | therapeutics in the clinic | 3 |
23169026 | 32,268,066 | Bronchiolitis as a feature of kartagener syndrome: a case report | Kartagener syndrome (KS), also known as immotile cilia syndrome or as a primary ciliary dyskinesia, is characterized by the triad of situs inversus, bronchiectasis, and chronic pansinusitis. A few studies reported that diffuse bronchiolitis might be one of the characteristic features of the lung in KS. We aimed to present the radiologic characteristics of KS, including diffuse bronchiolitis, sinus aplasia, and situs inversus totalis in a single case. | Gold Standard | clinical characteristics or disease pathology | 0 |
23169612 | 32,625,011 | Chest CT in bronchopulmonary dysplasia: clinical and radiological correlations | Chest CT is very sensitive in assessing pulmonary damage in bronchopulmonary dysplasia (BPD) and radiological findings in BPD are well described. Validated CT scores are available to assess BPD, as available in other pulmonary diseases such as cystic fibrosis. To investigate whether there is a correlation between radiological pulmonary lesions and relevant BPD clinical data (gestational age, type and duration of mechanical ventilation, and severity of BPD) and assess the usefulness of a CT score in evaluating clinical severity. Retrospective study of 19 premature infants with BPD born between 1998 and 2007 who underwent at least one chest CT during their first year of life. A total of 29 CT were blindly evaluated by two radiologists for the presence or absence of pulmonary parenchymal abnormalities described in BPD (areas of decreased attenuation, presence of bullae/emphysema, bronchial wall thickening, bronchiectasis, linear, and subpleural opacities). This score was then compared with the most relevant clinical data. All CT scans showed abnormalities. The most frequent lesion was bronchial wall thickening observed in all patients, followed by linear (89.5%) and subpleural (89.5%) opacities. Areas of decreased attenuation were found in 68.4%. Bullae/emphysema and bronchiectasis were the less frequent item described (26.3% and 21.1%, respectively). The presence of areas of decreased attenuation significantly correlated with BPD severity (P = 0.03). However, there was no significant correlation between the CT score and clinical data. This study demonstrates the potential usefulness of chest CT score to assess the severity of BPD. Areas of decreased attenuation seem the most sensitive item to predict BPD severity. More patients are needed to validate this approach and to evaluate the long-term usefulness of CT scan. | Gold Standard | clinical characteristics or disease pathology | 0 |
23192669 | 23,644,165 | A pilot study of the characterization of hepatic tissue strain in children with cystic-fibrosis-associated liver disease (CFLD) by acoustic radiation force impulse imaging | Progressive fibrotic alterations of liver tissue represent a major complication in children with cystic fibrosis. Correct assessment of cystic-fibrosis-associated liver disease (CFLD) in clinical routine is a challenging issue. Sonographic elastography based on acoustic radiation force impulse imaging (ARFI) is a new noninvasive approach for quantitatively assessing in vivo elasticity of biological tissues in many organs. To characterize ARFI elastography as a diagnostic tool to assess alteration of liver tissue elasticity related to cystic fibrosis in children. ARFI elastography and B-mode US imaging were performed in 36 children with cystic fibrosis. The children's clinical history and laboratory parameters were documented. According to the findings on conventional US, children were assigned to distinct groups indicating severity of hepatic tissue alterations. The relationship between US findings and respective elastography values was assessed. Additionally, differences between ARFI elastography values of each US group were statistically tested. Children with sonomorphologic characteristics of fibrotic tissue remodeling presented significantly increased values for tissue elasticity. Children with normal B-mode US or discrete signs of hepatic tissue alterations showed a tendency toward increased tissue stiffness indicating early tissue remodeling. Assessment of children with CFLD by means of ARFI elastography yields adequate results when compared to conventional US. For detection of early stages of liver disease with mild fibrotic reactions of hepatic tissue, ARFI elastography might offer diagnostic advantages over conventional US. Thus, liver stiffness measured by means of elastography might represent a valuable biological parameter for evaluation and follow-up of CFLD. | Gold Standard | clinical characteristics or disease pathology | 0 |
23195144 | 71,454,536 | Association among posture, lung function and functional capacity in cystic fibrosis | The purpose of this study was to evaluate the correlations within pulmonary function, functional capacity, and posture in adult patients with cystic fibrosis (CF). A secondary aim was to evaluate the correlation between patient quality of life and postural assessment variables. A cross-sectional study was conducted on fourteen patients with CF. Patients were subjected to a postural analysis (postural assessment software) and measurements of pulmonary function (spirometry, whole body plethysmography, and carbon monoxide diffusing capacity) and functional capacity (6-min walking test). All patients completed the Cystic Fibrosis Questionnaire-Revised (CFQ-R). Most patients were male (57%), and the median age of the patients was 24.5 (22-34). The forced expiratory volume in one second, the 6-min walking distance, total lung capacity, and airway resistance were significantly correlated with the vertical alignment of the chest (ρ = -0.57, P < 0.05; ρ = -0.65, P < 0.01; ρ = 0.54, P < 0.05; and ρ = 0.67, P < 0.01, respectively). The 'physical' domain of the CFQ-R was significantly correlated with the vertical alignment of the chest (ρ = -0.74, P < 0.01), and the 'limitations' domain of the CFQ-R was significantly correlated with the angle of the hip (ρ = -0.55, P < 0.05). The present study shows that abnormalities in pulmonary function and functional capacity are associated with postural changes in adults with CF. However the severity of the postural abnormalities does not negatively influence the CFQ-R domains. | Gold Standard | clinical characteristics or disease pathology | 0 |
23198241 | 14,521,856 | CT and MRI Findings of Hepatic Involvement in Rendu-Osler-Weber Disease | Rendu-Osler-Weber disease is a rare autosomal dominant disorder. Hepatic involvement manifests itself as vascular, parenchymal, and biliary lesions with characteristic telangiectasias and vascular shunts. In a 37-year-old female patient, dynamic contrast-enhanced upper abdominal CT and MRI were performed. CT and MRI revealed dilated celiac trunk and hepatic artery. On early arterial phase, dilated hepatic veins showed significant enhancement. On arterial and portal venous phases, liver showed significantly heterogeneous contrast enhancement and showed homogenous enhancement in the hepatic parenchymal phase. On the magnetic resonance cholangiopancreatography, irregular biliary ducts with strictures and dilatation were seen. | Gold Standard | clinical characteristics or disease pathology | 0 |
23199770 | 205,530,348 | A new location of angiokeratoma circumscriptum | Angiokeratomas are papular telangiectasias having a common histology of ectasia of the superficial dermal vessels surmounted by a hyperkeratotic epidermis. The patient was a 9-year-old girl born of non-consanguineous parents after a well-followed pregnancy with problem-free delivery at term. From birth, she had a tumefaction of the left side of the nose and the left half of the upper lip that gradually increased in size without obstructing the nasal orifice and bled easily. Examination revealed the presence of tumefaction of the left nostril and the left half of the upper lip projecting towards the contralateral side especially in the nose. It was soft and painless, with the presence at the surface of dull red keratotic papules of 1 to 2 mm in diameter. Examination of the nasal mucosa revealed the same appearance of papules. Angiokeratoma circumscriptum is a rare congenital malformation, the rarest of five types. Since its initial description in 1890, few cases have been reported. However, female predominance has been noted with a male/female sex ratio of 1/3. It appears to be due to a genetic mutation that is probably autosomal, but the site of which is still unknown. In view of the special features of this case, several diagnoses were suggested, including Rendu Osler's disease, superficial lymphangioma and verrucous angioma. The particularity of this case is that it includes the first description of this site, which posed a therapeutic problem, especially concerning the choice of laser type to be used. | Gold Standard | clinical characteristics or disease pathology | 0 |
23217263 | 16,517,046 | Jejunoileal atresia and cystic fibrosis: don’t miss it | BackgroundWhile an increased prevalence of cystic fibrosis (CF) in patients with jejunal atresia and ileal atresia (JIA) has been described previously, it still may not be a practice routine to indicate a sweat test or DNA test for CFTR mutations in newborns presenting with JIA. Leading textbooks do not mention JIA as a possible presenting clinical feature of CF. We describe two cases of JIA with a delayed diagnosis of CF (4 months [post mortem] and 19 months). This led to a retrospective review of all patients with JIA in our hospital. We hypothesised that also in the past although indicated further testing for CF had not always been performed.MethodsOver an 18-year period from January 1991 until December 2008, all cases of JIA in our centre were reviewed (n=50). We compared patients who have been tested for CF (n=18) with patients who have not been tested for CF (n=32), with respect to their patient characteristics, either by logistic regression analysis or a nonparametric test (p<0.05).ResultsOf all 50 patients the proportion of infants actually tested for CF was 18 (36%). A statistical significant difference between the group of patients who were tested for CF versus the group of those who were not tested was found in a higher occurrence of postoperative bilious retention after 7 days (56% versus 25%, respectively), and postoperative complications (78% versus 34%, respectively). CF was confirmed in 4 (8%).ConclusionTesting for CF in newborns presenting with JIA does not appear to be common practice. A timely diagnosis of CF leads to presymptomatic treatment and has beneficial effects on morbidity and mortality. CF should be tested for in all children with JIA. We recommend a sweat test for term children and CFTR DNA testing as a first step for preterm infants. Medical professional awareness may be increased if future editions of leading text books in the relevant fields should include JIA as an indication to follow an appropriate CF-diagnostic algorithm.Trial registrationStatement on reporting of a clinical trial: This article is not based on a clinical trial. | Gold Standard | clinical characteristics or disease pathology | 0 |
23230532 | 3,449,818 | Vagal nerve stimulation for pharmacoresistant epilepsy in children | Vagus nerve stimulation (VNS) is an adjunctive treatment for adult patients with pharmacoresistant epilepsy. Little is known about VNS therapy for children with epilepsy. This article will: (1) Review the contemporary medical literature related to VNS therapy in children with epilepsy, (2) describe the experience of VNS treatment in 153 children less than 18 years of age, in the University of California, Los Angeles (UCLA) Pediatric Epilepsy Surgery Program, from 1998 to 2012, and (3) describe the surgical technique used for VNS implantation at UCLA. Review of the literature finds that despite different etiologies and epilepsy syndromes in children, VNS appears to show a similar profile of efficacy for seizure control compared to adults, and low morbidity and mortality. The UCLA experience is similar to that reported in the literature for children. VNS constitutes about 21% of our pediatric epilepsy surgery volume. We have implanted VNS in infants as young as six months of age and the most common etiology is the Lennox-Gastaut Syndrome. About 5% of the patients are seizure-free with VNS therapy and there is a low rate of surgically related complications. The UCLA surgical approach emphasizes minimal direct manipulation of the vagus nerve and adequate wire loops, to prevent a lead fracture. In summary, VNS is a viable palliative treatment for medically refractory epilepsy in children, with outcomes and complications equal to adult patients. Being a small child is not a contraindication for VNS therapy, if needed for refractory epilepsy. | Gold Standard | therapeutics in the clinic | 3 |
23232196 | 27,757,424 | Does hereditary hemorrhagic telangiectasia affect olfactory or gustatory function? | The olfactory and gustatory functions of hereditary hemorrhagic telangiectasia (HHT) patients have not been documented by validated tests. Disorders of the nasal/oral cavity may interfere with the olfactory and gustatory functions. Fifty-four HHT patients were investigated by smell/taste tests. HHT patients provided subjective ratings in areas such as ability to perceive smell/taste. "Sniffin' Sticks" were used for smell tests, and taste strips were used for taste tests. HHT patients rated their subjective olfactory and gustatory function on a visual analog scale from 0 (none) to 100 (high) as 65.3 ± 27.7 and 68.1 ± 25.1, respectively. Comparison of smell test results of HHT patients with normative data of sex- and age-matched controls from Hummel et al. revealed that HHT patients had lower threshold values, whereas there was no difference in identification and discrimination values. HHT patients were hyposmic. In the case of taste qualities, all values (sweet, sour, salty, and bitter) in HHT patients were lower than those in normative data of Mueller et al. However, HHT patients were not hypogeusic. The duration of disease, extranasal manifestation, and treatments did not significantly correlate with smell/taste test values. Compared with healthy people, HHT patients exhibit reduced olfactory and gustatory function; however, HHT patients are hyposmic and not hypogeusic. This chemosensory deficit may highlight an early sign of disease and has no correlation with disease severity. HHT patients should be informed about these potential disease manifestations, thus enabling them to improve their quality of life. | Gold Standard | clinical characteristics or disease pathology | 0 |
23246127 | 29,251,914 | High prevalence of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia | Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder causing mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs). Pulmonary hypertension (PH) is considered an uncommon complication of HHT whose impact on the survival of these patients is currently unknown. From January 1995 to December 2008, 29 hospitalized patients with definite HHT were included and followed until January 2011. Data on demographics, clinical symptoms and survival were recorded. PH was classified according to echocardiographic probability. A CT angiogram was performed in 24 of the 29 patients with HHT and AVMs were detected in 16 of them (67%): hepatic in 58%, pulmonary in 33% and spinal in 3%; 37% had both pulmonary and hepatic AVMs. Transthoracic Doppler echocardiography (TTE) was performed in 21 patients. PH was considered possible in 4 (14%) and probable in 9 (31%). The mean age at diagnosis was lower in patients with PH than in patients without PH (54±16.5 years vs 73±8.8 years, p=0.002). PH was more prevalent in patients with AVMs (56 vs. 23%, p=0.036). The mean follow-up of the entire cohort was 6±4.4 years (range: 2 months-17 years), during this time 18 patients died (62%; mean age 73±8.1 years). Patients with PH died at a younger age (68±8.4 vs. 79±2.7 years, p=0.015) than those without PH. PH is a severe condition that significantly reduces survival on HHT patients. PH should be suspected in all HHT patients with dyspnea and hepatic AVMs. | Gold Standard | clinical characteristics or disease pathology | 0 |
23252400 | 205,115,020 | West syndrome caused by ST3Gal-III deficiency | West syndrome consists of infantile spasms, hypsarrhythmia, and developmental arrest. Most patients remain mentally retarded and many develop Lennox-Gastaut syndrome. Using homozygosity mapping followed by exome sequencing we identified an ST3GAL3 mutation in three infants with West syndrome. ST3GAL3 encodes a sialyltransferase involved in the biosynthesis of sialyl-Lewis epitopes on cell surface-expressed glycoproteins. The mutation affected an essential sialyl-motif and abolished enzymatic activity. Abnormalities in proteins involved in forebrain γ-aminobutyric acid (GABA)ergic synaptic growth and function were recently proposed to account for infantile spasms. Dysfunctional ST3GAL3 may thus result in perturbation of the posttranslational sialylation of proteins in these pathways. | Gold Standard | disease mechanism | 2 |
23271804 | 205,258,862 | Tangled bank of experimentally evolved Burkholderia biofilms reflects selection during chronic infections | How diversity evolves and persists in biofilms is essential for understanding much of microbial life, including the uncertain dynamics of chronic infections. We developed a biofilm model enabling long-term selection for daily adherence to and dispersal from a plastic bead in a test tube. Focusing on a pathogen of the cystic fibrosis lung, Burkholderia cenocepacia, we sequenced clones and metagenomes to unravel the mutations and evolutionary forces responsible for adaptation and diversification of a single biofilm community during 1,050 generations of selection. The mutational patterns revealed recurrent evolution of biofilm specialists from generalist types and multiple adaptive alleles at relatively few loci. Fitness assays also demonstrated strong interference competition among contending mutants that preserved genetic diversity. Metagenomes from five other independently evolved biofilm lineages revealed extraordinary mutational parallelism that outlined common routes of adaptation, a subset of which was found, surprisingly, in a planktonic population. These mutations in turn were surprisingly well represented among mutations that evolved in cystic fibrosis isolates of both Burkholderia and Pseudomonas. These convergent pathways included altered metabolism of cyclic diguanosine monophosphate, polysaccharide production, tricarboxylic acid cycle enzymes, global transcription, and iron scavenging. Evolution in chronic infections therefore may be driven by mutations in relatively few pathways also favored during laboratory selection, creating hope that experimental evolution may illuminate the ecology and selective dynamics of chronic infections and improve treatment strategies. | Gold Standard | disease mechanism | 2 |
23292041 | 8,445,678 | Ciliary ultrastructure in patients with chronic rhinosinusitis and primary ciliary dyskinesia | The Cilia represent one of the main mechanisms contributing to the clearance of microorganisms and particles from the respiratory epithelium. Primary ciliary dyskinesia (PCD) is a genetically determined disorder characterized by irreversible systemic dysmotility of the cilia. Secondary ciliary dyskinesia (SCD) differs from primary defects on the reversible ultrastructural alterations that can occur after any insult to a previously normal mucosa. Hence, this study aimed to describe and compare the main ultrastructural ciliary features in PCD and SCD through transmission electron microscopy. The most frequent PCD abnormalities were missing or short dynein arms, missing central microtubules, and displacement of one of the nine peripheral doublets. The most common changes found in SCD were compound cilia and peripheral microtubule alterations associated with modifications of the respiratory epithelium. PCD presented a higher percentage of altered cilia (>30 %) when compared to SCD (5 %), demonstrating that SCD is more limited in area than PCD. Whereas in PCD the changes in the dynein arms and in the central microtubules are fundamental for diagnostic confirmation, the diagnosis of SCD usually involves compound cilia and disarrangements in peripheral microtubules. | Gold Standard | clinical characteristics or disease pathology | 0 |
23299155 | 7,288,373 | Significance of fractional exhaled nitric oxide measurements in detecting primary ciliary dyskinesia in Saudi children | To examine the usefulness of fractional exhaled nitric oxide (FENO) measurements in detecting primary ciliary dyskinesia (PCD) in children. This observational study was conducted at the Department of Pediatrics and Physiology, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia from January 2011 to December 2011. The study population consisted of 22 children with symptoms suggestive of PCD and the diagnosis was confirmed by ciliary biopsy. Using the American Thoracic Society guidelines, measurements of FENO were performed in 22 subjects with proven PCD biopsies and in 11 healthy age-matched subjects. No significant differences were found on the basis of age or ventilatory function tests between the PCD patients and control groups. Fractional exhaled nitric oxide values were significantly lower in children with PCD (6.19+/-1.43) compared to control group (17.00+/-6.30) (CI: -14.854 to -5.927, p<0.0001). Rhinorrhea was seen in 7 (31.8%), recurrent acute otitis media in 16 (72.7%), chronic otitis media in 5 (22.7%), recurrent sinusitis in 5 (22.7%), chronic productive cough in 8 (36.4%), bronchospasm in 11 (50%), and dextrocardia in 3 (13.6%) subjects. There was no correlation between age, FENO, and ventilatory function parameters. The measurement of FENO appears to be a useful tool for screening children for PCD. It can complement other tests such as nasal biopsy and electron microscopy studies. | Gold Standard | clinical characteristics or disease pathology | 0 |
23303231 | 10,969,771 | A case of combined syndrome of juvenile polyposis and hereditary hemorrhagic telangiectasia associated with SMAD4 mutation | A 47-year-old man was found to have abnormal findings on chest radiography. Chest computed tomography (CT) and magnetic resonance imaging (MRI) showed that he had a pulmonary arteriovenous malformation. He had experienced epistaxis when he was a junior high school student, and since then, the symptom had frequently recurred. Further, he had telangiectasia on the lips. Thus, he was given a diagnosis of hereditary hemorrhagic telangiectasia (HHT). Endoscopy revealed gastric telangiectasia, and in addition, his colon had many juvenile polyps. When he was 49 years of age, he underwent genetic analysis for HHT. A diagnosis of juvenile polyposis-HHT combined syndrome (JP-HHT) was made since a heterozygous germline 4-base deletion in exon 9 of SMAD4 was detected. To the best of our knowledge, this is the first case of JP-HHT associated with SMAD4 mutation in Japan. | Gold Standard | clinical characteristics or disease pathology | 0 |
23312966 | 5,474,544 | Hereditary hemorrhagic telangiectasia, liver vascular malformations and cardiac consequences | HHT patients with liver vascular malformations (VMs) may develop high-output cardiac failure requiring liver transplant in few cases. Our aim is to show that echocardiography is a good tool to evaluate the severity of hepatic vascular malformations in HHT and can improve medical management in HHT patients. The study is a cross-sectional study of cardiac parameters in HHT patients with dyspnea in a single referral center. All HHT patients with dyspnea, consecutively seen at HHT reference center in Lyon between May 2007 and November 2009 were included and had hepatic vascular Ultrasound and Echocardiography. Echocardiographic measures included cardiac output (CO) and index (CI), left ventricle (LV) filling pressures, and pulmonary artery pressure. Then, patients were classified in 4 groups according to the severity: group 1 (normal values), group 2 with isolated high CI, group 3 with high CI and increased LV-filling pressures and group 4 with increased LV-filling pressures and pulmonary hypertension. Fifty-two HHT-patients were analyzed. Eight patients were in group 1, 25 in group 2, 6 in group 3 and 13 in group 4. Age, NYHA class dyspnea, edema, atrial fibrillation, hepatic artery diameter, and BNP (brain natriuretic peptide) levels significantly increased from groups 1 to 4 as well as left atrial area, and presence of mitral regurgitation. Patients with associated pulmonary VMs (n=11) did not show any clinical or echocardiographic differences. Performing echocardiography in HHT patients with dyspnea allowed us to better understand the physiological processes of high-CO failure complicating liver vascular malformations and may improve follow-up of patients and treatment decisions. | Gold Standard | clinical characteristics or disease pathology | 0 |
23320130 | 222,719 | Oxidative stress contributes to endothelial dysfunction in mouse models of hereditary hemorrhagic telangiectasia | Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia caused by mutations in endoglin (ENG; HHT1) or activin receptor-like kinase (ALK1; HHT2) genes, coding for transforming growth factor-β (TGF-β) superfamily receptors. We demonstrated previously that endoglin and ALK1 interact with endothelial NO synthase (eNOS) and affect its activation. Endothelial cells deficient in endoglin or ALK1 proteins show eNOS uncoupling, reduced NO, and increased reactive oxygen species (ROS) production. In this study, we measured NO and H(2)O(2) levels in several organs of adult Eng and Alk1 heterozygous mice, to ascertain whether decreased NO and increased ROS production is a generalized manifestation of HHT. A significant reduction in NO and increase in ROS production were found in several organs, known to be affected in patients. ROS overproduction in mutant mice was attributed to eNOS, as it was L-NAME inhibitable. Mitochondrial ROS contribution, blocked by antimycin, was highest in liver while NADPH oxidase, inhibited by apocynin, was a major source of ROS in the other tissues. However, there was no difference in antimycin- and apocynin-inhibitable ROS production between mutant and control mice. Our results indicate that eNOS-derived ROS contributes to endothelial dysfunction and likely predisposes to disease manifestations in several organs of HHT patients. | Gold Standard | disease mechanism | 2 |
23323127 | 11,166,008 | Two cases of high output heart failure caused by hereditary hemorrhagic telangiectasia | High-output cardiac failure is a rare complication of hereditary hemorrhagic telangiectasia (HHT) usually caused by shunting of blood through atriovenous malformations (AVMs) in the liver. We describe two cases of high output heart failure due to large hepatic AVMs. Clinical suspicion of HHT based on detailed history taking and physical examination is essential for early detection and proper management of heart failure associated with HHT. | Gold Standard | clinical characteristics or disease pathology | 0 |
23334068 | 5,719,689 | Long-term use of clobazam in Lennox-Gastaut syndrome: experience in a single tertiary epilepsy center | Clobazam (CLB) is a 1,5-benzodiazepine, which is known to be effective for treating refractory partial epilepsy. We have evaluated the long-term efficacy and tolerability of CLB as an add-on therapy in patients with Lennox-Gastaut syndrome (LGS). Forty-six patients with LGS who had received CLB add-on therapy were enrolled in this study. We retrospectively reviewed their clinical characteristics, including type of seizures, use of CLB, efficacy, adverse events, and retention rate. The mean±SD dose of CLB was 0.70±0.37 mg/kg per day (range, 0.16-1.60 mg/kg per day). After 1 month on CLB, 15 patients (32.6%) became seizure-free and 10 patients (21.7%) had 50% or greater seizure reduction. Response to CLB was not significantly associated with age, sex, or etiology (symptomatic or not). Five (10.8%) of 46 patients maintained seizure remission for more than 12 months. Tolerance developed in 48.0% of initial responders, and the 3-year retention rate by the Kaplan-Meier method was 76.6%. Seven patients (15.2%) reported adverse events, including somnolence and behavioral change, but only one discontinued CLB. Clobazam add-on therapy was effective and very tolerable in patients with LGS. | Gold Standard | therapeutics in the clinic | 3 |
23351611 | 1,613,086 | Pulmonary arteriovenous malformations presenting as difficult-to-control asthma: a case report | Although pulmonary arteriovenous malformations are relatively rare disorders, they are an important part of the differential diagnosis of common pulmonary problems, such as hypoxemia, dyspnea on exertion and pulmonary nodules. An 11-year-old Croatian boy of Mediterranean origin with a history of asthma since childhood was admitted to our hospital for evaluation of difficult-to-control asthma during the previous six months. A chest X-ray showed a homogeneous soft tissue mass in the lingual area. Computed tomography angiography of the thorax showed two pulmonary arteriovenous malformations, one on each side of the lungs. Diagnosis of hereditary hemorrhagic telangiectasia was made clinically by Curaçao criteria. Genetic analysis revealed a mutation in the endoglin gene. The patient was treated with embolotherapy with good clinical outcome. We present a case of pulmonary arteriovenous malformations masquerading as refractory asthma. | Gold Standard | clinical characteristics or disease pathology | 0 |
23354062 | 25,834,593 | Localization of epileptogenic zones in Lennox-Gastaut syndrome using frequency domain source imaging of intracranial electroencephalography: a preliminary investigation | Although intracranial electroencephalography (iEEG) has been widely used to localize epileptogenic zones in epilepsy, visual inspection of iEEG recordings does not always result in a favorable surgical outcome, especially in secondary generalized epilepsy such as Lennox-Gastaut syndrome (LGS). Various computational iEEG analysis methods have recently been introduced to confirm the visual inspection results. Of these methods, high gamma oscillation in iEEG has attracted interest because a series of studies have reported a close relationship between epileptogenic zones and cortical areas with high gamma oscillation. Meanwhile, frequency domain source imaging of EEG and MEG oscillations has proven to be a useful auxiliary tool for identifying rough locations of epileptogenic zones. To the best of our knowledge, however, frequency domain source imaging of high gamma iEEG oscillations has not been studied. In this study, we investigated whether the iEEG-based frequency domain source imaging of high gamma oscillation (60-100 Hz) would be a useful supplementary tool for identifying epileptogenic zones in patients with secondary generalized epilepsy. The method was applied to three successfully operated on LGS patients, whose iEEG contained some ictal events with distinct high gamma oscillations before seizure onset. The resultant cortical source distributions were compared with surgical resection areas and with high gamma spectral power distributions on the intracranial sensor plane. While the results of the sensor-level analyses contained many spurious activities, the results of frequency domain source imaging coincided better with the surgical resection areas, suggesting that the frequency domain source imaging of iEEG high gamma oscillations might help enhance the accuracy of pre-surgical evaluations of patients with secondary generalized epilepsy. | Gold Standard | clinical characteristics or disease pathology | 0 |
23354437 | 10,891,307 | The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans | Primary ciliary dyskinesia (PCD) is characterized by dysfunction of respiratory cilia and sperm flagella and random determination of visceral asymmetry. Here, we identify the DRC1 subunit of the nexin-dynein regulatory complex (N-DRC), an axonemal structure critical for the regulation of dynein motors, and show that mutations in the gene encoding DRC1, CCDC164, are involved in PCD pathogenesis. Loss-of-function mutations disrupting DRC1 result in severe defects in assembly of the N-DRC structure and defective ciliary movement in Chlamydomonas reinhardtii and humans. Our results highlight a role for N-DRC integrity in regulating ciliary beating and provide the first direct evidence that mutations in DRC genes cause human disease. | Gold Standard | disease mechanism | 2 |
23354748 | 45,661,599 | AmrZ modulates Pseudomonas aeruginosa biofilm architecture by directly repressing transcription of the psl operon | Pseudomonas aeruginosa strains recovered from chronic pulmonary infections in cystic fibrosis patients are frequently mucoid. Such strains express elevated levels of alginate but reduced levels of the aggregative polysaccharide Psl; however, the mechanistic basis for this regulation is not completely understood. Elevated pslA expression was observed in an amrZ null mutant and in strains expressing a DNA-binding-deficient AmrZ. AmrZ is a transcription factor that positively regulates twitching motility and alginate synthesis, two phenotypes involved in P. aeruginosa biofilm development. AmrZ bound directly to the pslA promoter in vitro, and molecular analyses indicate that AmrZ represses psl expression by binding to a site overlapping the promoter. Altered expression of amrZ in nonmucoid strains impacted biofilm structure and architecture, as structured microcolonies were observed with low AmrZ production and flat biofilms with amrZ overexpression. These biofilm phenotypes correlated with Psl levels, since we observed elevated Psl production in amrZ mutants and lower Psl production in amrZ-overexpressing strains. These observations support the hypothesis that AmrZ is a multifunctional regulator mediating transition of P. aeruginosa biofilm infections from colonizing to chronic biofilms through repression of the psl operon while activating the algD operon. | Gold Standard | disease mechanism | 2 |
23361110 | 527,235 | Exhaled molecular profiles in the assessment of cystic fibrosis and primary ciliary dyskinesia | Early diagnosis and monitoring of disease activity are essential in cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). We aimed to establish exhaled molecular profiles as the first step in assessing the potential of breath analysis. Exhaled breath was analyzed by electronic nose in 25 children with CF, 25 with PCD and 23 controls. Principle component reduction and canonical discriminant analysis were used to construct internally cross-validated ROC curves. CF and PCD patients had significantly different breath profiles when compared to healthy controls (CF: sensitivity 84%, specificity 65%; PCD: sensitivity 88%, specificity 52%) and from each other (sensitivity 84%, specificity 60%). Patients with and without exacerbations had significantly different breath profiles (CF: sensitivity 89%, specificity 56%; PCD: sensitivity 100%, specificity 90%). Exhaled molecular profiles significantly differ between patients with CF, PCD and controls. The eNose may have potential in disease monitoring based on the influence of exacerbations on the VOC-profile. | Gold Standard | clinical characteristics or disease pathology | 0 |
23390474 | 16,445,273 | Nanoduct sweat conductivity measurements in 2664 patients: relationship to age, arterial blood gas, serum electrolyte profiles and clinical diagnosis | The Nanoduct(®) device has acceptable diagnostic accuracy, but there is not enough systematic data supporting its usage in the diagnosis of cystic fibrosis (CF). A retrospective review of patients with an indication for the sweat test was conducted. The conductivity test was repeated in patients who had values higher than 60 mmol/L, and they were referred for sweat chloride measurements. Associations between sweat conductivity measurements and age, gender, (pH, HCO(3), pCO(2), Na, K, Cl), family history, consanguinity, indications for the test and number of hospitalization were studied. Among 2,664 patients, 16 children had sweat conductivity values higher than 80. The median age of patients diagnosed with CF was 4 months old. Age, pH, HCO(3), Na, Cl, K and the sweat conductivity test were statistically related (P < 0.001). The ROC curve showed very high agreement between the 2nd conductivity test and the sweat test. Patients suspected to have CF can be screened using the Nanoduct(®) conductivity device in non-qualified centers. | Gold Standard | clinical characteristics or disease pathology | 0 |
23401183 | 40,909,670 | Hereditary hemorrhagic telangiectasia: how accurate are the clinical criteria? | The clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria. Three out of four criteria are required for a definite clinical diagnosis HHT, two criteria are considered "possible" HHT, and 0 or 1 criterion makes the diagnosis unlikely. However, these consensus diagnostic criteria have not been validated. We report on the diagnostic accuracy of the clinical criteria. A total of 450 consecutive persons ≥16 years of age were screened for HHT between May 2004 and September 2009, including a chest CT to screen for pulmonary arteriovenous malformations (AVMs). We selected 263 first-degree relatives of disease-causing mutation carriers who underwent mutation analysis. Genetic test results were considered the gold standard. The family mutation was present in 186 patients (mean age 42.9 ± 14.6 yr; 54.8% female). A clinical diagnosis was definite, "possible", and unlikely in 168 (90.3%), 17 (9.1%), and 1 (0.5%) patient, respectively. In 77 persons the family mutation was absent (mean age 37.1 ± 12.3 yr, 59.7% female). In this group a clinical diagnosis was definite, possible, and unlikely in 0, 35 (45.5%), and 42 (54.5%) persons, respectively. The positive predictive value of a definite clinical diagnosis was 100% (95% CI 97.8-100), the negative predictive value of an unlikely diagnosis 97.7% (95% CI 87.9-99.6). Of 52 patients with "possible" HHT, 17 (32.7%) displayed an HHT-causing mutation. The Curaçao clinical criteria have a good diagnostic performance. Genetic testing is particularly helpful in patients with a "possible" clinical diagnosis HHT. | Gold Standard | clinical characteristics or disease pathology | 0 |
23409955 | 43,297,579 | Reduction of seizure frequency after epilepsy surgery in a patient with STXBP1 encephalopathy and clinical description of six novel mutation carriers | Mutations in STXBP1 have been identified in a subset of patients with early onset epileptic encephalopathy (EE), but the full phenotypic spectrum remains to be delineated. Therefore, we screened a cohort of 160 patients with an unexplained EE, including patients with early myoclonic encephalopathy (EME), Ohtahara syndrome, West syndrome, nonsyndromic EE with onset in the first year, and Lennox-Gastaut syndrome (LGS). We found six de novo mutations in six patients presenting as Ohtahara syndrome (2/6, 33%), West syndrome (1/65, 2%), and nonsyndromic early onset EE (3/64, 5%). No mutations were found in LGS or EME. Only two of four mutation carriers with neonatal seizures had Ohtahara syndrome. Epileptic spasms were present in five of six patients. One patient with normal magnetic resonance imaging (MRI) but focal seizures underwent epilepsy surgery and seizure frequency dropped drastically. Neuropathology showed a focal cortical dysplasia type 1a. There is a need for additional neuropathologic studies to explore whether STXBP1 mutations can lead to structural brain abnormalities. | Gold Standard | disease mechanism | 2 |
23415449 | 6,221,643 | Copy number variants in adult patients with Lennox-Gastaut syndrome features | Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy with complex etiology. To explore possible genetic predispositions and causes of LGS, we have searched for copy number variants (CNVs). We studied 21 patients with LGS or LGS-like epilepsy for CNVs using whole-genome array comparative genomic hybridization (aCGH). Eight patients (38%) carried rare CNVs that might contribute to their phenotype. The pathogenicity could be questioned in some of them, but in four patients (19%) a causative role was considered highly probable. Three had CNVs and clinical features consistent with known genetic syndromes: 22q13.3 deletion, 2q23.1 deletion, and MECP2 duplication. There is a high frequency of rare CNVs in adult patients with LGS-like epilepsy. The phenotypes of these background disorders may be obscured by the effects of intractable seizures and massive antiepileptic drug treatment. Previously, syndromic disorders were primarily identified by their clinical features; however, a genome wide approach with identification of the genotype might shed light on the phenotype. | Gold Standard | disease mechanism | 2 |
23418344 | 22,913,440 | Sperm-associated antigen-17 gene is essential for motile cilia function and neonatal survival | Primary ciliary dyskinesia (PCD), resulting from defects in cilia assembly or motility, is caused by mutations in a number of genes encoding axonemal proteins. PCD phenotypes are variable, and include recurrent respiratory tract infections, bronchiectasis, hydrocephaly, situs inversus, and male infertility. We generated knockout mice for the sperm-associated antigen-17 (Spag17) gene, which encodes a central pair (CP) protein present in the axonemes of cells with "9 + 2" motile cilia or flagella. The targeting of Spag17 resulted in a severe phenotype characterized by immotile nasal and tracheal cilia, reduced clearance of nasal mucus, profound respiratory distress associated with lung fluid accumulation and disruption of the alveolar epithelium, cerebral ventricular expansion consistent with emerging hydrocephalus, failure to suckle, and neonatal demise within 12 hours of birth. Ultrastructural analysis revealed the loss of one CP microtubule in approximately one quarter of tracheal cilia axonemes, an absence of a C1 microtubule projection, and other less frequent CP structural abnormalities. SPAG6 and SPAG16 (CP proteins that interact with SPAG17) were increased in tracheal tissue from SPAG17-deficient mice. We conclude that Spag17 plays a critical role in the function and structure of motile cilia, and that neonatal lethality is likely explained by impaired airway mucociliary clearance. | Gold Standard | disease mechanism | 2 |
23437356 | 2,644,534 | Hand-held tidal breathing nasal nitric oxide measurement--a promising targeted case-finding tool for the diagnosis of primary ciliary dyskinesia | Nasal nitric oxide (nNO) measurement is an established first line test in the work-up for primary ciliary dyskinesia (PCD). Tidal breathing nNO (TB-nNO) measurements require minimal cooperation and are potentially useful even in young children. Hand-held NO devices are becoming increasingly widespread for asthma management. Therefore, we chose to assess whether hand-held TB-nNO measurements reliably discriminate between PCD, and Healthy Subjects (HS) and included Cystic Fibrosis (CF) patients as a disease control group known to have intermediate nNO levels. In this cross sectional, single centre, single occasion, proof-of-concept study in children and adults with PCD and CF, and in HS we compared feasibility, success rates, discriminatory capacity, repeatability and agreement between a hand-held electrochemical device equipped with a nNO software application sampling at flow rates 2 ml/s or 5 ml/s, and two stationary chemiluminescence devices, applying both tidal breathing and velum closure techniques. Measurements were done in 16 PCD patients, 21 patients with CF and 20 HS aged between 3.8 and 60.9 years. Hand-held TB-nNO showed high success rate (96.5-100%) vs. velum closure nNO techniques (70.2-89.5%). Hand-held TB-nNO sampling at flow rate 5 ml/s showed equally high discriminative power (PCD vs. HS [p<0.0001] and PCD vs. CF [p<0.0001]) and reaching close to 100% sensitivity and specificity, superior repeatability (CV% = 10%) and equal limits of agreement compared to TB-nNO by stationary devices and even compared to velum closure sampling. Hand-held TB-nNO discriminates significantly between PCD, CF and HS and shows promising potential as a widespread targeted case-finding tool for PCD, although further studies are warranted before implementation. | Gold Standard | clinical characteristics or disease pathology | 0 |
23439260 | 12,314,951 | Improvement of ischemic cholangiopathy in three patients with hereditary hemorrhagic telangiectasia following treatment with bevacizumab | The ischemic biliary phenotype of hereditary hemorrhagic telangiectasia (HHT) is rare but distinct, with progressive biliary tree ischemia usually resulting in an irreversible secondary sclerosing cholangiopathy. When clinically severe, liver transplant is often indicated. We report three patients with marked HHT associated biliary disease, in whom prolonged anti-vascular endothelial growth factor therapy (bevacizumab) notably reversed imaging evidence of biliary disease and clinically obviated need for liver transplantation during the first year of follow-up. | Gold Standard | therapeutics in the clinic | 3 |
23465587 | 9,674,977 | Polyunsaturated fatty acid-enriched diet therapy for a child with epilepsy | The ketogenic diet (KD) is a high-fat, low-carbohydrate diet with an established efficacy for treating medically refractory epilepsy in children. Fatty acids are the most important constituent of the KD in all aspects of efficacy and complications. Among fatty acids, polyunsaturated fatty acids (PUFAs) increase anticonvulsant properties and reduce the complications associated with the high-fat diet. Here, we report a 7-year-old boy with Lennox-Gastaut syndrome combined with mitochondrial respiratory chain complex I deficiency, whose medically intractable seizures have been successfully controlled with a PUFA-enriched modified Atkins diet without any significant adverse events. The diet consists of canola oil and diverse menu items like fish and nuts instead of olive oil and has an ideal 1:2.8 ratio of omega-3 to omega-6. In addition, fractionation of this boy's plasma showed normal levels of fatty acids, including omega-3 (alpha-linoleic acid, eicosapentaenoic acid) and omega-6 (linoleic acid, arachidonic acid) as well as monounsaturated fatty acids (oleic acid). Plasma docosahexanoic acid remained low after PUFA-enriched diet therapy. PUFA-enriched diet therapy is likely to increase the efficacy of diet therapy and reduce complications of a high-fat diet in children with refractory epilepsy. | Gold Standard | therapeutics in the clinic | 3 |
23489890 | 206,314,674 | Clinical analysis of catastrophic epilepsy in infancy and early childhood: results of the Far-East Asia Catastrophic Epilepsy (FACE) study group | We studied children younger than 6years old who developed catastrophic epilepsy and were registered in the FACE study group to clarify their clinical characteristics and prevalence of seizure as well as epilepsy types. Subjects were prospectively recruited from children with epilepsy who satisfied the following criteria and underwent intensive examination between 2009 and 2012 in 14 collaborative centers: (1) younger than 6years old and (2) more than 10 seizures/month refractory to all available medical treatments including ACTH therapy, leading to significant psychosocial morbidity. We analyzed epilepsy onset age, predominant seizure type, etiology, neuropsychological findings, and syndromic classification according to the pre-determined registration format. A total of 314 children were enrolled in this study. Epilepsy onset age in 239 cases (80%) was younger than 12months. The most frequent seizure type was epileptic spasms (ES), followed by generalized tonic seizures (GTS), which accounted for 42% and 20%, respectively. West syndrome (WS) was the most frequent epileptic syndrome and accounted for 37%, followed by unclassified epilepsy at 21%, neocortical epilepsy at 19%, Lennox-Gastaut syndrome at 12%, Dravet syndrome at 4%, Rasmussen syndrome at 2%, and others. The two most frequent causes of epilepsy were cortical dysplasia and chromosomal anomalies, as shown in 16% and 6%, respectively. However, the etiology of nearly one half of all patients remained unknown. Psychomotor development was already worse than a moderate degree in 62% of subjects at the first examination. The highest proportion of catastrophic epilepsy was WS and its related syndromes featuring ES and GTS, followed by neocortical epilepsy, whose psychomotor development was significantly retarded at examinations. | Gold Standard | clinical characteristics or disease pathology | 0 |
23504457 | 25,410,033 | MAST205 Competes with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-associated Ligand for Binding to CFTR to Regulate CFTR-mediated Fluid Transport* | Background: CFTR is an important cAMP-regulated chloride channel. Results: MAST205 and CAL compete for binding to CFTR to regulate the expression level and function of CFTR. Conclusion: MAST205 is a regulator for CFTR. Significance: Targeting the MAST205-CFTR complex has potential clinical implications for treating CFTR-related diseases such as cystic fibrosis and secretory diarrheas. The PDZ (postsynaptic density-95/discs large/zona occludens-1) domain-based interactions play important roles in regulating the expression and function of the cystic fibrosis transmembrane conductance regulator (CFTR). Several PDZ domain-containing proteins (PDZ proteins for short) have been identified as directly or indirectly interacting with the C terminus of CFTR. To better understand the regulation of CFTR processing, we conducted a genetic screen and identified MAST205 (a microtubule-associated serine/threonine kinase with a molecular mass of 205 kDa) as a new CFTR regulator. We found that overexpression of MAST205 increased the expression of CFTR and augmented CFTR-mediated fluid transport in a dose-dependent manner. Conversely, knockdown of MAST205 inhibited CFTR function. The PDZ motif of CFTR is required for the regulatory role of MAST205 in CFTR expression and function. We further demonstrated that MAST205 and the CFTR-associated ligand competed for binding to CFTR, which facilitated the processing of CFTR and consequently up-regulated the expression and function of CFTR at the plasma membrane. More importantly, we found that MAST205 could facilitate the processing of F508del-CFTR mutant and augment its quantity and channel function at the plasma membrane. Taken together, our data suggest that MAST205 plays an important role in regulating CFTR expression and function. Our findings have important clinical implications for treating CFTR-associated diseases such as cystic fibrosis and secretory diarrheas. | Gold Standard | disease mechanism | 2 |
23527104 | 18,840,349 | The protein kinase TPL2 is essential for ERK1/ERK2 activation and cytokine gene expression in airway epithelial cells exposed to pathogen-associated molecular patterns (PAMPs) | The epithelium forms a physical barrier important to the detection of pathogens. P. aeruginosa infections are frequently encountered in Cystic Fibrosis lungs, lead to ERK1/ERK2 activation and contribute to tissue destruction. We report here that in bronchial airway epithelial cells (BEAS-2B), diffusible material from P. aeruginosa and TLR2, TLR3 and TLR5 ligands activates ERK1/ERK2 via the protein kinase TPL2 and not the growth factor receptor EGFR. Activation of TPL2 by these agonists in airway epithelial cells requires the protein kinases TAK1 and IKKβ in accordance with the previously reported model of activation of TPL2 in macrophages. Inhibition of TPL2 activity with a pharmacological inhibitor (Compound 1) not only prevented ERK1/ERK2 activation but also decreased cytokine synthesis in response to pathogen-associated molecular patterns. These results suggest that inhibition of the protein kinase TPL2 is an attractive strategy to decrease inflammation in the lungs when it is not warranted. | Gold Standard | disease mechanism | 2 |
23532242 | 35,768,734 | Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial. | IMPORTANCE
Macrolide antibiotics such as erythromycin may improve clinical outcomes in non-cystic fibrosis (CF) bronchiectasis, although associated risks of macrolide resistance are poorly defined.
OBJECTIVE
To evaluate the clinical efficacy and antimicrobial resistance cost of low-dose erythromycin given for 12 months to patients with non-CF bronchiectasis with a history of frequent pulmonary exacerbations.
DESIGN, SETTING, AND PARTICIPANTS
Twelve-month, randomized (1:1), double-blind, placebo-controlled trial of erythromycin in currently nonsmoking, adult patients with non-CF bronchiectasis with a history of 2 or more infective exacerbations in the preceding year. This Australian study was undertaken between October 2008 and December 2011 in a university teaching hospital, with participants also recruited via respiratory physicians at other centers and from public radio advertisements.
INTERVENTIONS
Twice-daily erythromycin ethylsuccinate (400 mg) or matching placebo.
MAIN OUTCOME MEASURES
The primary outcome was the annualized mean rate of protocol-defined pulmonary exacerbations (PDPEs) per patient. Secondary outcomes included macrolide resistance in commensal oropharyngeal streptococci and lung function.
RESULTS
Six-hundred seventy-nine patients were screened, 117 were randomized (58 placebo, 59 erythromycin), and 107 (91.5%) completed the study. Erythromycin significantly reduced PDPEs both overall (mean, 1.29 [95% CI, 0.93-1.65] vs 1.97 [95% CI, 1.45-2.48] per patient per year; incidence rate ratio [IRR], 0.57 [95% CI, 0.42-0.77]; P = .003), and in the prespecified subgroup with baseline Pseudomonas aeruginosa airway infection (mean difference, 1.32 [95% CI, 0.19-2.46]; P = .02). Erythromycin reduced 24-hour sputum production (median difference, 4.3 g [interquartile range [IQR], 1 to 7.8], P = .01) and attenuated lung function decline (mean absolute difference for change in postbronchodilator forced expiratory volume in the first second of expiration, 2.2 percent predicted [95% CI, 0.1% to 4.3%]; P = .04) compared with placebo. Erythromycin increased the proportion of macrolide-resistant oropharyngeal streptococci (median change, 27.7% [IQR, 0.04% to 41.1%] vs 0.04% [IQR, -1.6% to 1.5%]; difference, 25.5% [IQR,15.0% to 33.7%]; P < .001).
CONCLUSION AND RELEVANCE
Among patients with non-CF bronchiectasis, the 12-month use of erythromycin compared with placebo resulted in a modest decrease in the rate of pulmonary exacerbations and an increased rate of macrolide resistance.
TRIAL REGISTRATION
anzctr.org.au Identifier: ACTRN12609000578202. | Gold Standard | patient-based therapeutics | 4 |
23568730 | 42,473,580 | Clinical features and genetic screening of hereditary hemorrhagic telangiectasia | To analyze clinical features of 4 families with hereditary hemorrhagic telangiectasia (HHT) and potential mutations of ENG, ACVRL1 and SMAD4 genes. Four unrelated HHT patients and their affected family members were analyzed. All exons and flanking regions of ENG, ACVRL1 and SMAD4 genes were analyzed with PCR and direct sequencing and multiplex ligation-dependent probe amplification (MLPA) methods. Eleven patients from the 4 families were enrolled in this study. Two ENG and 1 ACVRL1 mutations were identified, among which an ENG mutation (c.207G>A; p.L69L) and an ACVRL1 mutation (c.817C>T; p.L273L) have been previously reported. In addition, a novel ENG mutation (c.1004A>T; p.Q335L) has been found in 3 different families. Similar mutations were not detected in 200 healthy individuals. No mutations of ENG, ACVRL1 and SMAD4 were found in the fourth family. A novel mutation c.1004A>T (p. Q335L) of ENG has been identified in patients with HHT. And there is significant phenotypic variability and genetic heterogeneity with the disease. | Gold Standard | disease mechanism | 2 |
23575755 | 9,732,451 | Bronchial fistula after lobar size reduction for bilateral lung transplantation in Kartagener's syndrome: a surgical challenge | Bilateral lung transplantation was performed in a 52-year old man with end-stage Kartagener's syndrome. A postimplantation right lower lobectomy was required for volume reduction and dextrocardia. A bronchial fistula developed with an intractable colonized residual pleural cavity. Closure was obtained successfully with multiple-stage procedures including decortication, muscle flap and an open-window thoracostomy without modification of the immunosuppressive protocol. | Gold Standard | therapeutics in the clinic | 3 |
23583057 | 8,047,321 | Glycemic index treatment using Japanese foods in a girl with Lennox-Gastaut syndrome | We introduced a low glycemic index treatment using Japanese ethnic foods to a 13-year-old girl with Lennox-Gastaut syndrome caused by tuberous sclerosis complex. She had previously refused the modified Atkins diet within 2 weeks of diet treatment because of its restrictiveness. The low glycemic index treatment was implemented by limiting the daily carbohydrate intake to 50 g of foods with a glycemic index of less than 50 relative to that of glucose, which included udon, soba, and unpolished Japonica rice with natto. One month after the initiation of the diet therapy, the clusters of tonic seizures for 30 to 60 minutes during sleep were reduced from two or three times per week to once or twice per month, and the frequent myoclonic seizures in the awake state disappeared. She has been on the diet therapy for more than 1 year, and the efficacy of the diet has been sustained. Low glycemic index treatment should be considered for patients with medication-resistant epilepsy who cannot tolerate restrictive diet therapies. Japanese ethnic foods can be used for this diet therapy. | Gold Standard | therapeutics in the clinic | 3 |
23583175 | 206,586,274 | Modeling neural crest induction, melanocyte specification, and disease-related pigmentation defects in hESCs and patient-specific iPSCs | Melanocytes are pigment-producing cells of neural crest (NC) origin that are responsible for protecting the skin against UV irradiation. Pluripotent stem cell (PSC) technology offers a promising approach for studying human melanocyte development and disease. Here, we report that timed exposure to activators of WNT, BMP, and EDN3 signaling triggers the sequential induction of NC and melanocyte precursor fates under dual-SMAD-inhibition conditions. Using a SOX10::GFP human embryonic stem cell (hESC) reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human NC induction. Subsequent maturation of hESC-derived melanocytes yields pure populations that match the molecular and functional properties of adult melanocytes. Melanocytes from Hermansky-Pudlak syndrome and Chediak-Higashi syndrome patient-specific induced PSCs (iPSCs) faithfully reproduce the ultrastructural features of disease-associated pigmentation defects. Our data define a highly specific requirement for WNT signaling during NC induction and enable the generation of pure populations of human iPSC-derived melanocytes for faithful modeling of pigmentation disorders. | Gold Standard | disease mechanism | 2 |
23636454 | 4,477,434 | RACK1 interacts with filamin-A to regulate plasma membrane levels of the cystic fibrosis transmembrane conductance regulator | Mutations in cystic fibrosis transmembrane regulator (CFTR), a chloride channel in the apical membranes of secretory epithelial cells, underlie the fatal genetic disorder cystic fibrosis. Certain CFTR mutations, including the common mutation ΔF508-CFTR, result in greatly decreased levels of active CFTR at the apical membrane. Direct interactions between CFTR and the cytoskeletal adaptors filamin-A (FlnA) and Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) stabilize the expression and localization of CFTR at the plasma membrane. The scaffold protein receptor for activated C kinase 1 (RACK1) also stabilizes CFTR surface expression; however, RACK1 does not interact directly with CFTR and its mechanism of action is unknown. In the present study, we report that RACK1 interacts directly with FlnA in vitro and in a Calu-3 airway epithelial cell line. We mapped the interaction between RACK1 and FlnA to the WD4 and WD6 repeats of RACK1 and to a segment of the large rod domain of FlnA, consisting of immunoglobulin-like repeats 8-15. Disruption of the RACK1-FlnA interaction causes a reduction in CFTR surface levels. Our results suggest that a novel RACK1-FlnA interaction is an important regulator of CFTR surface localization. | Gold Standard | disease mechanism | 2 |
23653583 | 9,851,274 | Hereditary Hemorrhagic Telangiectasia: Breakpoint Characterization of a Novel Large Deletion in ACVRL1 Suggests the Causing Mechanism | Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Mutations in either ENG or ACVRL1 account for around 85% of cases, and 10% are large deletions and duplications. Here we present a large novel deletion in ACVRL1 gene and its molecular characterization in a 3 generation Italian family. We employed short tandem repeats (STRs) analysis, direct sequencing, multiplex ligation-dependant probe amplification (MLPA) analysis, and 'deletion-specific' PCR methods. STRs Analysis at ENG and ACVRL1 loci suggested a positive linkage for ACVRL1. Direct sequencing of this gene did not identify any mutations, while MLPA identified a large deletion. These results were confirmed and exactly characterized with a 'deletion-specific' PCR: the deletion size is 4,594 bp and breakpoints in exon 3 and intron 8 show the presence of short direct repeats of 7 bp [GCCCCAC]. We hypothesize, as causative molecular mechanism, the replication slippage model. Understanding the fine mechanisms associated with genomic rearrangements may indicate the nonrandomness of these events, highlighting hot spots regions. The complete concordance among MLPA, STRs analysis and 'deletion-specific PCR' supports the usefulness of MLPA in HHT molecular analysis. | Gold Standard | disease mechanism | 2 |
23670536 | 43,452,048 | The effect of anterior palatine blocks on bleeding in hereditary hemorrhagic telangiectasia nasal surgery | When combined with local sphenopalatine (SP) injection and moderate hypotension, transoral or transcutaneous local injection of the anterior palatine (AP) vessels reduces intraoperative bleeding in hereditary hemorrhagic telangiectasia (HHT) patients undergoing nasal surgery. Retrospective chart review of 55 consecutive HHT patients undergoing a bevacizumab injection for recalcitrant epistaxis. Nineteen patients received local injections to only the SP vasculature, and 36 patients received AP and SP injections. Main outcome variable was estimated blood loss during nasal surgery. Independent variables included sex, age, epistaxis severity score, surgical techniques (including laser), and blood pressure parameters (baseline, preinduction, and postintubation). The mean blood loss in HHT patients receiving SP injections alone was 111 mL, whereas it was 22 mL for those receiving both AP + SP injections. This difference between groups approached statistical significance (P = .075). Blood pressure parameters were similar in both groups with no appreciable difference between intraoperative systolic and mean arterial blood pressure. The addition of either sublabial or transcutaneous AP injection to the standard SP block markedly reduces blood loss in HHT epistaxis nasal surgery. | Gold Standard | therapeutics in the clinic | 3 |
23675457 | 5,657,234 | Enhanced responses to angiogenic cues underlie the pathogenesis of hereditary hemorrhagic telangiectasia 2 | Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic vascular disease in which arteriovenous malformations (AVMs) manifest in skin and multiple visceral organs. HHT is caused by heterozygous mutations in endoglin (ENG), activin receptor-like kinase 1 (ALK1), or SMAD4. ALK1 regulates angiogenesis, but the precise function of ALK1 in endothelial cells (ECs) remains elusive. Since most blood vessels of HHT patients do not produce pathological vascular lesions, ALK1 heterozygous ECs may be normal unless additional genetic or environmental stresses are imposed. To investigate the cellular and biochemical phenotypes of Alk1-null versus Alk1-heterozygous ECs, we have generated pulmonary EC lines in which a genotype switch from the Alk1-conditional allele (Alk1 (2f)) to the Alk1-null allele (Alk1 (1f)) can be induced by tamoxifen treatment. Alk1-null (1 f/1 f) ECs displayed increased migratory properties in vitro in response to bFGF compared with Alk1-het (2 f/1 f) ECs. The 1 f/1 f-ECs formed a denser and more persistent tubular network as compared with their parental 2 f/1 f-ECs. Interestingly, the response to BMP-9 on SMAD1/5 phosphorylation was impaired in both 2 f/1 f- and 1 f/1 f-ECs at a comparable manner, suggesting that other factors in addition to SMADs may play a crucial role for enhanced angiogenic activity in 1 f/1 f-ECs. We also demonstrated in vivo that Alk1-deficient ECs exhibited high migratory and invasive properties. Taken together, these data suggest that enhanced responses to angiogenic cues in ALK1-deficient ECs underlie the pathogenesis of HHT2. | Gold Standard | disease mechanism | 2 |
23676596 | 22,130,597 | Hereditary hemorrhagic telangiectasia with pulmonary arteriovenous malformations and embolic strokes treated successfully with video-assisted thoracoscopic resection | A 67-year-old hypoxic woman was admitted following two episodes of cerebral infarction. Based on the clinical presentation and radiological findings, a diagnosis of hereditary hemorrhagic telangiectasia was made and the cerebral ischemic complications were considered to have been caused by paradoxical embolizations related to pulmonary arteriovenous malformations (PAVMs). We performed video-assisted thoracoscopic surgery (VATS) and identified turbulent thrombi in one of the PAVMs that were capable of circulating systemically and inducing embolic strokes. The condition of the patient improved immediately following VATS. This case suggests that VATS may be a preferred therapeutic option in the treatment of patients with PAVM accompanying recurrent episodes of life-threatening complications such as strokes. | Gold Standard | therapeutics in the clinic | 3 |
23702711 | 34,402,080 | Three-dimensional co-cultures of human endothelial cells and embryonic stem cell-derived pericytes inside a microfluidic device | Organs-on-chips are microengineered in vitro tissue structures that can be used as platforms for physiological and pathological research. They provide tissue-like microenvironments in which different cell types can be co-cultured in a controlled manner to create synthetic organ mimics. Blood vessels are an integral part of all tissues in the human body. Development of vascular structures is therefore an important research topic for advancing the field of organs-on-chips since generated tissues will require a blood or nutrient supply. Here, we have engineered three-dimensional constructs of vascular tissue inside microchannels by injecting a mixture of human umbilical vein endothelial cells, human embryonic stem cell-derived pericytes (the precursors of vascular smooth muscle cells) and rat tail collagen I into a polydimethylsiloxane microfluidic channel with dimensions 500 μm × 120 μm × 1 cm (w × h × l). Over the course of 12 h, the cells organized themselves into a single long tube resembling a blood vessel that followed the contours of the channel. Detailed examination of tube morphology by confocal microscopy revealed a mature endothelial monolayer with complete PECAM-1 staining at cell-cell contacts and pericytes incorporated inside the tubular structures. We also demonstrated that tube formation was disrupted in the presence of a neutralizing antibody against transforming growth factor-beta (TGF-β). The TGF-β signaling pathway is essential for normal vascular development; deletion of any of its components in mouse development results in defective vasculogenesis and angiogenesis and mutations in humans have been linked to multiple vascular genetic diseases. In the engineered microvessels, inhibition of TGF-β signaling resulted in tubes with smaller diameters and higher tortuosity, highly reminiscent of the abnormal vessels observed in patients with one particular vascular disease known as hereditary hemorrhagic telangiectasia (HHT). In summary, we have developed microengineered three-dimensional vascular structures that can be used as a model to test the effects of drugs and study the interaction between different human vascular cell types. In the future, the model may be integrated into larger tissue constructs to advance the development of organs-on-chips. | Gold Standard | disease mechanism | 2 |
23729109 | 27,071,409 | Early genetic diagnosis in patients with HHT induced severe nosebleed | To study the early gene diagnosis of hereditary hemorrhagic telangiectasia (HHT) induced severe nosebleed. Clinical features of 23 family members in two HHT pedigrees were examined. Genomic DNA was extracted from peripheral blood samples. PCR amplification was conducted to screen ENG and ACVRL-1 genes with their specific primers. Direct sequencing was performed to detect the mutation. Mutation analysis was carried out to evaluate its significance. A heterozygous c. 263A > G mutation was identified in exon 3 of ACVRL-1 in 6 out of 11 members in NMG-1 pedigree. In GD-2 pedigree, 5 of 11 members carried c. 199C > G mutation. Mutation detection rate was 100% in subjects with nosebleed history and 25% in family members without epistaxis. Gene diagnosis characterized by high sensitivity and specificity is of great practi-cal significance and early genetic screening should be a clinical routine test for HHT induced severe nosebleed. | Gold Standard | disease mechanism | 2 |
23757023 | 23,438,806 | Mechanosensitive ATP release maintains proper mucus hydration of airways | The clearance of mucus from the airways protects the lungs from inhaled noxious and infectious materials. Proper hydration of the mucus layer enables efficient mucus clearance through beating of cilia on airway epithelial cells, and reduced clearance of excessively concentrated mucus occurs in patients with chronic obstructive pulmonary disease and cystic fibrosis. Key steps in the mucus transport process are airway epithelia sensing and responding to changes in mucus hydration. We reported that extracellular adenosine triphosphate (ATP) and adenosine were important luminal autocrine and paracrine signals that regulated the hydration of the surface of human airway epithelial cultures through their action on apical membrane purinoceptors. Mucus hydration in human airway epithelial cultures was sensed by an interaction between cilia and the overlying mucus layer: Changes in mechanical strain, proportional to mucus hydration, regulated ATP release rates, adjusting fluid secretion to optimize mucus layer hydration. This system provided a feedback mechanism by which airways maintained mucus hydration in an optimum range for cilia propulsion. Understanding how airway epithelia can sense and respond to changes in mucus properties helps us to understand how the mucus clearance system protects the airways in health and how it fails in lung diseases such as cystic fibrosis. | Gold Standard | disease mechanism | 2 |
23770633 | 27,193,460 | Adjunctive Madopar for ultrarefractory epilepsy? Preliminary observations | The optimum drug treatment for ultrarefractory epilepsy after failure of seven prior antiepileptic drugs (AEDs) remains uncertain. Prompted by reports that adjunctive amantadine or l-dopa has been useful for children with refractory absence seizures and Lennox-Gastaut syndrome, we studied the utility of dopaminergic agents for adults with ultrarefractory epilepsy. We assessed seizure control following adjunctive treatment for up to 12 months with the dopaminergic agent Madopar© in three adult patients with ultrarefractory epilepsy following brain injury or with Lennox-Gastaut syndrome, who had not achieved sustained seizure remission during past treatment with at least seven lifetime AEDs. The adjunctive use of Madopar was associated with a reduction or remission of tonic-clonic seizures in two patients. However, Madopar seemed to have aggravated absence seizures in the patient with Lennox-Gastaut syndrome. Although our preliminary observations do not and cannot establish the efficacy or safety of adjunctive Madopar, it may be an option for treatment of ultrarefractory focal seizures in adults if confirmed by randomized controlled trials. | Gold Standard | therapeutics in the clinic | 3 |
23772318 | 10,943,480 | A rare case of respiratory disorders associated with two autosomal recessive diseases and male infertility | The study of nasal ciliary beat frequency (CBF) and ultrastructure may contribute to the understanding of pathognomonic cases of male infertility associated with defects in sperm motility. This study was designed to report a particular case of male infertility, characterized by the association of two respiratory autosomal recessive genetic diseases (alpha-1-antitrypsin deficiency [AAT-D] and primary ciliary dyskinesia [PCD]). A 39-year-old patient with complete sperm immotility, AAT-D, and bronchiectasis was studied in the Laboratory of Male Fertility, the Department of Urology, the Respiratory Center of a Pediatric Hospital, and in the Department of Clinical Medicine of a Rehabilitation Respiratory Hospital. Family history, physical examination, hormonal analysis, microbial assays, semen analysis, nasal ciliary function, and structure study by digital high-speed video photography and transmission electron microscopy are described. A noninvasive nasal biopsy to retrieve ciliated epithelium lining the inferior surface of the inferior nasal turbinates was performed and CBF was determined. Beat pattern was slightly curved and rigid, not wide, and metacronic in all the observed fields analyzed. CBF was 8.2 Hz in average (reference value, 10-15 Hz) Ultrastructural assay revealed absence of the inner dynein arms in 97% of the cilia observed. The final infertility accurate diagnosis was achieved by the study of nasal CBF and ultrastructure contributing to the patient health management and genetic counseling while deciding fatherhood. Beyond this particular case, the present report may open a new field of studies in male infertility, mainly in cases of asthenozoospermia. | Gold Standard | clinical characteristics or disease pathology | 0 |
23789012 | 9,433,716 | Esophageal adenocarcinoma in a 40-year-old man with cystic fibrosis: coincidence or not? | To report a case of esophageal cancer in an adult patient with cystic fibrosis (CF) and review the relationship between these 2 diseases. A 40-year-old man with CF presented with worsening epigastric pain, weight loss, and upper gastrointestinal (GI) bleeding. Endoscopy revealed innumerable masses in the distal esophagus. The workup revealed esophageal adenocarcinoma metastatic to the liver and the lungs. Abnormal mucous secretions in CF patients impair the innate GI mucosal barriers. The incidence of both gastroesophageal reflux disease and GI malignancies is higher in patients with CF. Patients with CF now survive long enough to potentially experience the consequences of long-term acid exposure, including esophagitis, Barrett esophagus, and esophageal cancer. Our case report adds to a small but growing body of evidence that CF is a significant risk factor for GI malignancies, including esophageal adenocarcinoma. Controlled studies are needed to determine whether a causal relationship truly exists. | Gold Standard | clinical characteristics or disease pathology | 0 |
23794345 | 9,896,809 | Two juvenile polyps, hereditary hemorrhagic telangiectasia and SMAD4 mutation | An adolescent girl with recurrent iron deficiency anemia, epistaxis, cyanosis, hypoxemia, clubbing, two juvenile polyps in the colon, oro-naso-pharyngeal telangiectasias, multiple arterio-venous malformations of the lungs, and a new homozygous mutation in SMAD4 gene is reported. Patients with juvenile polyps should be examined carefully for mucocutaneus findings and digital clubbing. When a combination of these signs is noted, a genetic testing is warranted inspite of low polyp count in order to prevent potential risk of malignancy and other complications. | Gold Standard | disease mechanism | 2 |
23798057 | 5,244,341 | Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia | Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive, genetically heterogeneous disorder characterized by ciliary dysfunction resulting in chronic oto-sino-pulmonary disease, respiratory distress in term neonates, laterality (situs) defects, and bronchiectasis. Diagnosis has traditionally relied on ciliary ultrastructural abnormalities seen by electron microscopy. Mutations in radial spoke head proteins occur in PCD patients with central apparatus defects. Advances in genetic testing have been crucial in addressing the diagnostic challenge. Here, we describe a novel splice-site mutation (c.921+3_6delAAGT) in RSPH4A, which leads to a premature translation termination signal in nine subjects with PCD (seven families). Loss-of-function was confirmed with quantitative ciliary ultrastructural analysis, measurement of ciliary beat frequency and waveform, and transcript analysis. All nine individuals carrying c.921+3_6delAAGT splice-site mutation in RSPH4A were Hispanic with ancestry tracing to Puerto Rico. This mutation is a founder mutation and a common cause of PCD without situs abnormalities in patients of Puerto Rican descent. | Gold Standard | disease mechanism | 2 |
23800974 | 18,004,560 | MiR-205 is downregulated in hereditary hemorrhagic telangiectasia and impairs TGF-beta signaling pathways in endothelial cells | Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by arteriovenous malformations and hemorrhages. This vascular disease results mainly from mutations in 2 genes involved in the TGF-β pathway (ENG and ALK1) that are exclusively expressed by endothelial cells. The present study identified miR-27a and miR-205 as two circulating miRNAs differentially expressed in HHT patients. The plasma levels of miR-27a are elevated while those of miR-205 are reduced in both HHT1 and HHT2 patients compared to healthy controls. The role of miR-205 in endothelial cells was further investigated. Our data indicates that miR-205 expression displaces the TGF-β balance towards the anti-angiogenic side by targeting Smad1 and Smad4. In line, overexpression of miR-205 in endothelial cells reduces proliferation, migration and tube formation while its inhibition shows opposite effects. This study not only suggests that detection of circulating miRNA (miR-27a and miR-205) could help for the screening of HHT patients but also provides a functional link between the deregulated expression of miR-205 and the HHT phenotype. | Gold Standard | disease mechanism | 2 |
23805858 | 3,067,734 | HHT diagnosis by Mid-infrared spectroscopy and artificial neural network analysis | BackgroundThe vascular disorder Hereditary Hemorrhagic Telangiectasia (HHT) is in general an inherited disease caused by mutations in the TGF-β/BMP receptors endoglin or ALK1 or in rare cases by mutations of the TGF-β signal transducer protein Smad4 leading to the combined syndrome of juvenile polyposis and HHT. HHT is characterized by several clinical symptoms like spontaneous and recurrent epistaxis, multiple telangiectases at sites like lips, oral cavity, fingers, nose, and visceral lesions like gastrointestinal telangiectasia, pulmonary, hepatic, cerebral or spinal arteriovenous malformations. The disease shows an inter- and intra-family variability in penetrance as well as symptoms from mild to life threatening. Penetrance is also depending on age. Diagnosis of the disease is based on the presence of some of the listed symptoms or by genetic testing. HHT diagnosis is laborious, time consuming, costly and sometimes uncertain. Not all typical symptoms may be present, especially at a younger age, and genetic testing does not always identify the disease causing mutation.MethodsInfrared (IR) spectroscopy was investigated as a potential alternative to the current diagnostic methods. IR-spectra were obtained by Fourier-transform Mid-IR spectroscopy from blood plasma from HHT patients and a healthy control group. Spectral data were mathematically processed and subsequently classified and analysed by artificial neural network (ANN) analyses and by visual analysis of scatter plots of the dominant principal components.ResultsThe analyses showed that for HHT a disease specific IR-spectrum exists that is significantly different from the control group. Furthermore, at the current stage with the here used methods, HHT can be diagnosed by Mid-IR-spectroscopy in combination with ANN analysis with a sensitivity and specificity of at least 95%. Visual analysis of PCA scatter plots revealed an inter class variation of the HHT group.ConclusionIR-spectroscopy in combination with ANN analysis can be considered to be a serious alternative diagnostic method compared to clinical and genetically based methods. Blood plasma is an ideal candidate for diagnostic purposes, it is inexpensive, easy to isolate and only minimal amounts are required. In addition, IR-spectroscopy measurement times are fast, less than one minute, and diagnosis is not based on interpretation of may be uncertain clinical data. And last but not least, the method is inexpensive. | Gold Standard | clinical characteristics or disease pathology | 0 |
23812912 | 5,620,702 | West syndrome, microcephaly, grey matter heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2 mutation | West syndrome (WS) is an epileptic encephalopathy of childhood, defined by the presence of clustered spasms usually occurring before the age of 1 year, hypsarrhythmia on EEG that is notoriously difficult to define, and developmental arrest or regression. The incidence of WS is 1:3200 live births with an aetiology-dependent prognosis. Up to 80% of children with symptomatic WS suffer from mental retardation, and approximately 50% develop Lennox-Gastaut syndrome. Using homozygosity mapping followed by exome sequencing, we identified a ADP-ribosylation factor (ARF) guanine nucleotide-exchange factor two (brefeldin A-inhibited) (ARFGEF2) mutation in five related infants with WS. ARFGEF2 is involved in the activation of ARFs by accelerating replacement of bound guanosine diphosphate (GDP) with Guanosine triphosphate (GTP), and is involved in Golgi transport. A mutation in ARFGEF2 has been previously described only once, causing microcephaly and periventricular heterotopia. Here, we describe a novel ARFGEF2 mutation in five related patients presenting with WS, microcephaly, periventricular heterotopia and thin corpus callosum. | Gold Standard | disease mechanism | 2 |
23815177 | 10,241,217 | High expression of midkine in the airways of patients with cystic fibrosis | Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in impaired host defense during cystic fibrosis (CF), where Pseudomonas aeruginosa becomes a key pathogen. We investigated the expression pattern of the antibacterial growth factor midkine (MK) in CF and the possible interference with its activity by the altered airway microenvironment. High MK expression was found in CF lung tissue compared with control samples, involving epithelia of the large and small airways, alveoli, and cells of the submucosa (i.e., neutrophils and mast cells). In CF sputum, MK was present at 100-fold higher levels, but was also subject to increased degradation, compared with MK in sputum from healthy control subjects. MK exerted a bactericidal effect on P. aeruginosa, but increasing salt concentrations and low pH impaired this activity. Molecular modeling suggested that the effects of salt and pH were attributable to electrostatic screening and a charge-neutralization of the membrane, respectively. Both the neutrophil elastase and elastase of P. aeruginosa cleaved MK to smaller fragments, resulting in impaired bactericidal activity. Thus, MK is highly expressed in CF, but its bactericidal properties may be impaired by the altered microenvironment, as reflected by the in vitro conditions used in this study. | Gold Standard | disease mechanism | 2 |
23820266 | 139,148 | γ-Glutamyltransferase catabolism of S-nitrosoglutathione modulates IL-8 expression in cystic fibrosis bronchial epithelial cells | S-nitrosoglutathione (GSNO) is an endogenous nitrosothiol involved in several pathophysiological processes. A role for GSNO has been envisaged in the expression of inflammatory cytokines such as IL-8; however, conflicting results have been reported. γ-Glutamyltransferase (GGT) enzyme activity can hydrolyze the γ-glutamyl bond present in the GSNO molecule thus greatly accelerating the release of bioactive nitric oxide. Expression of GGT is induced by oxidative stress, and activated neutrophils contribute to GGT increase in cystic fibrosis (CF) lung exudates by releasing GGT-containing microvesicles. This study was aimed at evaluating the effect of GSNO catabolism mediated by GGT on production of IL-8 in CF transmembrane regulation protein-mutated IB3-1 bronchial cells. The rapid, GGT-catalyzed catabolism of GSNO caused a decrease in both basal and lipopolysaccharide-stimulated IL-8 production in IB3-1 cells, by modulating both NF-κB and ERK1/2 pathways, along with a decrease in cell proliferation. In contrast, a slow decomposition of GSNO produced a significant increase in both cell proliferation and expression of IL-8, the latter possibly through p38-mediated stabilization of IL-8 mRNA. Our data suggest that the differential GSNO catabolism mediated by GGT enzyme activity can downregulate the production of IL-8 in CF cells. Hence, the role of GGT activity should be considered when evaluating GSNO for both in vitro and in vivo studies, the more so in the case of GSNO-based therapies for cystic fibrosis. | Gold Standard | disease mechanism | 2 |
23827423 | 44,510,867 | Lennox-Gastaut syndrome symptomatic to hypothalamic hamartoma: evolution and long-term outcome following surgery | Lennox-Gastaut syndrome is a catastrophic childhood cryptogenic or symptomatic epilepsy. Hypothalamic hamartomas cause refractory epilepsy often consistent with Lennox-Gastaut syndrome. Children with Lennox-Gastaut syndrome were defined by a triad of multiple generalized seizure types, slow spike-and-wave on EEG, and mental retardation. Twenty-one of 159 hypothalamic hamartoma patients (14%) met the diagnostic criteria of Lennox-Gastaut syndrome. The median age of patients at epilepsy onset was 0.9 years (range, birth to 9 years). Six of the 21 patients (28%) had preceding infantile spasms. All patients underwent different surgical approaches, including endoscopic, transcallosal, orbitozygomatic resections, and radiosurgery treatment. Five of the 21 (24%) were seizure free with an additional 9 (42%) having at least >90% seizure reduction. Only 1 patient was not effectively treated (<50% seizure reduction). Eighty-eight percent of parents reported improvement in behavioral functioning. Shorter duration of epilepsy prior to surgery was a significant predictor of surgical outcome. Patients with Lennox-Gastaut syndrome symptomatic to hypothalamic hamartomas have better postsurgical outcome due to other etiologies compared with cryptogenic and symptomatic Lennox-Gastaut syndrome patients. However, compared with overall hypothalamic hamartomas postsurgical outcomes, this cohort was less favorable. Earlier surgery may lead to better outcomes. | Gold Standard | therapeutics in the clinic | 3 |
23850002 | 206,314,784 | Outcomes of epilepsy surgery in childhood-onset epileptic encephalopathy | to evaluate the outcomes and role of epilepsy surgery in children with intractable epileptic encephalopathy (EE). ninety-five children (64 boys, 31 girls) with intractable EE were treated by epilepsy surgery at Severance Children's Hospital from 2003 to 2008. Surgical treatments included lobar resection, hemispherotomy and corpus callosotomy (CC). Seventy-six children were Lennox-Gastaut syndrome (LGS), and 19 had West syndrome. of the 76 patients with LGS, CC was performed in 37 patients (48.7%), lobar resection in 29 (38.2%) and hemispherotomy in 10 (13.2%). Of the 19 patients with West syndrome, respective surgery was performed in 15 patients (78.9%) and CC in 4 (21.1%). Of the patients receiving respective surgery, Engel's class I outcomes were achieved for 24 of 39 (61.5%) of LGS patients, and for 9 of 15 (60.0%) of West syndrome. Malformations of cortical development were commonly observed, appearing in 73.5% (36/49). In neuropsychiatric tests, 19 of 27 with LGS demonstrated improvement in postoperative cognitive function. More significant intellectual improvement correlated well with shorter epilepsy duration, good seizure outcomes, and decreased number of antiepileptic drugs. epilepsy surgery should be considered in treating childhood intractable EE with expectation of improvement of both seizure and cognitive outcomes, even in cases of LGS. | Gold Standard | therapeutics in the clinic | 3 |
23872636 | 11,429,452 | DYX1C1 is required for axonemal dynein assembly and ciliary motility | DYX1C1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deleting exons 2-4 of Dyx1c1 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease, laterality defects and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1 c.T2A start-codon mutation recovered from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also caused laterality and ciliary motility defects. In humans, we identified recessive loss-of-function DYX1C1 mutations in 12 individuals with PCD. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans showed disruptions of outer and inner dynein arms (ODAs and IDAs, respectively). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU). Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4). | Gold Standard | disease mechanism | 2 |
23910813 | 32,315,772 | Use of pumpless extracorporeal lung assist as rescue therapy in adolescent with cystic fibrosis | There is abundant evidence that artificial ventilation can aggravate pre-existing lung disease, which may contribute to morbidity and mortality. This is especially true for patients with air leakages. This case report describes the use of a pumpless extracorporeal lung assist as a rescue therapy to provide time to heal during the mechanical ventilation of a 16-year-old with cystic fibrosis who could not be managed via conventional means. | Gold Standard | therapeutics in the clinic | 3 |
23927801 | 28,278,234 | [Prospective multicenter study on long-term ketogenic diet therapy for intractable childhood epilepsy]. | OBJECTIVE
To evaluate the efficacy and safety of long-term ketogenic diet (KD) on the children with intractable epilepsy.
METHOD
This was a prospective, open-label study of intractable epilepsy patients treated with the classic KD with a lipid-to-nonlipid ratio 4:1 between October 2004 and July 2011 at five Chinese epilepsy centers. A total of 299 patients were enrolled. The patients were divided into different groups according to age (including the below-1-year-old group, 1-to-3-year-old group, 3-to-6-year-old group, 6-to-10-year-old group, and over-10-year-old group), etiology (cryptogenic epilepsy, symptomatic epilepsy, and idiopathic epilepsy), and the seizure types (included infantile spasm, Lennox-Gastaut syndrome, Ohtahara syndrome, tuberous sclerosis, Dravet syndrome, generalized epilepsy, and partial epilepsy). Parents were assigned to write seizure diaries which recorded the seizure presentations, tolerability, and complications associated with the KD. Patients' weight and height were measured every week. Blood β-hydroxybutyric acid, blood sugar, and urinary ketone bodies were monitored closely. Patients were followed up through telephone calls by the nutritionists every month and regular outpatient visits or hospitalizations were recommended at all time-points which included the third, sixth and twelfth month after initiation. Efficacy was measured through seizure frequency. The variables related to the efficacy were also analyzed. SPSS 17.0 was used for all statistical analysis.
RESULT
At 3, 6, and 12 months after initiation, 65.9%, 44.8%, and 26.4% patients remained on the diet, and 37.4%, 26.1%, and 20.4% had a > 50% reduction in their seizure frequency, including 21.7%, 10.7%, and 11.0% who became seizure free, respectively. At 24 months after initiation, 29 patients remained on the diet, and 28 patients had a > 90% seizure reduction, including five became seizure free. At 36 months after initiation, 7 patients remained on the diet, and all of them had a > 90% seizure reduction, including five became seizure free. No significant variables were related to the efficacy. Most complications were mild and reversible by conservative treatment. Gastrointestinal disturbances were the main complications, which included vomiting, diarrhea, constipation, and abdominal cramp. Severe complications occurred in four cases, including severe metabolic disturbances and severe pneumonia.
CONCLUSION
The KD is a safe and effective alternative therapy for intractable childhood epilepsy. | Gold Standard | patient-based therapeutics | 4 |
23934111 | 1,334,452 | De novo mutations in epileptic encephalopathies | Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders. | Gold Standard | disease mechanism | 2 |
23948769 | 19,910,166 | Causes and imaging patterns of tree-in-bud opacities | Multiple causes for tree-in-bud (TIB) opacities have been reported. However, to our knowledge the relative frequencies of the causes have not been evaluated. The purpose of this study was to determine the relative frequency of causes of TIB opacities and identify patterns of disease associated with TIB opacities. Cases with TIB opacities in the radiology report in 2010 were identified by searching the Radiology Information System. Medical records and CT scan examinations were reviewed for the causes of TIB opacities. Patterns of disease associated with TIB opacities were evaluated. Causes for TIB opacities were established in 166 of 406 (40.9%) cases. Respiratory infections (119 of 166, 72%) with mycobacteria (65 of 166, 39%), bacteria (44 of 166, 27%), viruses (four of 166, 3%), or multiple organisms (six of 166, 4%) were most common. Aspiration was the cause in 42 of 166 (25%). Alternating areas of normal lung with regions of small airways disease (TIB opacities, bronchiectasis) (random small airways pattern) was specific (0.92) for Mycobacterium avium complex infection. Nearly uniform distribution of bronchiectasis (widespread bronchiectasis pattern) was specific for "diseases predisposing to airway infection" (specificity 0.92), such as cystic fibrosis, primary ciliary dyskinesia, allergic bronchopulmonary aspergillosis, and immunodeficiency states. Consolidation and TIB opacities (bronchopneumonia pattern) were usually due to bacterial infection or aspiration. Dependent distribution (specificity 0.79) and esophageal abnormality (specificity 0.86) with TIB opacities were associated with aspiration. Chronicity of findings was associated with mycobacterial infection (P < .0001, sensitivity 0.96). Acuteness of findings was associated with bacterial infection (P < .001, specificity 0.87). TIB opacities are most often a manifestation of infections or aspiration. Patterns of disease can provide clues to the most likely diagnosis. | Gold Standard | clinical characteristics or disease pathology | 0 |
23981349 | 6,792,330 | Compound heterozygosity in GPR56 with bilateral frontoparietal polymicrogyria | Polymicrogyria is caused by a diverse etiology, one of which is gene mutation. At present, only one gene (GPR56) is known to cause polymicrogyria, which leads to a distinctive phenotype termed bilateral frontoparietal polymicrogyria (BFPP). BFPP is an autosomal recessive inherited human brain malformation with abnormal cortical lamination. Here, we identified compound heterozygous GPR56 mutations in a patient with BFPP. The proband was a Japanese female born from non-consanguineous parents. She presented with mental retardation, developmental motor delay, epilepsy exhibiting the feature of Lennox-Gastaut syndrome, exotropia, bilateral polymicrogyria with a relatively spared perisylvian region, bilateral patchy-white-matter MRI signal changes, and hypoplastic pontine basis. GPR56 sequence analysis revealed a c.107G>A substitution leading to a p.S36N, and a c.113G>A leading to a p.R38Q. Although affected individuals with compound heterozygosity in GPR56 have not been previously described, we presume that compound heterozygosity of these two mutations in a ligand binding domain within the extracellular N-terminus of protein could result in BFPP. In addition, we observed unusually less involvement of perisylvian cortex for polymicrogyria, and Lennox-Gastaut syndrome for epilepsy, which are likely common features in patients with BFPP caused by GPR56 mutations. | Gold Standard | disease mechanism | 2 |
24012506 | 13,079,319 | Corpus callosotomy is a valuable therapeutic option for patients with Lennox-Gastaut syndrome and medically refractory seizures | We present our experience with corpus callosotomy (CC) in a developing country with limited resources in patients with Lennox-Gastaut syndrome (LGS) and medically refractory seizures. All patients with LGS who underwent CC for medically refractory epilepsy at Namazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran from May 2009 through March 2012 were reviewed in a retrospective study. Presurgical evaluation included clinical history, neurological examination, a 2-hour video-EEG recording, and 1.5-T MRI. Outcome was evaluated at 6, 12, and 24 months postoperatively. We considered the outcome as a success if the patients were either seizure-free or had more than 85% reduction in seizure frequency compared to their preoperative status. Eighteen patients (14 males and 4 females) had surgery. Overall, seizures in 11 patients (61.1%) responded favorably one year after surgery; this figure was 6 out of 9 patients (66.6%) two years after surgery. Seven patients (38.8%) were free of disabling seizures one year after CC; this figure was three out of nine patients (33.3%) two years after CC. Three patients (16.6%) were free of all seizure types one year after surgery. Ten patients (55.5%) had no postoperative complications of any kind. Corpus callosotomy is an effective palliative surgical procedure for patients with LGS with intractable seizures whose seizures are not amenable to focal resection. This is a feasible treatment option for patients, even for those in developing countries with limited resources. | Gold Standard | therapeutics in the clinic | 3 |
24019633 | 20,296,338 | A case of Kartagener's syndrome: Importance of early diagnosis and treatment | Kartagener's syndrome is a very rare congenital malformation comprising of a classic triad of sinusitis, situs inversus and bronchiectasis. Primary ciliary dyskinesia is a genetic disorder with manifestations present from early life and this distinguishes it from acquired mucociliary disorders. Approximately one half of patients with primary ciliary dyskinesia have situs inversus and, thus are having Kartagener syndrome. We present a case of 12 year old boy with sinusitis, situs inversus and bronchiectasis. The correct diagnosis of this rare congenital autosomal recessive disorder in early life is important in the overall prognosis of the syndrome, as many of the complications can be prevented if timely management is instituted, as was done in this in this case. | Gold Standard | clinical characteristics or disease pathology | 0 |
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