Detection of copy number variations in epilepsy using exome data.

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.

Novel biallelic SZT2 mutations in 3 cases of early-onset epileptic encephalopathy.

The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non-syndromic intellectual disabilities. In this study, we identified by whole-exome sequencing compound heterozygous SZT2 mutations in 3 patients with early-onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice-site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size.

Total hip replacement for neck of femur fracture: Comparing outcomes with matched elective cohort.

INTRODUCTION: Current literature suggests that total hip replacement (THR) is superior to hemiarthroplasty (HA) for neck of femur fracture in selected group of patients. The outcomes of THR undertaken for trauma setting remain unclear when comparing with elective THR. We compared the outcomes of THR trauma cohort with best-matched elective cohort. METHODS: We retrospectively reviewed 102 patients that underwent THR due to trauma from 2011 to 2013. We had access to 90 cases with complete records. Another 90 matched elective cases were obtained from local arthroplasty database. The elective cases were matched for gender, surgical approaches, surgeon's grade, types of implant, patient's age at operation date of ±5 years and operation date of ±60days. Subsequently, the selection criteria were relaxed to patient's age at operation date of ±10 years and operation date of ±60days. Unmatched cases were excluded. Complications and death rate were compared. RESULTS: The average age for both cohorts was 70 years. The trauma cohort had statistically significant lower BMI and longer hospital stay (p=0.001). The Functional Comorbidity Index (FCI) and Charlson Age Comorbidity Index (CACI) were the same for both cohorts, reflecting an active patient selection for THR in our centre. The trauma cohort had higher surgical complication rate (9% vs 4%), particularly higher dislocation rate (7% vs 1%); and higher medical complication rate (32% vs 6%). These were consistent with the literature. Contrary to literature, the trauma cohort had six dislocations that five of them were done via anterolateral approach. Among the eight trauma cases with surgical complications, six cases were performed by trainees. The cause of surgical complications remains unclear due to the nature of retrospective study. The trauma cohort had higher death rate than the elective cohort (14% vs 4%), with one post-operative cardiac arrest in the trauma cohort. The rest were non-orthopaedic related deaths, ranging between four months to four years. CONCLUSION: A more robust way of selecting trauma patients for THR is warranted to reduce morbidity and mortality. Follow-up for the trauma cohort is warranted, as the patients are likely to outlive the implants.

Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency.

OBJECTIVE: To describe the current treatment; clinical, biochemical, and molecular findings; and clinical follow-up of patients with aromatic l-amino acid decarboxylase (AADC) deficiency. METHOD: Clinical and biochemical data of 78 patients with AADC deficiency were tabulated in a database of pediatric neurotransmitter disorders (JAKE). A total of 46 patients have been previously reported; 32 patients are described for the first time. RESULTS: In 96% of AADC-deficient patients, symptoms (hypotonia 95%, oculogyric crises 86%, and developmental retardation 63%) became clinically evident during infancy or childhood. Laboratory diagnosis is based on typical CSF markers (low homovanillic acid, 5-hydroxyindoleacidic acid, and 3-methoxy-4-hydroxyphenolglycole, and elevated 3-O-methyl-l-dopa, l-dopa, and 5-hydroxytryptophan), absent plasma AADC activity, or elevated urinary vanillactic acid. A total of 24 mutations in the DDC gene were detected in 49 patients (8 reported for the first time: p.L38P, p.Y79C, p.A110Q, p.G123R, p.I42fs, c.876G>A, p.R412W, p.I433fs) with IVS6+ 4A>T being the most common one (allele frequency 45%). CONCLUSION: Based on clinical symptoms, CSF neurotransmitters profile is highly indicative for the diagnosis of aromatic l-amino acid decarboxylase deficiency. Treatment options are limited, in many cases not beneficial, and prognosis is uncertain. Only 15 patients with a relatively mild form clearly improved on a combined therapy with pyridoxine (B6)/pyridoxal phosphate, dopamine agonists, and monoamine oxidase B inhibitors.

A novel cognitive interpretation of breast cancer thermography with complementary learning fuzzy neural memory structure.

Early detection of breast cancer is the key to improve survival rate. Thermogram is a promising front-line screening tool as it is able to warn women of breast cancer up to 10 years in advance. However, analysis and interpretation of thermogram are heavily dependent on the analysts, which may be inconsistent and error-prone. In order to boost the accuracy of preliminary screening using thermogram without incurring additional financial burden, Complementary Learning Fuzzy Neural Network (CLFNN), FALCON-AART is proposed as the Computer-Assisted Intervention (CAI) tool for thermogram analysis. CLFNN is a neuroscience-inspired technique that provides intuitive fuzzy rules, human-like reasoning, and good classification performance. Confluence of thermogram and CLFNN offers a promising tool for fighting breast cancer.

Ovarian cancer diagnosis by hippocampus and neocortex-inspired learning memory structures.

Early detection and accurate staging of ovarian cancer are the keys to improving survival rate. However, at present there is no single diagnosis modality that is sufficiently sensitive. DNA microarray analysis is an emerging technique that has potential for ameliorating the hardship in early detection and staging of ovarian disease. However, microarray data is ultra-huge and difficult to analyze. Hence, computational intelligence methods are often utilized to assist in the diagnosis and analysis process. Fuzzy Neural Networks (FNN) are more suitable for this task as FNN provides not only the accuracy, but also the interpretability of its reasoning process. Hippocampus-inspired Complementary Learning FNN (CLFNN) is able to rapidly derive fuzzy sets and formulate fuzzy rules. CLFNN uses positive and negative learning, and hence it reduces the effect of the curse of dimensionality and is capable of modeling the dynamics of the problem space with relatively good classification performance. One of its successors, a hybrid of complementary hippocampal learning and associative neocortical learning called Pseudo Associative Complementary Learning (PACL), is a structure that seeks to functionally model the memory consolidation process. Both PACL and CLFNN have human-like reasoning that allows physicians to examine their computation using familiar terms. They can construct intuitive fuzzy rules autonomously to justify their reasoning, which is important to generate trust among the users. Hence, CLFNN and PACL are applied as a diagnostic decision support system in ovarian cancer diagnosis. The experimental results are encouraging.

The role of coronary bypass surgery for 'left main equivalent' coronary disease: the Coronary Artery Surgery Study registry.

Combined proximal left anterior descending and proximal left circumflex, or "left main equivalent" (LMEQ), disease defines a prognostic angiographic high-risk patient population. We assessed the effect of coronary bypass surgery compared with medical therapy in 903 patients with LMEQ disease by stratified life table and Cox regression analysis. The 5 year survival rates of the 639 and 264 patients who received surgical vs medical therapy was 85% vs 55%, respectively (p less than .001). Analysis of patient subsets stratified by age, angina class, right coronary disease, and ejection fraction revealed a significant survival benefit for surgically treated patients in most strata. Cox regression analysis revealed improved survival for surgically treated patients after adjustment for important baseline variables known to influence prognosis. Surgically treated patients had significantly less angina and need for antianginal drugs compared with the medically treated group. When the Coronary Artery Surgery Study randomized and randomizable LMEQ patients were analyzed, coronary bypass surgery improved 5 year survival when preoperative ejection fraction was under 0.50 but not when ejection fraction was 0.50 or higher. Thus coronary bypass surgery prolongs and improves quality of life (as defined by angina status and need for antianginal drugs) in most patients with LMEQ disease but does not appear to improve 5 year survival in a small subset of LMEQ patients who are asymptomatic after myocardial infarction or who have mild chronic stable angina and are under age 65 with well-preserved left ventricular function.