Exome sequencing revealed a novel biallelic deletion in the DCAF17 gene underlying Woodhouse Sakati syndrome.

Woodhouse Sakati syndrome (WSS, MIM 241080) is a rare autosomal recessive genetic condition characterized by alopecia, hypogonadism, hearing impairment, diabetes mellitus, learning disabilities and extrapydamidal manifestations. Sequence variants in the gene DCAF17, encoding nucleolar substrate receptor, were identified as the underlying cause of inherited WSS. Considerable phenotypic heterogeneity exists in WSS with regard to severity, organs involvement and age of onset, both in inter-familial and intra-familial cases. In this study, the genetic characterization of a consanguineous pedigree showing mild features of WSS was performed, followed by structural analysis of truncated protein. Exome sequencing identified a novel single base deletion variant (c.270delA; K90Nfs8*) in third exon of the gene DCAF17 (RefSeq; NM_025000), resulting in a truncated protein. Structural analysis of truncated DCAF17 revealed absence of amino acid residues crucial for interaction with DDB1. Taken together, the data confirmed the single base pair deletion as the underlying cause of this second report of WSS from Pakistan. This signifies the vital yet unexplored role of DCAF17 both in development and maintenance of adult tissues homeostasis.

A novel deletion mutation in the DSG4 gene underlies autosomal recessive hypotrichosis with variable phenotype in two unrelated consanguineous families.

BACKGROUND: Autosomal recessive hypotrichosis is a rare human hereditary disorder presenting as sparse scalp hair or as woolly hair occurring on various parts of the body. Various forms of isolated hypotrichosis have been reported to date. Mutations in at least 11 genes have been reported to cause hypotrichosis. AIMS: To investigate the clinical and genetic basis of autosomal recessive hypotrichosis in two unrelated consanguineous families. METHODS: Genotyping by highly polymorphic microsatellite markers established linkage in both families to the DSG4 gene on chromosome 18q21. PCR amplification of exons and intron-exon borders of the DSG4 gene was performed, and the products sequenced to search for disease-causing sequence variants. RESULTS: Clinical investigation revealed typical hypotrichosis in the affected members of one family, while other affected members showed presence of monilethrix-like scalp hair. Sequence analysis of DSG4 revealed a novel deletion mutation (c.85-1_191del) in the affected subjects of both families. CONCLUSIONS: This study further extends the body of evidence that mutations in the DSG4 gene result in both hypotrichosis and monilethrix-like scalp hair.

Relationship of thyroid transcription factor 1 to EGFR status in non-small-cell lung cancer.

BACKGROUND: Activating mutations of the epidermal growth factor receptor (EGFR) gene are known to drive a proportion of non-small-cell lung cancers. Identification of lung cancers harbouring such mutations can lead to effective treatment using one of the agents that targets and blocks egfr-mediated signalling. METHODS: All specimens received at the BC Cancer Agency (Vancouver) for EGFR testing were prospectively identified and catalogued, together with clinical information and EGFR status, over a 14-month period. RESULTS: Specimens from 586 patients were received for EGFR testing, and EGFR status was reported for 509 patients. No relationship between specimen type or site of origin and EGFR test failure rate was identified. Concurrent immunohistochemical (ihc) status for thyroid transcription factor 1 (ttf1) was available for 309 patients. The negative predictive value of ttf1-negative status by ihc was 94.2% for predicting negative EGFR status. CONCLUSIONS: In patients with limited tissue available for testing, a surrogate for EGFR status would aid in timely management. Immunohistochemistry for ttf1 is readily available and correlates highly with EGFR status. In conjunction with genetic assays, ttf1 could be used to optimize an EGFR testing strategy.

Clinical and genetic variables associated with acute arousal and nonarousal-related cardiac events among subjects with long QT syndrome.

In patients with the long QT syndrome (LQTS), the occurrence of cardiac events (syncope or cardiac arrest) is frequently associated with acute arousal caused by exercise, swimming, emotion, or noise. However, cardiac events may also occur during sleep or with ordinary daily activities. The purpose of this study was to determine whether there are differential clinical, electrocardiographic, and genetic features among LQTS patients who experienced cardiac events with and without acute arousal. We identified 1,325 patients with cardiac events from the International LQTS Registry. Based on the precipitating conditions of the first event, 427 patients were classified as arousal, 345 as nonarousal, and the remaining 553 were unknown (not classifiable). Gene linkage was known in 78 of the 772 patients with classifiable first events. The age at first cardiac event was significantly younger in the arousal than the nonarousal group (11.7 vs. 15.5 years, respectively; p<0.001). The arousal-type patients had a higher rate of subsequent cardiac events during follow-up after the index event than the nonarousal-type patients (p = 0.02). Arousal-related cardiac events occurred in 85% of LQT1, 67% of LQT2, and 33% of LQT3 patients (p = 0.008). This study provides evidence that the genotype is an important determinant of the LQTS phenotype in terms of arousal and nonarousal-related cardiac events.

Asthma and the risk of cardiac events in the Long QT syndrome. Long QT Syndrome Investigative Group.

While acquiring data for the International Long QT Syndrome Registry, we noticed that a number of patients referred for long QT syndrome (LQTS) were affected by asthma. The effect of asthma comorbidity on clinical course of LQTS has not been studied. This study aimed to evaluate the prevalence of asthma in patients with LQTS, determine the influence of asthma comorbidity on outcome of LQTS patients, and to investigate the confounding effects of beta mimetics and beta blockers on the occurrence of cardiac events in asthmatic patients. The influence of asthma on risk of cardiac events (syncope, aborted cardiac arrest, or LQTS death) was evaluated after accounting for age, gender, QTc, and RR interval duration, beta-blocker and beta-mimetic use. Asthma was identified in 226 (5.2%) of 4,310 studied LQTS family members. Longer QTc duration was associated with higher incidence of asthma (p <0.001). Asthma was independently associated with significantly increased risk of cardiac events in affected LQTS patients (hazard ratio 1.32; p = 0.048) and in borderline-affected family members (hazard ratio 2.08; p = 0.004) after adjustment for QTc, RR interval, and gender. An increased risk of cardiac events in asthmatic patients observed before beta-blocker therapy was reduced after initiation of treatment with beta blockers. In conclusion, the occurrence of asthma in LQTS patients increases with QTc duration. Asthma comorbidity in LQTS patients is associated with an increased risk of cardiac events. The asthma-associated increase in the risk of LQTS-related cardiac events is diminished after initiation of beta-blocker therapy, suggesting a possible role of beta-receptor modulation underlying asthma-LQTS association.

Effect of nutritional therapy on polyamine metabolism in severely traumatized patients.

The polyamines (PA) spermidine (SD) and spermine and their precursor putrescine (PU) play a leading role in the regulation of protein, RNA and DNA synthesis. We examined the role of PA along with other biomarkers of injury in eight victims of multiple trauma in the early post-traumatic period when they were hypermetabolic and highly catabolic. Intravenous nutritional therapy (TPN) was started 48 to 60h after trauma and continued for 6 days. The basal response to severe trauma was a significant (twofold to threefold) rise in urinary PU (p = 0.05) and SD (p = 0.025) levels compared to normal subjects. Six days of TPN further enhanced the basal excretion of PU (157%) and SD (137%) peaking on the third day. There was a 20% reduction in the excretion of 3-methylhistidine on the first day of TPN, but it was still 40% above normal on the sixth day. The negative nitrogen balance was improved but not reversed. Injury stimulated ribonuclease and catecholamine levels were also enhanced by nutritional therapy, peaking on the first and fourth day of TPN, respectively. This study demonstrated for the first time elevated levels of PA in trauma patients that correlated well with the other known measures of protein metabolic response to injury and changes during nutritional therapy. Extracellular PA levels could be used as markers of both catabolic pathology in trauma and of its response to nutritional therapy.

A suggested vaccine formulation for the control of pneumococcal meningitis in Egypt.

Mortality rates of pneumococcal meningitis ranges from 13-60% in different parts of the world. Reports of pneumococci with multiple antibiotic resistance add urgency to the need for developing means of primary prevention. A 14-valent pneumococcal vaccine was licensed in 1977, and a 23-valent pneumococcal vaccine in 1983. In the present work 131 strains of pneumococci isolated from meningitis cases in Egypt were identified and serotyped by Quellung reaction. The most frequently isolated serotype was serotype 1 (32%). Serotypes 6A, 9L, 12A, 19A and 29 were next in prevalence. The age groups 0-18 years were the most frequently affected groups (79%) and over 18 years of age were only 21% of total cases. A vaccine formulation is suggested to have a coverage rate against pneumococcal meningitis cases of 79.3% and 89.3% of a proposed 14-valent vaccine and 23-valent vaccine versus to coverage rate of 48% and 54% of 14-valent and 23-valent International vaccines respectively. According to the age distribution of cases and the isolated serotypes a vaccination could be recommended during the first two years of age in order to protect the most frequently infected groups.

[Morphological and biosynthetic activity of Trichothecium roseum in relation to the polynuclear conidia of the fungus]. / Morfologicheskaia i biosinteticheskaia aktivnost' Trichothecium roseum v sviazi s mnogoiadernost'iu konidii griba

The effect of the number of the nuclei on the morphological and synthetic variability was studied with the conidia of Trichothecium roseum. Treatment of suspensions of the conidia with 0.5--1.0 percent solutions of colchicine during two hours increased the number of the nuclei in the conidia, induced the formation of giant colonies, and augmented the ability to produce antibiotics. No reliable differences have been found in the levels of proteolytic activity between the control strains and the strains treated with colchicine.