Internalised capillaries, neuromyopathy and myalgia.

Internalised capillaries are described in the muscle fibres of two adult males who complained of exertional myalgia. In one patient, "bundles" of internalised capillaries were found in 2% of the Type 1 fibres and many of the Type 1 fibres exhibited non-specific cytoarchitectural changes. The other had hereditary motor and sensory neuropathy (HMSN) Type 2 and his muscle biopsy exhibited the more conventional single and double internalised capillaries in 3% of the muscle fibres in addition to the anticipated neuropathic changes. Electron microscopy revealed the presence of paracrystalline inclusions in the mitochondria of muscle of both patients. Dystrophin was normal on both immunogold/silver staining and immunoblotting. Sixty five of 77 recorded patients with evidence of internalisation of capillaries have been males and 10 are known to have complained of muscle cramps or severe myalgia. An ischaemic pathogenetic predisposition is proposed as a possible stimulus to the capillary internalisation, formation of paracrystalline mitochondrial inclusions and myalgia.     

Evidence of a long QT founder gene with varying phenotypic expression in South African families.

We report five South African families of northern European descent (pedigrees 161, 162, 163, 164, and 166) in whom Romano-Ward long QT syndrome (LQT) segregates. The disease mapped to a group of linked markers on chromosome 11p15.5, with maximum combined two point lod scores, all generated at theta = 0, of 15.43 for the D11S922, 10.51 for the D11S1318, and 14.29 for the tyrosine hydroxylase (TH) loci. Recent studies have shown that LQT is caused by an Ala212Val mutation in a potassium channel gene (KVLQT1) in pedigrees 161 to 164. We report that the same mutation is responsible for the disease in pedigree 166. Haplotype construction showed that all the families shared a common haplotype, suggesting a founder gene effect. DNA based identification of gene carriers allowed assessment of the clinical spectrum of LQT. The QTc interval was significantly shorter in both carriers and non-carriers in pedigree 161 (0.48 s and 0.39 s, respectively) than the same two groups in pedigree 161 (0.52 s and 0.42 s, respectively). The spectrum of clinical symptoms appeared more severe in pedigree 162. The possible influence of modulating genetic factors, such as HLA status and sex of family members, on the expression of an LQT founder gene is discussed.     

Evaluation of mathematic models to assess platelet kinetics

Twelve mathematic methods used to calculate the mean platelet survival time were compared by determining the "goodness of fit" of the models to the platelet survival curves of 15 reference subjects and 54 patients. Platelets were labeled with [111In]oxine. The linear (LN), exponential, weighted mean, multiple hit (MH), Dornhorst (DH), Meuleman (ML), alpha order (AO), and polynomial (PO) mathematic models were investigated. The goodness of fit for the exponential model was determined by the nonlinear least squares method (EP), and also by the linear least squares method on logarithmically transformed data (EX) as is recommended. The modified weighted mean (MWM) and the usual weighted mean method (WM) obtained with these exponential models were tested. The Dornhorst (DH10) and Meuleman (ML10) models, where the potential age-dependent platelet survival times were kept constant at 10 days, were also evaluated. The goodness of fit results, expressed as % s.d. indicated that the LN (5.2%), EX (5.0%), EP (4.4%), WM (3.7%), DH10 (3.7%), and ML10 (3.7%) models all fitted the data significantly worse than the MWM, MH, DH, ML, AO, and PO models (range 3.2-3.3%). The mean platelet survival time determined with the MH model differed significantly from the results with the DH, ML, and AO models. The results of mean platelet survival time calculated with different mathematic models cannot, therefore, be compared directly. The models that fitted the platelet survival curve well varied slightly in sensitivity to noise as is indicated by the coefficient of variation of the mean platelet survival time estimates for the reference subjects (range 7.9-12.0%). Fitting data to at least two mathematic models has definite advantages. Data on which the calculations are based are probably invalid if the following are true: (a) if the mean platelet survival time estimated with the alpha order model is shorter than that estimated with the EP, MWM, or MH models, or (b) the mean platelet survival time estimated with either the DH, ML, AO, or PO models, is longer than the LN, MWM, or MH estimate of the mean platelet survival time. We conclude that the mean platelet survival time can be reliably estimated by fitting the data to either the MWM method (if limited computing facilities are available) or the MH model. Confidence in the result will be increased if considered in conjunction with the finding obtained with one other model; in those cases where the platelet survival time is very short, the alpha order model is recommended.(ABSTRACT TRUNCATED AT 400 WORDS)     

Oesophageal and other cancer patterns in four selected districts of Transkei,Southern Africa: 1985-1990

New data regarding the incidence of oesophageal and other cancers during the period 1985-1990 are reported for all clinics and hospitals in four selected districts of Transkei, Southern Africa i.e Kentani, Butterworth, Lusikisiki and Bizana. Active and passive methods were used to obtain the hospital-based cancer registry data. The mean annual number of cancer cases recorded for the period 1985-1990 was 292. Age-standardized incidence rates (ASIIR, African Standard) for all recorded cancers were 81.4 and 52.6/100,000 for males and females, respectively. Histopathogical examination of 52.6% of recorded tumours revealed that 67.3% were squamous carcinomas, 21.7% adenocarcinomas and the remainder non-epithelial neoplasms. Cancer of the oesophagus (EC) was the most frequently recorded cancer and accounted for 46.5% of the cases with mean ASIR of 46.7 and 19.2/100,000 for males and females, respectively. The male/female ratio was 2:4:1. The highest mean ASIR per annum for OC in males (55.6/100,000) occurred in Kentani and in females (22.3/100,000) in Lusikisiki, whereas the lowest rates in both sexes (37.0 and 11.7/100,000 respectively) occurred in Bizana. Comparison of the OC rates in the four districts of Transkei during 1985-1990 with previously reported trends, confirms a consistently high rate in the south-western district of Kentani during the past 35 years and progressively increasing rates in the north-eastern districts of Bizana and Lusikisiki. These results have profound implications for further epidemiological and aetiological studies on OC in Transkei, but need to be corroborated by data from other sources such as statistics on histologically diagnosed cancer in Transkei by district in the South African National Cancer Registry. The second most frequently recorded cancer among males was liver cancer with a mean annual ASIR of 6.0/100,0000 and a male: female ratio of 3:1. The most frequently recorded cancer with a mean annual AISR of 20.9/100,000 followed by OC (19.2/100,000) and breast cancer (5.8/100,000).     

Oesophageal and other cancer patterns in four selected districts of the Transkei, Southern Africa:1985-1990

New data regarding the incidence of oesophageal and other cancers during the period 1985-1990 are reported for all clinics and hospitals in four selected districts of Transkei, Southern Africa i.e. Kentani, Butterworth, Lusikisiki and Bisana. Active and passive methods were used to obtain the hospital-based cancer registry data. The mean annual number of cancer cases recorded for the period 1985-1990 was 292. Age-standardised incidence rates (ASIR, African standard) for all recorded cancer were 81.4 and 52.6/100,000 for males and females respectively. Histopathological examination of 52.6% of recorded tumors revealed that 67.3% were squamous carcinomas, 21.7% adenocarcinomas and the remainder non-epithelial neoplasm. Cancer of the oesophagus (OC) was the most frequently recorded cancer and accounted for the 46.5% of the cases with mean ASIR of 46.7 and 19.2/100,000 for males and females respectively. The male/female ratio was 2.4:1. The highest mean ASIR per annum for OC in males (55.6/100,000) occurred in Kentani and in females (22.3/100,000) in Lusikisiki, whereas the lowest rates in both sexes (37.0 and 11.7/100,000 respectively) occurred in Bizana. Comparison of the OC rates in the four districts of Transkei during 19985-1990 with previous reported trends, confirms a consistently high rate in the south-western districts of Kentani during the past 35 years and progressively increasing rates in the north-eastern districts of Bizana and Lusikisiki. These results have profound implications for further epidemiological and aetiological studies on OC in Transkei, but we need to be corroborated by data form other sources such as statistics on histologically diagnosed cancer in Transkei by districts in the South African National Cancer Registry. The second most frequent recorded cancer among males was liver cancer with a mean annual ASIR of 6.0/ 100,000 and male:female ratio of 3:1. The most frequent recorded cancer among females was cervical cancer with a mean annual ASIR of 20.9/100,000 followed by OC (19.2/100,000) and breast cancer (5.8/100,000).     

Physical activity,mental health and well-being of adults during initial COVID-19 containment strategies: A multi-country cross-sectional analysis

ObjectivesTo assess physical activity (PA), mental health and well-being of adults in the United Kingdom (UK), Ireland, New Zealand and Australia during the initial stages of National governments’ Coronavirus disease (COVID-19) containment responses.DesignObservational, cross-sectional.MethodsAn online survey was disseminated to adults (n = 8,425; 44.5 ± 14.8y) residing in the UK, Ireland, New Zealand and Australia within the first 2-6 weeks of government-mandated COVID-19 restrictions. Main outcome measures included: Stages of Change scale for exercise behaviour change; International Physical Activity Questionnaire (short-form); World Health Organisation-5 Well-being Index; and the Depression Anxiety and Stress Scale-9.ResultsParticipants who reported a negative change in exercise behaviour from before initial COVID-19 restrictions to during the initial COVID-19 restrictions demonstrated poorer mental health and well-being compared to those demonstrating either a positive-or no change in their exercise behaviour (p < 0.001). Whilst women reported more positive changes in exercise behaviour, young people (18-29y) reported more negative changes (both p < 0.001). Individuals who had more positive exercise behaviours reported better mental health and well-being (p < 0.001). Although there were no differences in PA between countries, individuals in New Zealand reported better mental health and well-being (p < 0.001).ConclusionThe initial COVID-19 restrictions have differentially impacted upon PA habits of individuals based upon their age and sex, and therefore have important implications for international policy and guideline recommendations. Public health interventions that encourage PA should target specific groups (e.g., men, young adults) who are most vulnerable to the negative effects of physical distancing and/or self-isolation.     

In vitro effect of a thrombin inhibition peptide selected by phage display technology

A repeated selection of phages from a cyclic heptapeptide phage display library resulted in the enrichment of phages that bind to human -thrombin. One clone of the binding phages that competed with PPACK for binding to thrombin and that had the best binding characteristics was chosen. The amino acid sequence of the peptide displayed on this phage was determined and a peptide with the sequence, Cys-Asn-Arg-Pro-Phe-Ile-Pro-Thr-Cys was synthesised. This peptide, thrombin-inhibiting peptide (TIP), is a full competitive inhibitor of thrombin with an inhibition constant (K_i) of 0.4974 mM. It lengthened the thrombin time and inhibited thrombin-induced platelet activation and the platelet release reaction, both in a dose-dependent manner. It also reduced platelet adhesion onto a human microvascular endothelial matrix in the parallel plate flow chamber under both arterial and venous shear conditions. Thus, we have selected and synthesised a cyclic heptapeptide that competes with PPACK to bind to thrombin and that can be developed as a direct antithrombin.     

ADPase activity of normal and atherosclerotic human aorta intima.

ADP plays a key role in platelet aggregation and the enzymatic removal of this nucleotide may be important in the pathogenesis of intravascular thrombosis and atherosclerosis. Aortic intima extracts have ADPase activity and is able to remove small quantities of ADP efficiently. ADPase activity was assayed by measuring the catabolism of 2 micrometer 14C-ADP (final concentration) by the tissue extracts. Extracts prepared from normal, moderately and severely atherosclerotic human aortic initimas showed a significant progressive decrease in ADPase activity with increasing atherosclerosis. ADPase activity of the arch, thoracic and abdominal regions of normal aortas did not vary significantly, and thus did not correlate with the anatomical distribution of atherosclerosis. Vascular ADPase activity seems relevant in thrombogenesis since it may be a link between blood platelets and blood vessel wall interaction.