Effects of various inhibitors of phenylethanolamine N-methyltransferase on pulsatile release of LH in ovariectomized rats

This study was undertaken to investigate whether hypothalamic adrenaline is involved in pulsatile LH release in rats. Various inhibitors of phenylethanolamine N-methyltransferase (PNMT), the enzyme which catalyses the conversion of noradrenaline to adrenaline, were administered to freely moving ovariectomized rats bearing an atrial cannula. Blood samples were taken continuously from 09.00 to 11.00 h and from 14.30 to 17.00 h. The drugs were administered either at 11.00 h only or at both 11.00 and 14.00 h. The various treatments with the vehicle or an inhibitor of peripheral PNMT, SKF 29661, produced no decrease in any parameter of pulsatile LH release. A single injection of one of the central PNMT inhibitors, SKF 64139 or LY 134046, at 11.00 h had no effect on LH release, but when given at both times the drugs suppressed the mean LH level, pulse frequency and amplitude. The effect of these drugs on the level of dopamine, noradrenaline and adrenaline in the hypothalamus (including preoptic area) was assessed. There was no effect on the concentration of the catecholamines after SKF 29661. None of the treatments with SKF 64139 or LY 134046 resulted in a change in the level of dopamine or noradrenaline; the double dose did, however, produce a significantly greater depletion of adrenaline than that which was achieved with the single injection. These results suggest that the maintenance of normal LH pulses is dependent upon the presence of a sufficient level of hypothalamic adrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Old and new cardiovascular risk factors: from unresolved issues to new opportunities

With the aim of identifying areas that may deserve some further thinking the present review deliberately points out controversial issues in cardiovascular research and risk assessment. In the first part of the review general aspects are addressed regarding the evaluation of risk factors. A first point of concern is the frequent practice of combining different vascular events and effects in different vascular beds into a single endpoint. Furthermore, verification of vascular events in clinical reality may be surprisingly inaccurate. Problems in risk assessment also arise from overlapping properties (shared pathophysiological pathways) of traditional risk factors like hypertension, obesity and diabetes. In the second part of the review unresolved issues concerning selected established and emerging risk factors are discussed. The difficulty of establishing causality in cardiovascular disease is addressed, using modification of LDL cholesterol and accumulating evidence for pleiotropic effects of the LDL cholesterol-lowering statins as an example. As an alternative or supplement to the notion of LDL-related cardiovascular risk it is proposed to distinguish between statin-sensitive and statin-insensitive cardiovascular risk. Finally the future prospects of selected new and emerging risk factors like CRP, homocysteine, asymmetrical dimethylarginine (ADMA), oxLDL, and isoprostanes are evaluated. In summary, imprecise terminology and varying definitions of "cardiovascular risk" may lead to a considerable blurring of our current risk estimates, which may also explain some presently controversial issues. With several new risk factors and substantial changes in lifestyle and treatment patterns on the horizon major changes in the hierarchy of risk factors may be inevitable.     

Molecular background of Rh D-positive,D-negative,D(el) and weak D phenotypes in Chinese

BACKGROUND AND OBJECTIVES: The aim of this study was to elucidate the genetic background of D-negative and D(el) in the Chinese population. MATERIALS AND METHODS: We investigated nine D-positive, 76 D-negative, 26 D(el) and three weak D Chinese individuals by amplification and sequencing of the complete coding region of the RHD gene from genomic DNA. A new RHD polymerase chain reaction with sequence-specific primers (PCR-SSP) method was developed with optimized specificity for typing Chinese individuals. RESULTS: In D-positive samples the RHD sequence was in complete concordance with RHD in other populations. In 12 of 76 (15.8%) D-negative individuals we detected regions of RHD. Three new alleles were found. All 26 D(el), as well as two weak D, individuals carried an RHD 1227A allele. In the remaining weak D sample we identified a weak D type 15. CONCLUSIONS: It should now be possible to correctly predict the RhD phenotype in Chinese subjects. D(el) can also be designated as a particular weak D type.     

A word of hope for ataxia trials in COVID-19 time and beyond

Journal of Neurology - The coronavirus disease 2019 (COVID-19) crisis confronted us, like many researchers worldwide, with an unforeseen challenge during the final stages of a randomized controlled...     

Submaximal arm crank ergometry: Effects of crank axis positioning on mechanical efficiency,physiological strain and perceived discomfort

Purpose: To evaluate the effect of the spatial orientation of the crank axis on mechanical efficiency, physiological strain and perceived discomfort in submaximal synchronous arm crank ergometry.

Methods: Twelve able-bodied individuals performed 12 submaximal exercise bouts of 3 minutes (women: 20 W/25 W; men: 25 W/35 W). The crank axis position was defined by elbow and shoulder angle.

Results: The results showed that a crank set-up with an elbow angle of 30° was more efficient than 15°; oxygen consumption and minute ventilation were significantly lower. No significant effects were seen for shoulder angle. Power output and gender showed obvious effects.

Discussion and conclusion: The magnitude of this effect and the absence of any significant shoulder angle effects may be due to the relative low exertion levels that were evaluated. An elbow angle of 30° flexion in arm crank exercise is favourable compared to an elbow angle of 15° in able-bodied untrained subjects.     

Sensitive methods for determining subclasses of IgG anti-A and anti-B in sera of blood-group-O women with a blood-group-A or -B child

The determination of the subclasses of IgG antibodies against blood groups A and B is important in order to improve our understanding and predict haemolytic disease of the newborn due to IgG anti-A or -B. We describe two techniques that circumvent the problem of the agglutination of A and B red cells by the corresponding IgG antibodies in saline: an antiglobulin consumption test and a modified solid-phase micro-immunofluorescence test. The results of the two techniques are compared with the results obtained in the indirect antiglobulin test beyond the saline agglutination titre in a microplate technique. The solid-phase micro-immunofluorescence test was the most sensitive for the determination of the subclasses of IgG anti-A and -B. Usually sera contained IgG2 anti-A, B in a higher titre than antibodies of other subclasses.     

Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III

Hereditary angioedema type III (HAEIII) is a rare inherited swelling disorder that is associated with point mutations in the gene encoding the plasma protease factor XII (FXII). Here, we demonstrate that HAEIII-associated mutant FXII, derived either from HAEIII patients or recombinantly produced, is defective in mucin-type Thr309-linked glycosylation. Loss of glycosylation led to increased contact-mediated autoactivation of zymogen FXII, resulting in excessive activation of the bradykinin-forming kallikrein-kinin pathway. In contrast, both FXII-driven coagulation and the ability of C1-esterase inhibitor to bind and inhibit activated FXII were not affected by the mutation. Intravital laser-scanning microscopy revealed that, compared with control animals, both F12^–/– mice reconstituted with recombinant mutant forms of FXII and humanized HAEIII mouse models with inducible liver-specific expression of Thr309Lys-mutated FXII exhibited increased contact-driven microvascular leakage. An FXII-neutralizing antibody abolished bradykinin generation in HAEIII patient plasma and blunted edema in HAEIII mice. Together, the results of this study characterize the mechanism of HAEIII and establish FXII inhibition as a potential therapeutic strategy to interfere with excessive vascular leakage in HAEIII and potentially alleviate edema due to other causes.     

Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease

It has been shown that treatment with miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) improves key clinical features of type I Gaucher disease after 1 year of treatment. This study reports longer-term efficacy and safety data. Patients who had completed 12 months of treatment with open-label miglustat (100-300 mg three times daily) were enrolled to continue with therapy in an extension study. Data are presented up to month 36. Liver and spleen volumes measured by CT or MRI were scheduled every 6 months. Biochemical and haematological parameters, including chitotriosidase activity (a sensitive marker of Gaucher disease activity) were monitored every 3 months. Safety data were also collected every 3 months. Eighteen of 22 eligible patients at four centres entered the extension phase and 14 of these completed 36 months of treatment with miglustat. After 36 months, there were statistically significant improvements in all major efficacy endpoints. Liver and spleen organ volumes were reduced by 18% and 30%, respectively. In patients whose haemoglobin value had been below 11.5 g/dl at baseline, mean haemoglobin increased progressively from baseline by 0.55 g/dl at month 12 (NS), 1.28 g/dl at month 24 (p =0.007), and 1.30 g/dl at month 36 (p =0.013). The mean platelet count at month 36 increased from baseline by 22 x 10(9)/L. No new cases of peripheral neuropathy occurred since previously reported. Diarrhoea and weight loss, which were frequently reported during the initial 12-month study, decreased in magnitude and prevalence during the second and third years. Patients treated with miglustat for 3 years show significant improvements in organ volumes and haematological parameters. In conclusion, miglustat was increasingly effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years.