Follistatin and activin A production by the male reproductive tract

Follistatin is a binding protein for the activin and inhibin family of hormones, regulating their biological activity. In the male reproductive tract, the interaction of these factors is likely to be involved in the regulation of the proliferation of several cell types. We have investigated the presence of follistatin and activin A in seminal plasma using specific immunoassays and have localized follistatin and activin/inhibin subunits in the adult human testis, prostate and seminal vesicle to establish their likely sources. High concentrations of immunoreactive follistatin were present in seminal plasma in normal men (mean 97.9 ng/ml; 1.43 ng/ml in peripheral plasma) and were similar in men with oligo/azoospermia and following vasectomy. Follistatin immunoreactivity was localized to both Leydig and Sertoli cells of the testis, and to epithelial cells of the prostate gland and seminal vesicle, which are likely to be the predominant sources of the hormone in seminal plasma. Activin A was also present in seminal plasma in normal men but was undetectable following vasectomy, thus deriving from the testis. Consistent with this finding, the betaA-subunit was immunolocalized in Sertoli and Leydig cells but was not present in seminal vesicle or prostate gland. The functional significance of the high concentrations of follistatin secreted into seminal plasma by the prostate gland and/or seminal vesicle is uncertain, but they may regulate the biological activity of testis-derived activin A and inhibin B.      

Vulvodynia: evolution of classification and management

The aim of this article is to make the reader familiar with the history and current status of vulvodynia. The account is presented as a historical survey, from the seventies to the nineties. It explains how and why the term came to be defined, and how some sub-groups – in particular dysaesthetic vulvodynia and vulval vestibulitis – have been identified and described. Their management is discussed. The importance of distinguishing these conditions from those which are variants of normal is stressed.
It is noted that these sub-groups have much in common, so that a degree of convergence or overlap has come to be recognised. In parallel with this, ideas concerning aetiology and optimal management have been clarified and are explored.
Appreciation of the present state of affairs, and of how it has been arrived at, will help to improve management. It will also facilitate the collection of data, which in turn may lead to further research and understanding of vulvodynia.     

Classification treesA possible method for iso-resource grouping in intensive care

Classification and grouping of clinical data into defined categories or hierarchies is difficult in intensive care practice. Diagnosis-related groups are used to categorise patients on the basis of diagnosis. However, this approach may not be applicable to intensive care where there is wide heterogeneity within diagnostic groups. Classification tree analysis uses selected independent variables to group patients according to a dependent variable in a way that reduces variation. In this study, the influence of three easily identified patient attributes on their length of intensive care unit stay was explored using classification analysis. Two thousand five hundred and forty-five critically ill patients from three hospitals were classified into groups so that the variation in length of stay within each group was minimised. In 23 out of 39 terminal groups, the interquartile range of the length of stay was ≤ 3 days.     

Inhibition of HERG K+ Current and Prolongation of the Guinea-Pig Ventricular Action Potential by 4-Aminopyridine

4-Aminopyridine (4-AP) has been used extensively to study transient outward K⁺ current ( I _TO,1) in cardiac cells and tissues. We report here inhibition by 4-AP of HERG (the human ether-à-go-go -related gene) K⁺ channels expressed in a mammalian cell line, at concentrations relevant to those used to study I _TO,1. Under voltage clamp, whole cell HERG current ( I _HERG) tails following commands to +30 mV were blocked with an IC₅₀ of 4.4 ± 0.5 m m . Development of block was contingent upon HERG channel gating, with a preference for activated over inactivated channels. Treatment with 5 m m 4-AP inhibited peak I _HERG during an applied action potential clamp waveform by ∼59 %. It also significantly prolonged action potentials and inhibited resurgent I _K tails from guinea-pig isolated ventricular myocytes, which lack an I _TO,1. We conclude that by blocking the α-subunit of the I _Kr channel, millimolar concentrations of 4-AP can modulate ventricular repolarisation independently of any action on I _TO,1.     

Histological studies of the elimination of Leishmania enriettii from skin lesions in the guinea-pig.

Nineteen guinea-pigs were each inoculated intradermally with 10(6) amastigotes of Leishmania enriettii, and the development of the lesions was followed from Weeks 4 to 10 with a view to elucidating the histological mechanisms involved with the elimination of parasites. Electron microscopic observations were made in 1 animal. Extensive necrosis of the parasite-laden macrophages was observed in 7 out of 7 animals at 4 and 5 weeks. In the ulcerated core of the lesion at 4 weeks no intact macrophages could be identified. Very many amastigotes were extracellular. Others were present in the cytoplasm of residual macrophages the cell walls of which had disintegrated. Necrosis was less marked at 8 weeks and absent in the resolving lesions at 10 weeks. Signs of stimulation or maturation of macrophages were only apparent when parasites were few. At 4 weeks macrophages were almost all of the non-stimulated form, but cytological evidence of activation became progressively more definite and widespread from 5 to 8 weeks, starting at the periphery of the lesion. Ultrastructural observations of amastigotes suggested that there might be more than one mechanism of degradation. It appeared that the majority of parasites were released through necrosis and discharged through the ulcer, and that intracellular degradation of the remaining parasites was important mainly in the later phase before resolution. The first phase was associated mainly with plasma-cell production, the second mainly with lymphocytes.     

Rationale for the histological spectrum of tuberculosis. A basis for classification

There is need to re-appraise the cellular response to Mycobacterium tuberculosis. Histological analysis of 54 untreated patients with established disease demonstrated a continuous spectrum of tissue responses in which six groups correlated with evidence of resistance to bacterial multiplication. A predominance of cases in the two middle groups (82%) signified an immunological equilibrium in middle grade resistant patients that is absent in related diseases such as leprosy and cutaneous leishmaniasis. The dominant feature was necrosis, which increased progressively across the spectrum. Its form varied from minimal fibrinoid change, through fine eosinophilic necrosis, to basophilic necrosis characterized by neutrophil karyorrhexis, and finally to an almost acellular lesion with many bacilli. Cytological differentiation of the granuloma was of subsidiary significance, mature epithelioid cells being found only in high resistant cases. No correlation was found for the number of lymphocytes. This classification is thought to be an accurate reflection of the immune state in relation to antigenic load. It raises a hitherto unconsidered possibility that "caseation", a loosely applied macroscopic term, may embrace immunologically distinct states. The classification of multiple lesions was consistent. Histology offers a promising basis for further immunopathological investigation.     

Anticipation in Huntington''s disease is inherited through the male line but may originate in the female.

Data from the US National Huntington's Disease Roster have been analysed in terms of the difference in age of onset (AO) between affected parents and affected offspring, that is, in terms of 'anticipation'. While mean AO in offspring of affected mothers did not differ greatly from AO in their mothers, the distribution of AO in the offspring of affected fathers falls into two groups, the larger group showing an AO only slightly younger than their affected fathers and a small group whose AO was, on average, 24 years younger than their affected fathers. Analysis of the grandparental origin of the Huntington allele suggests that while propensity to anticipation is heritable for a number of generations through the male line, it originates at the time of differentiation of the germ line of a male who acquires the Huntington allele from his mother. It is suggested that major anticipation indicates an epigenetic change in methylation of the nucleic acid of the genome, which is imposed in the course of the 'genomic imprinting', that is, in the mechanism by which the parental origin of alleles is indicated.