Calciphylaxis – a topical overview

'Calciphylaxis', a calcification syndrome associated with ischaemic cutaneous necrosis, is acquired naturally in humans in disease states. It is a life and limb-threatening complication, usually observed in patients with renal disease and secondary hyperparathyroidism, but known to occur in the absence of renal or parathyroid disease. The reported mortality rate, which ranges from 60-80%, relates to wound infection, sepsis and organ failure. It is a small-vessel vasculopathy, which is estimated to occur in about 4% of haemodialysis patients. Clinically, violaceous, reticulate areas of cutaneous necrosis and eschar may be evident, particularly in the extremities. In addition to the clinical picture, a raised calcium phosphorous product, an elevated parathyroid hormone level, radiographic evidence of vessel and soft-tissue calcification and the finding of mural calcification affecting small arteries and arterioles on histopathology help to confirm the diagnosis of this entity which generally has a poor prognosis. A high index of suspicion and an active multidisciplinary management approach, with rigorous attention to wound care and prevention of sepsis, are vital in the management of these patients. In this overview, we discuss the pathophysiology, clinical features and associations, risk factors, diagnosis and management issues relating to calciphylaxis.     

A longitudinal study of age-associated memory impairment

An 8-year longitudinal study of elderly people has provided data concerning age-associated impairment (AAMI). In 1985 a random sample of 146 persons aged 65 years or more, living in their own homes, were assessed using the Guild Memory Test the Mini–Mental State Examination (MMSE) and other ratings. After excluding 21% of the sample because they scored less than 24 on the MMSE, and another 34% who fulfilled other exclusion criteria, some 48% of the remainder (22% of the total sample) clearly fulfilled NIMH criteria for AAMI and a further 36% (16% of the total sample) were recorded as forgetful. The NIMH criteria are appropriate for certain research purposes but not in assessing prevalence of memory disorders. Follow–up interviews were conducted after 2, 4, 6 and 8 years. The mortality rate and development of dementia among those fulfilling criteria for AAMI appeared similar to the other non-demented groups of subjects; the mortality rate of those with MMSE scores below 24 was significantly higher. Guild test results at 2-yearly intervals showed considerable changes; half of those scoring least well who were retested showed improvement.     

Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy

The dominant cone-rod dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12-p13. The retinal- specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber's congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various cone and cone- rod dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant cone-rod dystrophy. RETGC-1 is only the fourth gene to be implicated in cone-rod dystrophy and this is the first report of dominant mutations in this gene.      

Congenital abnormalities in newborn lambs after infection of pregnant sheep with Akabane virus.

Akabane virus (a Bunyavirus) has been associated with epizootics of congenital deformities in cattle, sheep, and goats. Experimental studies using mouse-adapted virus inoculated intravenously into pregnant sheep gave an inapparent infection. Neutralizing antibodies were detected on day 5, and peaks in the titer were seen at days 10 and 48. Ewes infected at day 30 to 36 of pregnancy produced five (31% incidence) deformed lambs. Sera from four of these possessed neutralizing antibodies to Akabane virus before ingesting colostrum. Two lambs had arthrogryposis, hydranencephaly, kyphosis, scoliosis, and brachygnathia; one had micrencephaly; and the other two had porencephaly. The two lambs with arthrogryposis and hydranencephaly also had extensive lesions in other tissues. In the spinal cord there was a marked decrease in the number of ventral horn neurones and a depletion of myelin. Skeletal muscles showed marked atrophy. The medulla of the thymus possessed large Hassall's corpuscles and a reduced number of thymocytes in the cortex. It would appear that the pathogenic effects of Akabane virus are related to the gestational age (30 to 36 days) at which the fetus is infected. Akabane virus can now be included in the growing list of teratogenic viruses and provides an interesting system for studying such congenital diseases.     

Comparison between testosterone oenanthate-induced azoospermia and oligozoospermia in a male contraceptive study. IV. Suppression of endogenous testicular and adrenal androgens

Administration of supraphysiological doses of testosterone to normal men causes inhibition of spermatogenesis, but while most become azoospermic, 30-55% maintain a low rate of spermatogenesis. We have investigated whether there are differences in endogenous androgen production, of testicular and adrenal origin, which may be related to the degree of suppression of spermatogenesis. Thirty-three healthy Caucasian men were given weekly i.m. injections of 200 mg testosterone oenanthate (TE), 18 became azoospermic, while 15 remained oligozoospermic. Urinary excretion of epitestosterone, a specific testicular product, was reduced to <10% of pretreatment values, with no differences between the groups. Similar results were obtained for other markers of testicular steroidogenesis. Urinary and plasma adrenal androgens were also reduced during TE treatment: a statistically significant decrease in both (P < 0.001 and P < 0.05 respectively) was seen in the azoospermic but not oligozoospermic responders. These results suggest that testicular steroidogenesis is decreased to <10% by the administration of supraphysiological doses of exogenous testosterone. Differences in the degree of ongoing steroidogenesis in the testis do not appear to account for incomplete suppression of spermatogenesis, thus differences in androgen metabolism may underlie this heterogeneous response. A small but significant reduction in secretion of adrenal androgens was also detectable, the relevance of which is unclear.      

A locus for autosomal dominant anterior polar cataract on chromosome 17p

Inherited cataract is a clinically and genetically heterogeneous disease. Here we report the identification of a new locus for an autosomal dominant anterior polar cataract on the short arm of chromosome 17. To map this new locus we performed genetic linkage analysis with microsatellite markers in a four-generation pedigree. After exclusion of seven candidate loci for cataract, we obtained significant positive LOD scores for markers D17S849 (Z = 4.01 / theta = 0.05) and D17S796 (Z = 4.17 / theta = 0.05). Multipoint analysis gave a maximum LOD score of 5.2 (theta max = 0.06) between these two markers. From haplotype analysis, the cataract locus lies in the 13 cM interval between markers D17S849 and D17S796. This study provides the first genetic mapping of an autosomal dominant anterior polar cataract.      

Differential expression of FMR1, FXR1 and FXR2 proteins in human brain and testis

Lack of expression of the fragile X mental retardation protein (FMRP) results in mental retardation and macroorchidism, seen as the major pathological symptoms in fragile X patients. FMRP is a cytoplasmic RNA- binding protein which cosediments with the 60S ribosomal subunit. Recently, two proteins homologous to FMRP were discovered: FXR1 and FXR2. These novel proteins interact with FMRP and with each other and they are also associated with the 60S ribosomal subunit. Here, we studied the expression pattern of the three proteins in brain and testis by immunohistochemistry. In adult brain, FMR1, FXR1 and FXR2 proteins are coexpressed in the cytoplasm of specific differentiated neurons only. However, we observed a different expression pattern in fetal brain as well as in adult and fetal testis, suggesting independent functions for the three proteins in those tissues during embryonic development and adult life.