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.     

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.      

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.      

Cortical motor and somatosensory representation: effect of cerebral lesions

OBJECT: Changes in cortical representation in patients with cerebral lesions may alter the correlation between cortical anatomy and function. This is of potential clinical significance when the extent of cortical resection is based on surface anatomical landmarks. METHODS: Fifty-one patients with supratentorial lesions were studied. Nineteen harbored noncentral lesions (no involvement of pre- or postcentral gyrus), whereas 32 had central lesions. Control studies consisted of stimulation of the hand contralateral to the unaffected hemisphere. Positron emission tomography activation studies were performed using the [15O]H2O tracer. Somatosensory stimulation of the hand or foot was performed using a mechanical vibrator. Motor activation consisted of hand clenching or foot tapping. The t-statistic volumes were generated from images showing the mean change in regional cerebral blood flow, and coregistered with a T1-weighted magnetic resonance image. At the threshold selected, exclusive contralateral primary sensorimotor cortex activation was elicited in 100% of the control studies. A different pattern of cortical activation was associated with central lesions in 35 (78%) of 45 patients, which occurred significantly more often than with noncentral lesions (eight [31%] of 26 patients). The most common difference in the pattern of activation with central lesions was activation of cortical regions outside the central area (including the supplementary sensorimotor area and the secondary somatosensory cortex). No sensorimotor activation was observed in gyri adjacent to the pre- or postcentral gyrus. CONCLUSIONS: Central lesions are more frequently associated with altered patterns in activation than lesions in noncentral locations. Characteristic patterns include activation of secondary sensorimotor areas. The absence of activation in gyri adjacent to the sensorimotor strip has clinical significance for the planning of resections in the central area.     

Plasma cyclic nucleotide levels in acute leukemia patients

To verify the clinical usefulness of extracellular cyclic nucleotide determination as a tumor marker, plasma cyclic AMP (cAMP) and cyclic GMP (cGMP) levels were measured in 70 normal subjects and 173 acute leukemia patients studied in different stages of their disease. Mean plasma cAMP levels were similar in leukemic and normal subjects, although in 48 patients in the active stage of the disease, first diagnosis, or relapse, the cAMP values were below the normal range, and most of these patients failed to respond to chemotherapy. Plasma cGMP levels were markedly elevated in untreated patients, normalized in all patients who attained complete remission, and increased promptly to pretreatment values in patients who relapsed, suggesting that their determination may be useful to monitor the patients' response to treatment.     

Modulation by progestogens of the effects of oestrogen on hepatic endocrine function in postmenopausal women

OBJECTIVE: Oral but not transdermal oestrogen administration reduces IGF-I, and increases GH binding protein (GHBP) reflecting effects on hepatic endocrine function in postmenopausal women. As progestogens attenuate the effects of oestrogen on circulating lipid levels according to their androgenic properties, we have investigated the impact of progestogen types on the hepatic endocrine effects of oestrogen. DESIGN: Four progestogens differing in androgenicity were co-administered in a monthly cyclical regimen in random order to postmenopausal women receiving either oral (n = 9, premarin 1.25 mg) or transdermal (n = 10, Estraderm 100 microg patches twice weekly). The four progestogens were cyproterone acetate (CA 5 mg, antiandrogenic), dydrogesterone (20 mg, neutral), medroxyprogesterone acetate (MPA 10 mg, mildly androgenic), norethisterone (2.5 mg, androgenic). PATIENTS: Nineteen postmenopausal women (age 57 +/- 3 years, mean +/- SE) were studied. MEASUREMENTS: The effects of oestrogen alone and the combined effects with each progestogen type on IGF-I, GHBP, SHBG, cholesterol, triglycerides and lipoprotein(a) were investigated. RESULTS: Mean IGF-I fell while GHBP and SHBG levels increased with oral (P < 0.01) but not transdermal oestrogen administration. When the combined effects were examined, progestogens did not affect IGF-I, GHBP and SHBG during oral oestrogen treatment, while they significantly increased (P < 0.01) mean IGF-I levels during transdermal therapy. Among the progestogen types, only norethisterone prevented the fall in IGF-I induced by oral oestrogen. During transdermal therapy, MPA and norethisterone but not CA or dydrogesterone significantly increased (P < 0.005) IGF-I. The rise in GHBP induced by oral oestrogens tended to be lower during co-administration of MPA and norethisterone. The increase in SHBG induced by oral oestrogen was attenuated (P < 0.05) by norethisterone which was the only progestogen that lowered SHBG (P < 0.05) during transdermal oestrogen treatment. Mean IGF-I was higher (P < 0.001), GHBP and SHBG lower during co-administration of androgenic progestogens (MPA and norethisterone). CONCLUSIONS: Oestrogen effects on IGF-I, GHBP and SHBG are dependent on the route of administration with progestogens having variable effects. Among the progestogen types, norethisterone, the most androgenic, had the greatest effect, particularly on IGF-I. Progestogens modulate the effects of oestrogen on hepatic endocrine function in relation to their intrinsic androgenic properties. The modulatory effects of progestogens on IGF-I during oestrogen therapy may have long-term implications for lean body mass.