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.     

Michaelis-Menten metabolite formation kinetics: equations relating area under the curve and metabolite recovery to the administered dose

A computational approach which concomitantly determines the capacity-limited rate constants of parent drug elimination and metabolite formation is presented. The approach applies both the presently derived total excretory recovery versus dose relationships of the metabolite and the AUC versus dose relationships of the parent drug to identify the parameters. Three parent drug elimination conditions were assessed: pooled first-order, pooled Michaelis-Menten, and parallel first-order and pooled Michaelis-Menten kinetics. Model and parameter identification criteria are discussed. Literature data for theophylline and two of its metabolites in rats were examined to reveal pooled Michaelis-Menten elimination kinetics of theophylline and capacity-limited formation of the metabolites. The proposed technique is useful for quantitating commonly obtained nonlinear drug disposition data such as AUC and amount of metabolites excreted.     

Autopsy findings in two siblings with infantile Refsum disease

Summary Recognition of adrenal atrophy during a review of autopsy findings in two sisters who died at 8 months and 3 1/2 years prompted estimation of very long chain fatty acids, phytanic acid and pristanic acid on wet liver fixed in formalin for 12 years. These were shown to be markedly increased and defects in multiple peroxisomal functions and decrease in particulate catalase were shown in cultured fibroblasts, confirming an abnormality of peroxisomal biogenesis. The patients had presented with failure to thrive, recurrent diarrohea and vomiting, poor mental development, retinal pigmentation, blindness and in the older patient deafness, with only mild dysmorphic features. Autopsy in the older patient showed adrenal atrophy, cirrhosis, and foamy histiocytes in multiple organs. The brain showed no demyelination, little cytoarchitectural abnormality, occasional perivascular histiocytes in the grey matter and meninges and prominent Purkinje cells in the molecular layer of the cerebellum. In the younger patient the changes were very subtle in spite of the marked clinical similarity. Despite the young age at death the clinicopathological features are most suggestive of infantile Refsum disease. In many situations anatomical pathology can be very useful in the recognition and study of peroxisomal disorders.     

Determinants of elderly residential mobility in Southern China: Exploration and implications

It is a widely accepted observation that many older Hong Kong residents have lived periodically on the Chinese mainland since the relaxation of restrictions on cross-border mobility and the closer connection between Hong Kong and the mainland. This paper explores and compares the determinants of various modes of residential mobility by Hong Kong retirees to the Pearl River Delta based on the data of two samples—one from Hong Kong and the other from the mainland. The findings support those of studies in Western societies that the decision of elderly residential mobility can be effectively predicted by the personal attributes, place ties, and person ties of the retirees, and that the effects of these factors vary with different modes of retiree mobility. The implications of these findings for the formulation of migration and housing policies for the older population and the economic development of amenity communities are discussed. He is also a Research Associate at the Joint Centre of Excellence for Research on Immigration and Settlement in Toronto, Canada. His research interests are elderly residential mobility, gerontology and geriatrics education, and the help-seeking behavior of older people. Dr. Ma’s latest study concerns the utilization and accessibility of human services for older residents in Hong Kong. He is also a reviewer of several international journals. Dr. Chow’s research interests are social security policies and practice, social policies and services for older people, and family support. The focus of his latest research project is the service needs of new immigrants to Hong Kong.     

Hyperinsulinaemia and Na+, K+ -ATPase activity in thyrotoxic periodic paralysis

OBJECTIVE Thyrotoxic periodic paralysis (TPP) usually follows a heavy carbohydrate meal and this may be explained by hyperinsulinaemia stimulating Na⁺, K⁺ -ATPase activity. To clarify this the effect of glucose load on serum insulin concentration and platelet Na⁺, K⁺ -ATPase activity In thyrotoxic periodic paralysis (TPP) was examined. DESIGN In all subjects a standard 75-g glucose tolerance test was done and blood samples were taken at 0, 1 and 2 hours. SUBJECTS Twenty-five healthy controls (8 M and 17 F), 17 uncomplicated thyrotoxic patients (7M and 10 F), 15 TPP patients who presented with paralysis and 4 TPP patients after treatment with antithyrold drugs. MEASUREMENTS Plasma glucose was measured by the glucose oxidase method, serum insulin by radioimmunoassay and platelet Na⁺, K⁺ -ATPase by the release of phosphate from ATP. RESULTS TPP patients showed glucose intolerance (area under the curve (AUC) 16·5 ± 4·4 (mean ± SD) In TPP compared to 12·9 ± 4·5 In controls (P < 0·01) and hyperinsulinaemia (AUC 189·6 ±100·6 vs 98·5 ±53·4, P < 0·001). In uncomplicated thyrotoxicosis the results were similar to that in healthy controls. Platelet Na⁺, K⁺ -ATPase were significantly higher in thyrotoxic patients compared to controls and In TPP patients were even higher. Ingestion of glucose increased platelet Na⁺, K⁺ -ATPase in all groups. AUC for platelet Na⁺, K⁺ -ATPase in TPP patients were significantly higher than in uncomplicated thyrotoxicosis (601 ±99·3 vs 482 ± 109·4, P < 0·01) or healthy controls (320 ± 107·3). In the 4 TPP patients studied after antithyroid treatment the results were similar to healthy controls. CONCLUSION Patients with thyrotoxic periodic paralysis have hyperinsulinaemia and this is accompanied by higher Na⁺, K⁺-ATPase activity.     

What is the prognostic value of myocardial perfusion imaging using rubidium-82 positron emission tomography?

OBJECTIVES: The objective was to determine the prognostic value of rubidium-82 (82Rb) positron emission tomography (PET) myocardial perfusion imaging (MPI). BACKGROUND: 82Rb PET MPI accurately diagnoses coronary artery disease (CAD). However, there are limited data evaluating its prognostic value. METHODS: Follow-up (3.1 +/- 0.9 years) was obtained in 367 patients who underwent dipyridamole 82Rb PET MPI. Patients were divided into groups based on their summed stress score (SSS): group I, normal (<4); group II, mild (4 to 7); and group III, moderate (8 to 11) to severe (> or =12). RESULTS: There were significant differences among patients in the 3 SSS groups for hard events (cardiac death and myocardial infarction [MI]) (p < 0.001) and total cardiac events (hard events, revascularization and hospitalization) (p < 0.001). The annual hard events rates were 0.4%, 2.3%, and 7.0% in the normal, mild, and moderate-severe groups, respectively. In adjusted survival models, 82Rb PET SSS was the strongest predictor of total cardiac events and a significant predictor of hard events. Among patients referred for PET after 99mTc single-photon emission computed tomography, the annual total event rate was higher with abnormal versus normal SSS on PET (15.2% vs. 1.3%, p < 0.001). In patients with obesity, the annual total event rate was 11.1% with an abnormal scan and 1.5% with a normal scan (p < 0.001). CONCLUSIONS: This study shows that 82Rb PET MPI has significant prognostic value for predicting cardiac events, including death and MI. It also seems to have prognostic value in patients whose diagnosis remains uncertain after single-photon emission computed tomography MPI and in obese patients. The prognostic value of PET MPI may improve the management of cardiac patients.     

Polychlorinated and polybrominated biphenyl congeners and retinoid levels in rat tissues: structure-activity relationships.

The purpose of this study was to examine the structural requirements of polychlorinated and polybrominated biphenyls (PCBs and PBBs) for altering tissue levels of retinoids. Seven congeneric PCBs and PBBs were studied: 3,3',4,4'-tetrachlorobiphenyl (TCB), 2',3,3',4,5- and 3,3',4,4',5-pentachlorobiphenyls (-PeCBs), 3,3',4,4'- and 3,3',5,5'-tetrabromobiphenyls (-TBBs), 2,2',3,3',5,5'-hexachlorobiphenyl (-HCB), and 3,3',4,4',5,5'-hexabromobiphenyl (-HBB). Male Sprague-Dawley rats were fed a vitamin A-adequate diet (1.3 mg/kg) for 30 days before being given a single IP injection of one of seven polyhalogenated biphenyls (150 mumol/kg) in corn oil (10 ml/kg) or vehicle alone. Rats were killed 1 week later. Except for 3,3',4,4',5,5'-HBB, all PCBs and PBBs studied significantly decreased serum retinol levels and, except for 3,3',4,4',5,5'-HBB and 2,2',3,3',5,5'-HCB, all PCBs and PBBs also lowered the serum retinol-binding-protein (RBP) content. The activity of hepatic retinyl ester hydrolase (REH) was reduced by the treatment of 3,3',4,4',5-PeCB, 3,3',4,4'-TBB, and 3,3',4,4',5,5'-HBB. The levels of hepatic retinol were decreased by 2,2',3,3',5,5'-HCB, 2',3,3',4,5-PeCB, and 3,3',4,4',5-PeCB, while levels of hepatic retinyl palmitate were decreased by 2',3,3',4,5-PeCB, 3,3',4,4',5-PeCB, 3,3',4,4'-TCB, 3,3',4,4'-TBB, and 3,3',4,4',5,5'-HBB. The substantial decreases in hepatic retinyl palmitate levels could not be explained solely on the basis of hepatomegaly caused by acutely toxic PCBs and PBBs. All halogenated biphenyls which caused a decrease in hepatic retinyl palmitate also caused an increase in renal retinyl palmitate except 3,3',4,4',5-PeCB. In summary, the acutely toxic (nonortho substituted) congeners had pronounced effects on hepatic, renal, and serum retinoids whereas other biphenyls only decreased serum retinol levels. The effects of these seven compounds on REH activity were not correlated with the effects on serum retinol or RBP levels. Therefore, this study shows that the structure-activity relationships for altering hepatic retinoids differ from those for serum retinol, implying the involvement of multiple mechanisms.