Preduodenal mechanisms in initiating gallbladder emptying in man

The existence of preduodenal phases of gallbladder emptying in normal volunteers was investigated by evaluating the effect of sham feeding a sandwich (chew and spit) (n = 15), the sight and smell of food followed by sham feeding a cooked meal (n = 15), and gastric distension (intragastric balloon tube) (n = 9) on gallbladder emptying and comparing these responses with those after ingestion of a standard meal (n = 14). A control group given no intestinal stimuli were studied to determine the frequency of spontaneous emptying during fasting (n = 18). 99mTc-EHIDA (2,6 diethylphenylcarbamoylmethyliminodiacetic acid) was used as the biliary tracer. The frequency of gallbladder emptying during fasting was 0.0045/min. Thus, in any 20 min period emptying occurred spontaneously in only about 1 in 11 volunteers. Significant emptying (greater than 5 per cent over 20 min) occurred in 8 out of 15 volunteers after sham feeding a sandwich (P less than 0.001 versus control), in 8 out of 15 volunteers after sham feeding a cooked meal (P = 1.0 versus sandwich sham feed, n.s.), in 6 out of 9 volunteers after gastric distension (P less than 0.001 versus control) and in 14 out of 14 volunteers after meal ingestion. The rate of emptying was significantly greater in the gastric distension and meal ingestion groups compared with other groups (P less than 0.05). However, the emptying rate after sham feeding was not significantly different from spontaneous gallbladder emptying (P greater than 0.05, n.s.). There was no significant difference in time to onset of emptying between the four stimulus groups (P greater than 0.05, n.s.). These results suggest that pre-duodenal stimuli can evoke gallbladder emptying in man, although the precise physiological significance of this phenomenon remains to be established.     

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.     

Single-dose pharmacokinetics of paracetamol and its conjugates in Chinese non-insulin-dependent diabetic patients with renal impairment

Objective: A single oral dose of paracetamol (20 mg · kg⁻¹) was given to 38 Chinese patients with non-insulin-dependent diabetes mellitus (NIDDM) who had either normal renal function or varying degrees of renal impairment, with creatinine clearances ranging from 4 to 123 ml · min⁻¹ · 1.73 m⁻². The plasma and urinary concentrations of paracetamol and its major metabolites were measured by high-performance liquid chromatography (HPLC). Results: The absorption and elimination of paracetamol were unaffected by renal impairment. However, the area under the plasma concentration time curve and the elimination half-life of paracetamol metabolites increased significantly with worsening renal insufficiency. Mean renal clearances of paracetamol and its conjugates were significantly reduced in these subjects. There was no evidence of altered metabolic activation with renal impairment. Conclusion: The results demonstrate that paracetamol disposition is minimally affected by diabetic nephropathy; however, extensive accumulation of conjugates may occur. Received: 2 September 1996 / Accepted in revised form: 11 December 1996     

Endocrinology: Immunohistochemical sex steroid receptor distribution in endometrium from long-term subdermal levonorgestrel users and during the normal menstrual cycle

The bleeding problems experienced by users of subdermal levonorgestrelimplants (Norplant) remain unexplained. The aim of the presentstudy was to investigate the oestrogen (ER) and progesteronereceptor (PR) distribution in levonorgestrel-treated endometrialbiopsies from 31 subjects recruited in Jakarta, Indonesia, andto compare the sex steroid receptor immunostaining with thatof endometrium from 58 normally cycling women from Melbourne,Australia. Sex steroid receptor immunoreactivity was additionallycompared with days of exposure to subdermal levonorgestrel,serum oestradiol and progesterone levels and days of bleedingduring a 90-day reference period. An immunohistochemical techniquewith an alkaline phosphatase anti-alkaline phosphatase (APAAP)detection system for use in formalin-fixed paraffin wax embeddedendometrial tissue was employed. Significantly greater meanimmunostaining scores of stromal PR were observed in Norplantcompared with control endometrium at all stages across the cycle.No significant correlations were demonstrated between sex steroidreceptor immunostaining and days of exposure to subdermal levonorgestrel,serum oestradiol or progesterone concentrations or days of bleedingduring a 90-day reference period. Whether the elevated stromalPR immunostaining in Norplant-treated endometrium is a consequenceof increased synthesis or reduced turnover of receptor remainsunclear. As yet it is undetermined whether increased PR immunoreactivitycorresponds to an increase in number of functional PR.     

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.