Liver transplantation for the treatment of homozygous familial hypercholesterolaemia in an era of emerging lipid-lowering therapies.

Homozygous familial hypercholesterolaemia (FH) causes severe premature coronary artery disease because of very high levels of low density lipoprotein (LDL)-cholesterol. Standard lipid-lowering drugs and LDL-apheresis may not be sufficiently effective. Liver transplantation replaces defective LDL receptors and vastly improves the lipid profile, and we present the first report of an Australian adult to receive this treatment. Emerging drug treatments for FH may be alternatives to LDL-apheresis and transplantation, but long-term safety and efficacy data are lacking for all of these options.

Provocation of postural hypotension by insulin in diabetic autonomic neuropathy.

The effect of insulin administration on blood pressure has been investigated in eight diabetes with autonomic neuropathy. Systolic and diastolic pressures fell considerably after insulin in all of them. This effect was aggravated by tilting to the vertical position. Five patients fainted when upright with systolic blood pressures less than 50 mm. Hg. This hypotensive effect of insulin occurs whether it is administered intravenously, intramuscularly, or subcutaneously. The onset of the effect is almost immediate after intravenous insulin, is progressive, and may last for several hours. It coincides with a falling blood glucose level and occurs before hypoglycemic levels are reached, and it may be present when the blood glucose level is still elevated. Diurnal variations of postural hypotension have been recorded in some patients, the standing blood pressure falling with the onset of insulin action and rising again as the latter declines. Some of our patients were unable to differentiate between symptoms of hypoglycemia and hypotension. Postural hypotension may account for some episodes of sudden loss of consciousness without warning, usually attributed to hypoglycemia.

The influence of renal threshold on the interpretation of urine tests for glucose in diabetic patients.

A knowledge of the renal threshold for glucose is important in the interpretation of urine tests in diabetes. We describe a simple method for determining renal threshold from blood and urine tests performed by the patients themselves. In a group of 65 insulin-dependent diabetic patients there was a wide variation in renal threshold, with a mean of 130 mg/dl (range 54-180 mg/dl). Threshold tended to rise with age, and it is suggested that the higher the renal threshold, the higher is the mean blood glucose achieved by the patient (r = 0.50, P = < 0.001). The change in blood glucose required to convert urine tests from 0% to 2% is very variable and ranged from 36 to 288 mg/dl (mean 110 mg/dl). The simple method that we describe may improve understanding of the significance of urine test results without the necessity for hospital admission.

Sickle cell trait and diabetic retinopathy.

The presence of sickle cell trait and the prevalence and severity of retinopathy were assessed in 124 Negro diabetics. Sickle cell trait had no adverse effect on diabetic retinopathy.

An uncommon Essex-Lopresti fracture dislocation with radial displacement in distal direction: diagnosis and surgical treatment of a rare case.

Essex-Lopresti injuries are rare and present a clinical challenge. Incomplete diagnosis and treatment can lead to long-term instability, pain and functional impairment. We report on a clinical case of proximal radioulnar joint (PRUJ) and distal radioulnar joint (DRUJ) dislocation with unusual distal radial displacement and associated radial head shear fracture. The case was managed with closed reduction of the PRUJ and DRUJ followed by open reduction and fixation of the radial head. A high index of suspicion with thorough examination of the elbow, forearm and wrist and comprehensive imaging was important in reaching a complete diagnosis for appropriate treatment. Anatomical reduction of the PRUJ and DRUJ is essential to achieve optimal functional outcomes. Six months following the injury the patient made a satisfactory recovery with full range of movement; however, she continued to have mild to moderate general and moderate work-related disability.

Characterization of cytosolic glutathione peroxidase and phospholipid-hydroperoxide glutathione peroxidase genes in rainbow trout (Oncorhynchus mykiss) and their modulation by in vitro selenium exposure.

Selenium (Se) is an oligonutrient with both essential biological functions and recognized harmful effects. As the selenocysteine (SeCys) amino acid, selenium is integrated in several Se-containing proteins (selenoproteins), many of which are fundamental for cell homeostasis. Nevertheless, selenium may exert toxic effects at levels marginally above those required, mainly through the generation of reactive oxygen species (ROS). The selenium chemical speciation can strongly affect the bioavailability of this metal and its impact on metabolism, dictating the levels that can be beneficial or detrimental towards an organism. Glutathione peroxidase (GPxs) is the largest and the most studied selenoprotein family. Cytosolic glutathione peroxidase (cGPx, GPx1) and phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) are widely distributed throughout tissues, and play a pivotal role in regulating the oxidative status in the cell. In this study we have cloned GPx1 and GPx4 genes in rainbow trout (Oncorhynchus mykiss). The constitutive mRNA expression of these GPx genes was examined in 18 trout tissues and their responsiveness to Se availability was analysed using a rainbow trout liver cell line (RTL). An inorganic (sodium selenite, Na2SeO3) and organic (selenocysteine, Cys-Se-Se-Cys) selenocompound have been used as Se sources. GPx1 activity was also tested to verify the impact of transcript changes on the enzymatic function of these molecules. To understand if the results obtained from the transcript expression analysis were due to Se bioavailability or generation of ROS, the cytoxicity of the two selenocompounds was tested by measuring the impact of Se on cell membrane integrity. Lastly, Se availability was quantified by mass spectrophotometry to determine the amount of Se in the cell culture media, the Se background due to the foetal calf serum supplement and the contribution from the two selenocompounds used in the treatments. Three isoforms of genes for both GPx1 (GPx1a, 1b1 and 1b2) and GPx4 (GPx4a1, a2 and b) have been identified. The discovery of a third gene encoding for GPx1 and GPx4 hints that salmonids may have the biggest selenoproteome amongst all vertebrates. Transcripts of GPx4 genes were more highly expressed in most tissues examined in vivo (except blood, head kidney and spleen), whereas those of the GPx1 genes were more responsive to selenium exposure in vitro, especially to the organic form. Interestingly, GPx1a was the most sensitive to selenium availability in non stressful conditions, whereas GPx1b1 and GPx1b2 were highly induced by exposure to selenium levels that had some toxic effects on the cells. Although the different concentrations tested of the two selenocompounds modulate GPx1 transcript expression to various degrees, no significant change of GPx1 enzymatic activity was detectable. Our results lead us to conclude that trout GPx1 transcripts expression level may represent a sensitive biomarker for selenium intake, helping to evaluate if selenium concentration and chemical speciation impact on cell homeostasis.

Circadian desynchrony and metabolic dysfunction; did light pollution make us fat?

Circadian rhythms are daily oscillations in physiology and behaviour that recur with a period of 24h, and that are entrained by the daily photoperiod. The cycle of sunrise and sunset provided a reliable time cue for many thousands of years, until the advent of artificial lighting disrupted the entrainment of human circadian rhythms to the solar photoperiod. Circadian desynchrony (CD) occurs when endogenous rhythms become misaligned with daily photoperiodic cycles, and this condition is facilitated by artificial lighting. This review examines the hypothesis that chronic CD that has accompanied the availability of electric lighting in the developed world induces a metabolic and behavioural phenotype that is predisposed to the development of obesity. The evidence to support this hypothesis is based on epidemiological data showing coincidence between the appearance of obesity and the availability of artificial light, both geographically, and historically. This association links CD to obesity in humans, and is corroborated by experimental studies that demonstrate that CD can induce obesity and metabolic dysfunction in humans and in rodents. This association between CD and obesity has far reaching implications for human health, lifestyle and work practices. Attention to the rhythmicity of daily sleep, exercise, work and feeding schedules could be beneficial in targeting or reversing the modern human predisposition to obesity.

Disappearing diabetes.

For five years a nurse was treated for diabetes mellitus. She was found to have tampered with her blood and urine tests and later was believed to have fabricated her condition from the outset.

Cardiorespiratory arrest and diabetic autonomic neuropathy.

Twelve cardiorespiratory arrests in eight neuropathy are reported. Only one patient died at the time, but two others subsequently died suddenly at home. There was no evidence of myocardial infarction, cardiac arrhythmia, or hypoglycaemia at the time of arrest. In most of the episodes there was some interference with respiration, either by anaesthesia, drugs, or bronchopneumonia. Five of the episodes occured during or immediately after anaesthesia. It is suggested that the arrests were caused by defective respiratory rather than cardiovascular reflexes. Cardiorespiratory arrest appears to be a specific feature of diabetic autonomic neuropathy and may contribute to the mortality of this condition.

Cardiovascular effects of insulin.

Insulin increased the heart rates of seven diabetics with normal cardiovascular reflexes. This effect, which was not due to hypoglycaemia, was greater in the upright than in the supine position and was produced by as little as one unit given intravenously. This increase in heart rate may be a compensatory response to maintain cardiac output.

Recessive inheritance of diabetes: the syndrome of diabetes insipidus, diabetes mellitus, optic atrophy and deafness.

A few rare syndromes have been delineated in which diabetes mellitus is inherited in association with other conditions. This paper describes five patients, including four siblings in one family, who have diabetes insipidus, diabetes mellitus, optic atrophy and deafness (the DIDMOAD syndrome). The parents of both families are normal but are first cousins. All the patients have insulin-dependent diabetes mellitus with a typical juvenile-onset. The onset of diabetes insipidus was insidious and the symptoms could easily have been ascribed to poor control of diabetes mellitus. The importance of diagnosing diabetes insipidus is that all these patients had dilatation of the urinary tract varying from mild hydroureter to severe hydronephrosis and this improved with treatment of the diabetes insipidus. It is suggested that patients with diabetes mellitus and optic atrophy should have regular screening tests for diabetes insipidus since it is likely that they represent cases of the full syndrome with incomplete clinical expression. The occurrence of this rare syndrome in four siblings of unaffected parents indicates that the syndrome is due to a recessive gene, but the pathogenesis is unknown.

Diabetic autonomic neuropathy. The diagnostic value of heart rate monitoring.

The use of heart rate monitoring in the diagnosis of diabetic autonomic neuropathy, and its value in observing the natural history of this disorder, has been assessed. Two tests were used: measurement of heart rate variation during deep breathing and of heart rate change on standing up. Two hundred and eighty seven diabetics aged between 20 and 49 years were studied, and 21 of them were observed repeatedly over 3 to 5 years. Heart rate variation (HRV) on deep breathing proved to be the more sensitive diagnostic index of autonomic neuropathy and was abnormal or borderline in 62 of 64 patients with established autonomic symptoms. Autonomic abnormalities were also detected in some diabetics without autonomic symptoms especially in those with peripheral neuropathy, 30% of whom had abnormal HRV on deep breathing. Abnormal tests appeared to represent permanent autonomic damage and may be present for years without the development of autonomic symptoms, occasionally (7%) preceding any other manifestation of diabetic neuropathy. Serial observations of HRV on deep breathing over 3 to 5 years showed little change, although overall there was a small deterioration of autonomic function, with a decrease of HRV score of 1.0 per year. The tests used are simple, and provide quantitative bedside measurements of autonomic function. When heart rate variation is normal, autonomic neuropathy is virtually excluded.

Treatment of diabetic coma with continuous low-dose infusion of insulin.

Thirty-eight patients in diabetic coma from four different centres were treated with a continuous low-dose intravenous infusion of insulin at an average dose of 7.2 IU/hr. All patients recovered rapidly except for one profoundly shocked patient who died. The mean fall in plasma glucose was 58% four hours after the start of insulin. Blood ketone bodies and plasma free fatty acids showed a similar response. There was no significant difference in plasma glucose response according to severity of acidosis or previous treatment with insulin. Hypokalaemia was uncommon. In the treatment of diabetic coma this technique has proved simple, safe, and effective.