UK Prospective Diabetes Study (UKPDS) 14: association of angiotensin-converting enzyme insertion/deletion polymorphism with myocardial infarction in NIDDM

Summary The deletion allele of the insertion/deletion polymorphism of the angiotensin-converting enzyme gene has been suggested to be an independent risk factor for myocardial infarction, particularly in subjects judged to be low-risk by the criteria of lipid status and body mass index. In a prospective, matched case-control study, we have investigated the role of this polymorphism as a risk factor for myocardial infarction in 173 newly-diagnosed British Caucasian non-insulin-dependent diabetic subjects taken from the United Kingdom Prospective Diabetes Study who subsequently developed myocardial infarction and 297 control subjects from the same study population matched for known cardiovascular risk factors including age at diagnosis of diabetes, gender, blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride and smoking habit. A trend towards increased risk conferred by homozygosity for the deletion allele was observed in cases (odds ratio 1.63, p=0.09). When the population was stratified according to the matched risk factors, the deletion allele was associated with myocardial infarction in those with low plasma low-density lipoprotein cholesterol (odds ratio 3.67, p=0.002), or low triglyceride (odds ratio 3.14, p=0.005). The strongest association of the deletion allele with myocardial infarction was observed in subjects with both low low-density lipoprotein cholesterol and low triglyceride levels (odds ratio 9.0, p<0.001). These results show that the deletion allele is a risk factor for myocardial infarction in non-insulin-dependent diabetic patients who have a favourable lipid profile.Abbreviations ACE angiotensin-converting enzyme - MI myocardial infarction - I/D polymorphism insertion/deletion polymorphism - I allele insertion allele - D allele deletion allele - DD genotype homozygosity for the deletion allele - UKPDS United Kingdom Prospective Diabetes Study     

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m², peak plasma concentration 5.6±2.5 g/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal E_max equation. A good fit was found between day 1 AUC and neutrophil toxicity (R ²=0.77). All patients who had a day 1 AUC>2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m²). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R ²=98.9%). The equation AUC_pr=–0.376+0.631×C_4h+0.336×C_6h was validated on the test set with a relative mean predictive error of –0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St, Melbourne 3000, Australia     

Epinephrine transiently increases amino acid disappearance to lower amino acid levels in humans.

BACKGROUND: Infusion of epinephrine decreases plasma amino acid concentrations. However, the mechanism by which this decrement occurs is not well characterized. METHODS: Epinephrine was infused (40 ng/kg/min) for 2 hours into eight normal healthy adults. The essential amino acid tracers L-[1-(13)C]leucine and L-[phenyl-2H5]phenylalanine were infused before and during the epinephrine infusion and blood samples obtained to determine amino acid rates of appearance and disappearance from the time course of change in amino acid concentration and tracer enrichments. RESULTS: Epinephrine infusion decreased plasma leucine and phenylalanine concentrations over a period of 30 to 90 minutes after the start of the epinephrine infusion. Epinephrine infusion induced an immediate decrement in tracer enrichments. These changes defined sharp increases in both rate of appearance and rate of disappearance. By 30 minutes of epinephrine infusion, the rate of amino acid appearance from proteolysis had returned to baseline, but the rate of amino acid disappearance remained elevated for 90 minutes before returning to baseline. It was the protracted increase in amino acid disappearance that was responsible for the lowering of plasma amino acid concentrations. After this acute response, rates of amino acid appearance and disappearance returned to normal whereas plasma amino acid levels remained suppressed. CONCLUSIONS: Epinephrine transiently affects both rates of amino acid appearance and disappearance, with the net effect being increased in amino acid disappearance. However, epinephrine lowers amino acid concentrations beyond the period that it affects kinetics. These results suggest that the effect of epinephrine on amino acid metabolism is not detrimental and that epinephrine allows amino acid metabolism to proceed normally but at lower concentrations of amino acids.     

Ventral hernia synthetic mesh repair infected by Mycobacterium fortuitum.

We report the occurrence of a refractory infection caused by the "rapidly growing" nontuberculous mycobacterium, Mycobacterium fortuitum, after incisional hernia repair using synthetic mesh. The patient had previously undergone three herniorrhaphies incorporating polypropylene mesh. Multiple surgical debridements were required, along with complete removal of all the mesh, to eradicate the infection. Prolonged antimicrobial therapy with sulfamethoxazole, an agent active against the patient's isolate, was also used. Although this atypical mycobacterium has been reported to cause a variety of infections, including many types of periprosthetic infections, this case represents successful treatment of M. fortuitum infecting abdominal wall mesh.     

The effects of seasons and light therapy on G protein levels in mononuclear leukocytes of patients with seasonal affective disorder

BACKGROUND: Information-transducing heterotrimeric G proteins have been implicated previously in the mechanism of action of mood stabilizers and in the pathophysiology of mood disorders. Mononuclear leukocytes of patients with unipolar and bipolar depression have been characterized by reduced measures of the stimulatory and inhibitory G proteins. In this study, patients with seasonal affective disorder (SAD) were measured for mononuclear leukocyte G protein levels while depressed during the winter, following light therapy, and in remission during the summer. METHODS: Twenty-six patients with SAD and 28 healthy subjects were assessed in the study. The immunoreactivities of Gs alpha, Gi alpha, and Gbeta subunit proteins were determined by Western blot analysis of mononuclear leukocyte membranes with selective polyclonal antibodies for the various G subunit proteins, followed by densitometric quantitation using an image analysis system. RESULTS: Untreated patients with SAD and winter, atypical-type depression showed significantly reduced mononuclear leukocyte immunoreactive levels of Gs alpha and Gi alpha proteins, similar to previous observations in patients with nonseasonal major depression. The reduced G protein levels were normalized with 2 weeks of light therapy. The same patients while in remission during the summer had G protein levels that were similar to those of healthy subjects. CONCLUSIONS: G protein-immunoreactive measures in patients with SAD are suggested as a state marker for winter depression, which is normalized by light treatment and during the summer. We speculate that light may exert its effects via normalization of transducin (Gt protein) levels, which are thought to be reduced in winter depression.     

Family treatment for schizophrenia : the design and research application of therapist training models

The NIMH Treatment Strategies in Schizophrenia (TSS) collaborative study group investigated the efficacy of antisychotic drug maintenance strategies involving reduced medication exposure in interaction with applied and supportive family management for the long-term treatment of schizophrenia. Therapy was provided at five centers by 25 clinicians who did not participate in the development of the therapies. They were trained by two of the authors, I.R.H.F and C.W.M, in applied family management, a homebased treatment derived from the behavioral family therapy developed by them. Clinicians' characteristics, selection, and training methods, as well as patient rehospitalization rates, are reported for the two family management conditions. The TSS study represents a bridge between the development of a novel therapy and its dissemination in general clinical practice.     

Chronic (−)-isoprenaline infusion down-regulates β1- and β2-adrenoceptors but does not transregulate muscarinic cholinoceptors in rat heart

Regulation of -adrenoceptor (-ar) subtypes and transregulation of muscarinic cholinoceptors (mAchr) was examined in regions of rat heart after chronic infusion of (–)-isoprenaline (450 /kg per hour) for 14 days. Following (–)-isoprenaline infusion systolic blood pressure was reduced for 10 days but then gradually returned to control levels, whereas heart rate was increased for 7 days before declining to a level significantly above control. Heart weight to body weight ratio was increased in (–)-isoprenaline treated rats. -ar subtype densities were measured by quantitative autoradiography with [¹²⁵I]-cyanopindolol (CYP) in sinoatrial node (SA), atrioventricular node (AV), bundle of His (BH), left (LB) and right (RB) bundle branches, interventricular (IVS) and interatrial (IAS) septa, right atria (RA), apex (AX) and mitral valve (MV). ₁-ars were reduced by 59.1–74.2% in the AV conducting regions, 53.4% in the SA node and 43.3–53.4% in myocardial areas. ₂-ars were markedly reduced in myocardial regions (93.2–98.5%) and in pacemaker and conducting regions (87.7–97.8%). No changes in mAchr densities measured using [³H]-N-methyl scopolamine (NMS) occurred in the AV node, BH, LB, RB, IVS and IAS following (–)-isoprenaline infusion.Densities of ₁- and ₂-ars and mAchrs were also measured in ventricular homogenates from control and (–)-isoprenaline treated animals. -ar levels were significantly reduced (P < 0.05) in treated animals and the ratio of ₁- to ₂-ars increased after treatment. mAchr density in ventricular homogenates measured using either [³H]-NMS or [³H]-quinuclidinyl [phenyl-4-³H]benzilate (QNB) was unchanged. Homogenates of left and right ventricle also showed no change using [³H]-NMS.Organ bath studies were used to investigate the effect of (–)-isoprenaline infusion on negative inotropic and chronotropic effects of the non-selective muscarinic receptor agonist bethanechol in left and right atria, respectively. Lower concentrations of bethanechol (3 × 10^–10 to 10^–6 M) produced a negative inotropic response in isolated electrically driven left atria from (–)-isoprenaline treated rats, but not from control rats, with the slope of the curves being significantly different between groups (ANCOVA, P = 0.037). At concentrations of bethanechol from 10^–6 to 3 × 10^–4 M the negative inotropic response was not changed between (–)-isoprenaline treated and control animals. Bethanechol also produced a negative chronotropic response at lower concentrations (10^–10 to 10^–6 M) in (–)-isoprenaline treated rats, but not in controls. A second, steeper phase of the negative chronotropic response occurred at concentrations of bethanechol greater than 10^–6 M and was also seen in control rats.Expression of M₂ (cardiac) mAchrs (m₂Achr) in left and right ventricular tissues measured using a quantitative non-competitive polymerase chain reaction (PCR) assay showed a significant (P = 0.001) 28.5% increase in expression in left ventricle and a significant (P = 0.003) 21.5% decrease in expression in right ventricle after (–)-isoprenaline treatment, compared to controls. There was no significant difference in total ventricular m₂Achr expression between the two groups of rats. The results suggest that chronic -ar stimulation down-regulates both ₁- and ₂-ars, and appears to differentially transregulate m₂Achr expression, but not mAchr protein. Following (–)-isoprenaline infusion, muscarinic receptor mediated responses were sensitised, with no change in receptor densities, suggesting changes occur in the cell signalling system beyond the level of the receptor.