Impact of gender on relative rates of cardiovascular events in patients with diabetes

AimTo investigate whether diabetes confers higher relative risks of cardiovascular events in women compared with men using contemporary data and also whether such gender-differences are dependent on age.MethodsAll patients discharged from French hospitals in 2013 with at least 5 years of follow-up and no history of major adverse cardiovascular events including heart failure (MACE-HF; heart failure, myocardial infarction, ischaemic stroke, cardiovascular death) were identified and categorized by diabetes status. Overall and age-stratified incidence rates, hazard ratios (HRs) and women-to-men ratios (WMRs) for MACE-HF leading to hospitalization were also calculated. Adjustments were then made for age and baseline characteristics according to cardiovascular risk factors and non-cardiovascular comorbidities.ResultsThe study included 2,953,816 subjects, among whom 349,928 (11.9%) had diabetes. Of those with diabetes, the absolute rate of MACE-HF was higher in men than in women (96 vs 66 per 1000 person-years); corresponding absolute rates in men and women without diabetes were 44 vs 27 per 1000 person-years. Comparing those with and without diabetes, women had a higher unadjusted HR of MACE-HF (2.45, 95% CI: 2.42–2.47) than men (2.15, 95% CI: 2.14–2.17), with an adjusted WMR of 1.13 (95% CI: 1.12–1.15). HRs of MACE-HF related to diabetes were highest in women aged around 45 years and in the youngest men and decreased with advancing age in both these groups. However, HRs were higher in women of all ages > 40 years. After adjustment, this effect was more apparent for myocardial infarction (adjusted WMR: 1.43, 95% CI: 1.38–1.48) than for either ischaemic stroke (adjusted WMR: 1.10, 95% CI: 1.07–1.14) or heart failure (adjusted WMR: 1.13, 95% CI: 1.11–1.14).ConclusionAlthough men have higher absolute risks of cardiovascular complications, the relative risks of cardiovascular complications associated with diabetes are higher in women than in men.     

Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway

Myotubular myopathy (MTM1) is an X-linked disease, characterized by severe neonatal hypotonia and generalized muscle weakness, with pathological features suggesting an impairment in maturation of muscle fibres. The MTM1 gene encodes a protein (myotubularin) with a phosphotyrosine phosphatase consensus. It defines a family of at least nine genes in man, including the antiphosphatase hMTMR5/Sbf1 and hMTMR2, recently found mutated in a recessive form of Charcot-Marie-Tooth disease. Myotubularin shows a dual specificity protein phosphatase activity in vitro. We have performed an in vivo test of tyrosine phosphatase activity in Schizosaccharomyces pombe, indicating that myotubularin does not have a broad specificity tyrosine phosphatase activity. Expression of active human myotubularin inhibited growth of S.pombe and induced a vacuolar phenotype similar to that of mutants of the vacuolar protein sorting (VPS) pathway and notably of mutants of VPS34, a phosphatidylinositol 3-kinase (PI3K). In S.pombe cells deleted for the endogenous MTM homologous gene, expression of human myotubularin decreased the level of phosphatidylinositol 3-phosphate (PI3P). We have created a substrate trap mutant which shows relocalization to plasma membrane projections (spikes) in HeLa cells and was inactive in the S.pombe assay. This mutant, but not the wild-type or a phosphatase site mutant, was able to immunoprecipitate a VPS34 kinase activity. Wild-type myotubularin was also able to directly dephosphorylate PI3P and PI4P in vitro. Myotubularin may thus decrease PI3P levels by down-regulating PI3K activity and by directly degrading PI3P.     

Expression of idiotypic antibodies-1 and -2 and breastfeeding in relation to antibody levels against Haemophilus influenzae type B in children

The aim of the study was to determine the concentrations of serum antibodies against Haemophilus influenzae type b in preschool children in relation to the distribution of idiotypic antibodies 1 and 2 (Id-1 and Id-2) and the exposure to breastfeeding in infancy. Sera were obtained from 74 control children recruited in an earlier case-control study before the introduction of general Hib vaccination. Duration of breastfeeding was monitored, and prevalence of noninvasive infections was registered. Concentrations of IgG1 and IgG2 anti-Hib, as well as of total Id-1 and Id-2, were determined in ELISA. The expression of Id-1 antibodies increased with age in contrast to the Id-2 antibodies that were found only in children up to 24 months of age. Expression of Id-1 antibodies was positively correlated with higher anti-Hib levels of both the IgG1 and IgG2 isotype. Children expressing Id-2 antibodies showed higher IgG2 anti-Hib concentrations than those who did not have Id-2 (P = 0.001). The concentrations of neither Id-1 nor Id-2 antibodies were related to the duration of breastfeeding. Duration of breastfeeding was related to increased anti-Hib IgG2 in healthy children above 18 months of age. These study shows that the expression of idiotype-1 and idiotype-2 antibodies was associated with higher IgG2 anti-Hib concentration and that breastfeeding could enhance the anti-Hib IgG2 production in children.     

Chromatographic screening for zopiclone and metabolites in urine using liquid chromatography and liquid chromatography-mass spectrometry techniques

Zopiclone is a benzodiazepine-like hypnotic that was believed not to have any abuse potential. Nevertheless, during the past few years there have been an increasing number of reports on the abuse and misuse of zopiclone. Despite this, methods for screening analysis in urine are lacking. To investigate whether UV detection would be possible to use for this purpose, a liquid chromatography method with ultraviolet detection for analyzing zopiclone and its urinary metabolites was developed, with liquid chromatography-mass spectrometry for confirmation. The method was used for analyzing samples from subjects receiving methadone. The limits of detection were approximately 100 ng/mL in control urine samples and 500 ng/mL in urine samples from subjects receiving methadone. However, due to the high background in these patients' urine, a single therapeutic dose was impossible to detect.     

Multiple injections of coloured microspheres for islet blood flow measurements in anaesthetised rats: influence of microsphere size

We investigated if coloured microspheres could be used for repeated measurements of pancreatic islet blood flow in rats. An initial injection of 1.0-1.5 x 10(5) microspheres (black colour), with a size of 10 or 15 microm, was made into the ascending aorta, while an arterial reference sample was collected from the femoral artery. Twelve min later, 1 ml of saline or 30% D-glucose was injected intravenously. Three min after this injection a second injection of 10- or 15-microm microspheres (green colour) was given. The animals were then killed, and the pancreas and adrenals were removed and samples (150-200 mg) were secured from the duodenum, ileum, colon, right kidney and liver. The microsphere contents were determined with the aid of a freeze-thawing technique and blood flow values were calculated. Our results suggest that 10-microm microspheres, but not 15-microm microspheres, provide reproducible islet and total pancreatic blood flow measurements when repeatedly injected. Values for the blood flow to the intestines, kidney and liver were less sensitive to the size of the microspheres. We conclude that repeated administration of 15-microm microspheres induces a high risk for erroneous islet and total pancreatic blood flow measurements, whereas two such measurements can be performed if 10-microm microspheres are used.     

A systematic review of the peripheral analgesic effects of intraarticular morphine

The analgesic effects of intraarticular morphine are controversial. To systematically evaluate the effects, we performed a review of the literature and a metaanalysis of the peripheral effects of morphine injected intraarticularly. Research databases were searched to identify articles in which peripheral analgesic effects of morphine were studied in patients undergoing arthroscopic knee procedures under local, regional, or general anesthesia. The review was performed on three issues: does morphine injected intraarticularly produce analgesia, is it a dose-dependent effect, and, if so, is the effect systemic or mediated via peripheral opioid receptors? Visual analog score (VAS) and analgesic consumption were studied during the early phase (0-2 h), intermediate phase (2-6 h), and late phase (6-24 h) postoperatively after injection of morphine intraarticularly. Metaanalysis of these effect variables was performed by the weighted-analysis technique, and the essential homogeneity assumption was tested by the chi(2) test. Forty-five articles could be identified in which the effects of morphine were studied in a prospective, randomized manner, and 32 of these studies included a placebo control. Pooled analyses of data from 19 studies suitable for metaanalysis showed an improvement in analgesia after morphine compared with placebo in the order of 12-17 mm on the VAS during all three phases of treatment. Studies with high quality scores showed somewhat smaller improvements. Total analgesic consumption could not be analyzed statistically, but the number of studies showing decreased analgesic consumption or no differences between groups was identical (six and six). No clear dose-response effect was seen when VAS was used as a measure of pain, but it was seen when area under the curve was used as a measure of pain. A systemic effect of peripherally-injected morphine was not possible to exclude because of the very limited data available. We conclude from this metaanalysis that intraarticularly administered morphine has a definite but mild analgesic effect. It may be dose dependent, and a systemic effect cannot be completely excluded.     

Treatment, long-term outcome and prognostic variables in 214 unselected AML patients in Sweden

With the aim of describing an unselected series of acute myeloid leukaemias (AML) in adults, patients diagnosed 1987-1992 in the Orebro region of central Sweden were reviewed by investigating hospital records. By utilizing: (1) The Swedish Cancer Registry, (2) The Cause of Death Registry, (3) listings of pathology bone marrow reports and (4) listings of inpatient discharge diagnoses, we attempted to find all patients. Among secondary AML, only blast-crises of CML were excluded. A total of 214 cases of AML with a median age of 69.5 years were verified corresponding to a mean yearly incidence in adults of 5.4/100 000. Of all patients, 56% had received 'high-dose' induction treatment, 28% 'low-dose' treatment and 16% no cytostatic treatment. Median survival for all patients was 5.8 months and the probability of survival at 5 years was 9.3%. The 120 'high-dose' treated patients had a total CR rate of 67%, median CR duration 10.1 months and median survival 11.4 months. Age, LDH and kidney function were found to be independent prognostic variables for survival. The inclusion of patients unreferred from district hospitals makes this study unique as an example of unselected AML.