Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs

Aims/hypothesis  

Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes.     

Diet-induced metabolic change induces estrogen-independent allometric mammary growth

Lifetime breast cancer risk reflects an unresolved combination of early life factors including diet, body mass index, metabolic syndrome, obesity, and age at first menses. In parallel, the onset of allometric growth by the mammary glands around puberty is widely held to be estrogen (E)-dependent. Here we report that several physiological changes associated with metabolic syndrome in response to a diet supplemented with the trans-10, cis-12 isomer of conjugated linoleic acid lead to ovary-independent allometric growth of the mammary ducts. The E-independence of this diet-induced growth was highlighted by the fact that it occurred both in male mice and with pharmacological inhibition of either E receptor function or E biosynthesis. Reversal of the metabolic phenotype with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone abrogated diet-induced mammary growth. A role for hyperinsulinemia and increased insulin-like growth factor-I receptor (IGF-IR) expression during mammary growth induced by the trans-10, cis-12 isomer of conjugated linoleic acid was confirmed by its reversal upon pharmacological inhibition of IGF-IR function. Diet-stimulated ductal growth also increased mammary tumorigenesis in ovariectomized polyomavirus middle T-antigen mice. Our data demonstrate that diet-induced metabolic dysregulation, independently of ovarian function, stimulates allometric growth within the mammary glands via an IGF-IR-dependent mechanism.Epidemiological data consistently point to an early window of breast development as being sensitive to breast cancer risk factors associated with diet (1), body mass index (BMI) (2), obesity (3), and age at onset of puberty (4). This increased risk may reflect precocious breast development due to an earlier age at puberty (5) as a result of the obesity pandemic (6). However, lines of evidence indicate that this window is before the onset of puberty and first menses and is independent of ovarian function and increased BMI (7). Indeed, several studies point to a period of <10 y of age that confers the greatest risk to radiation-induced breast cancer (8), consistent with the fact that prepubescent female rats are most susceptible to chemical-induced mammary tumorigenesis (9). A role for diet during this period is highlighted by the fact that only girls who were 2–9 y old during the Dutch famine had an increased lifetime risk of developing breast cancer (10). Furthermore, data from a recent prospective study indicate that girls with a low BMI are at a greater risk for developing benign breast disease (11). Combined, lines of evidence such as these point to an early window of breast development before the onset of puberty that could be sensitive to one or more dietary components or diet-induced metabolic change.The majority of mammary gland (MG) development occurs during postnatal life and primarily initiates with a phase of allometric growth around the onset of puberty that results in extension of the ductal network from the nipple into the surrounding adipose stroma (12). This allometry is widely held to commence in response to the synthesis and secretion of estrogen (E) by the ovaries (13), where ovariectomy ablates ductal elongation (12) whereas E copotentiates the actions of growth hormone (GH) and its stroma-derived paracrine mediator, insulin-like growth factor-I (IGF-I) (14). Much of this regulation is conferred by the surrounding adipose microenvironment of the mammary fat pad, which itself is modified by diet and developmental state (15).Major clinical signs of metabolic syndrome include impaired insulin signaling associated with visceral adiposity, dyslipidemia, hypertension, and inflammation (16), where hepatic steatosis separately from obesity may more accurately correlate with impaired insulin signaling (17). A diet-dependent model that recapitulates many aspects of the metabolic syndrome involves feeding rodents the trans-10, cis-12 isomer of conjugated linoleic acid (10,12 CLA), an octadecadienoic fatty acid that is present in foodstuffs either due to the hydrogenation of vegetable oils (18) or at low levels due to biohydrogenation in ruminants (19). When 10,12 CLA is fed to mice, it dysregulates metabolic function coincident with lipoatrophy, transient hypertriglyceridemia, adipose tissue inflammation, hepatic steatosis, and hyperinsulinemia (20–22). The lipoatrophic effect of 10,12 CLA has led to its widespread adoption as a weight-loss supplement (23) that gives rise to elevated plasma triacylglycerol and LDL:HDL cholesterol levels (24). This collection of phenotypes induced by dietary 10,12 CLA therefore provides a useful and defined model of metabolic disruption for studying its effects on MG growth.Here we report that early allometric growth in the MG of mice occurs independently of estrogenic stimulation following diet-induced metabolic changes resulting from ingestion of 10,12 CLA. These data highlight not only that E-independent allometric growth of the mammary ducts is induced by a dietary component, but also that aspects of the metabolic syndrome elicit this growth, which may increase E-independent breast cancer risk.     

Comparison of patellar resurfacing versus nonresurfacing in total knee arthroplasty.

OBJECTIVES: To determine whether resurfacing the patellar component during total knee replacement (TKR) influences the clinical outcome. DESIGN: A retrospective study of data gathered prospectively during the recovery course of patients who underwent TKR with or without patellar resurfacing. SETTING: Victoria General Hospital, Halifax, NS. PATIENTS: One hundred and eighty-five patients operated on between 1992 and 1995. The inclusion criteria were (a) osteoarthritis, (b) replacement carried out by 2 independent surgeons, (c) no comorbid illness such as rheumatoid arthritis, cancer or infection, (d) pre- and postoperative attendance at the assessment clinics. INTERVENTION: TKR with (45) or without (140) patellar replacement. MAIN OUTCOME MEASURES: Range of motion (ROM), pain assessment, Hospital Severity Score (HSS) and complications. RESULTS: There was no statistical difference between the 2 groups with respect to ROM, pain, HSS and complications postoperatively. CONCLUSIONS: Resurfacing the patella during TKR does not seem to influence the clinical outcome with respect to ROM, pain and overall complications. The decision should be based on individual criteria, depending on the preoperative and intraoperative findings. Randomized clinical trials assessing ROM, pain, complications and cost-effectiveness with long-term follow-up are necessary to further investigate this controversial issue.     

Increase coverage of HIV and AIDS services in Myanmar

Myanmar is experiencing an HIV epidemic documented since the late 1980s. The National AIDS Programme national surveillance ante-natal clinics had already estimated in 1993 that 1.4% of pregnant women were HIV positive, and UNAIDS estimates that at end 2005 1.3% (range 0.7–2.0%) of the adult population was living with HIV. While a HIV surveillance system has been in place since 1992, the programmatic response to the epidemic has been slower to emerge although short- and medium-terms plans have been formulated since 1990. These early plans focused on the health sector, omitted key population groups at risk of HIV transmission and have not been adequately funded. The public health system more generally is severely under-funded.     

Possible interaction of genotypes at cystathionine β-synthase and methylenetetrahydrofolate reductase (MTHFR) in neural tube defects

Neural tube defects are a common, complex disorder with genetic and environmental components to risk. We investigated the previously reported interaction between homozygosity for the thermolabile variant at the methylenetetrahydrofolate reductase and heterozygosity for the 844ins68 allele at the cystathionine beta-synthase loci in cases with lumbosacral myelomeningocele and their parents. Using control allele frequencies from our sample pooled with those published in the literature, we confirm a marginally significant interaction at these two loci. This finding suggests that additional, larger studies are warranted to investigate this possible interaction in more detail.     

Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: This study sought to determine whether metformin improves vascular function or myocardial ischemia in nondiabetic subjects. BACKGROUND: Metformin prevents diabetes and may reduce coronary events in patients with diabetes, but effects on microvascular function and angina are not clear. METHODS: We conducted an 8-week double-blind, randomized, placebo-controlled study of metformin 500 mg twice a day in 33 nondiabetic women with a prior history of normal coronary angiography but two consecutive positive (ST-segment depression > or =1 mm) exercise tolerance tests. All parameters were measured at baseline and at 8 weeks, together with an in vivo assessment of forearm (skin) microvascular function using laser Doppler imaging combined with iontophoresis. RESULTS: In comparison with placebo (n = 17), metformin recipients (n = 16) showed significant reductions in weight and in homeostatic model assessment for insulin resistance (p < 0.05, intention to treat). Endothelium-dependent microvascular responses improved significantly with metformin (2-way repeated analysis of variance, p = 0.0003), but responses with placebo were unchanged (p = 0.50). A comparison of change in acetylcholine responses between metformin and placebo recipients was significant, whether analyzed by a 2-way analysis of variance (p < 0.0001) or change in area under curves (mean change +392 perfusion units, 95% confidence interval [CI] 20 to 764). Endothelium-independent responses were not altered. Maximal ST-segment depression (-0.84 mm, 95% CI -1.49 to -0.20, p = 0.013), Duke score (6.1 U, 95% CI 1.8 to 10.5, p = 0.008), and chest pain incidence (-0.11 episodes/day, 95% CI -0.22 to 0.00, p = 0.056) improved in metformin relative to placebo recipients. CONCLUSIONS: Metformin may improve vascular function and decrease myocardial ischemia in nondiabetic women with chest pain and angiographically normal coronary arteries. Larger controlled trials of longer duration are warranted.     

NIA0004Unsaturated fatty acids diminish the detrimental effects of saturated fatty acids on insulin signalling in human muscle by decreasing de novo ceramide production

Insulin resistance in skeletal muscle is associated with impaired oxidative capacity and reduced size, number and function of mitochondria. Insulin‐resistant individuals have lower adiponectin concentrations, a characteristic predating the development of type‐2 diabetes (T2D). The aim of this study was to test the potential role of adiponectin in mitochondrial bioenergetics in individuals predisposed to develop T2D, in adiponectin KO mice and in primary muscle cell culture. Individuals with a family history of T2D displayed lower plasma adiponectin concentration (P = 0.03), reduced PGC1β (P = 0.04) and mtFAM (P = 0.03) mRNA, lower mitochondrial content (P = 0.006), citrate synthase (P = 0.02) and (‐HAD (P = 0.03) activity, suggesting defective mitochondrial bioenergetics in skeletal muscle. In addition, AdipoR1 was the principle correlate of mitochondrial content (r² = 0.81), suggesting an important role in mitochondrial biogenesis. Knock out of adiponectin in mice was associated with low PGC1α and PPARδ mRNA (both, P < 0.05), reduced mitochondrial content (P < 0.05) and COX II activity (P < 0.05) and markers for type‐1 oxidative fibers in skeletal muscle. This suggests that mitochondrial function is dependent on circulating adiponectin. In primary cultures of human myotubes, treatment with adiponectin induced AMPKK/ AMPK activity, PGC1α protein, mitochondrial biogenesis (P < 0.05), palmitate oxidation (P < 0.05), citrate synthase (P < 0.05) and SOD activity (P < 0.05), and reduced mitochondrial membrane potential and the production of ROS (P < 0.05). The inhibition of adiponectin receptor expression by siRNA or of AMPK by a pharmacological agent blunted the induction in mitochondrial function. Our findings indicate a novel pathway in skeletal muscle by which adiponectin increase mitochondrial number and function and exerts an insulin sensitizing effect.