Effect of Dapagliflozin in DAPA-HF According to Background Glucose-Lowering Therapy

OBJECTIVETo determine whether the benefits of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF) and type 2 diabetes in the Dapagliflozin And Prevention of Adverse-Outcomes in Heart Failure trial (DAPA-HF) varied by background glucose-lowering therapy (GLT).RESEARCH DESIGN AND METHODSWe examined the effect of study treatment by the use or not of GLT and by GLT classes and combinations. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death.RESULTSIn the 2,139 type 2 diabetes patients, the effect of dapagliflozin on the primary outcome was consistent by GLT use or no use (hazard ratio 0.72 [95% CI 0.58–0.88] vs. 0.86 [0.60–1.23]; interaction P = 0.39) and across GLT classes.CONCLUSIONSIn DAPA-HF, dapagliflozin improved outcomes irrespective of use or no use of GLT or by GLT type used in patients with type 2 diabetes and HFrEF.     

Blood pressure and hypertension in middle-aged women in relation to weight and length at birth: a follow-up study

OBJECTIVES: To examine the relationship between indicators at birth and adult blood pressure and risk for developing hypertension at two age levels. DESIGN: Original midwife records of 438 women born at term participating in a prospective population study in G?teborg, Sweden with blood pressure and hypertension assessment at both 50 and 60 years of age. RESULTS: Systolic blood pressure at both age levels showed a U-shaped relationship to weight and length at birth. Hypertension prevalence at 60 years was significantly and inversely related to both weight and length at birth, but not at 50 years. Significantly higher risk for hypertension was found in the lowest birth weight quintile [odds ratio (OR) = 2.0, 95% confidence interval (CI) 1.1-3.8] and lowest birth length tertile (OR = 1.8, 95% CI 1.1-3.0), in relation to the middle quintile/tertile, with or without adjustment for adult body size (as body mass index), at 60 years but not at 50 years. At 50 years, hypertension risk decreased by 3% (95% CI 0.92-1.01) for every 100 g increase in birth weight and 6% (95% CI 0.83-1.05) per cm birth length. At age 60 years, hypertension risk decreased by 4% (95% CI 0.92-0.99) per 100 g birth weight and 10% (95% CI 0.81-0.99) per cm length. CONCLUSIONS: Size at birth was a predictor of hypertension risk in women at 60 years but not 50 years. This study supports the hypothesis that poor fetal growth, as measured by low weight or length at birth, may contribute to the development of hypertension in later life and that this relationship became stronger with age.     

Serotonin metabolism in the central nervous system following sepsis or portacaval shunt in the rat

Similar neurological disturbances and metabolic alterations have been observed in liver insufficiency and in bacterial sepsis. In both liver failure and sepsis an altered neurotransmitter profile in the central nervous system (CNS) has been implicated in the pathogenesis of encephalopathic symptoms. It has been suggested that equivalent disturbances in brain neurotransmitters, especially serotonin, play a role in the encephalopathy accompanying sepsis and liver failure. The objective of this study was to compare the CNS serotonin metabolism in rats with an end-to-side portacaval shunt (PCS) with that found in rats with 12 or 24 hr of intraabdominal sepsis. The metabolism of CNS serotonin was estimated after inhibition of two enzymes acting in the 5-hydroxyindole synthetic pathway (decarboxylase and monoamine oxidase). The 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined in different regions of the CNS, thereby permitting evaluation of the synthetic activity of the serotonin neurotransmitter system. As previously reported, a marked increase in CNS serotonin synthetic rate was noted following PCS. In contrast, and in contradistinction to several recent reports, no major changes in the CNS serotonin synthesis rate were present following 12 or 24 hr of sepsis. CNS levels of the serotonin metabolite 5-HIAA were elevated in both sepsis and PCS rats. These data indicate that sepsis and liver failure have different effects upon serotonin metabolism in the CNS and suggest that differing pathogenetic mechanisms may underlie the encephalopathy clinically associated with these conditions.     

AMP-activated protein kinase activation by adrenoceptors in L6 skeletal muscle cells: mediation by alpha1-adrenoceptors causing glucose uptake

AMP-activated protein kinase (AMPK), which functions as a sensor of cellular energy homeostasis, was phosphorylated after norepinephrine stimulation in L6 skeletal muscle cells. This effect was mediated by alpha1-adrenoceptors, with no stimulatory effects due to interactions at alpha2- or beta-adrenoceptors. Alpha1-adrenoceptors are Gq-coupled receptors, and calcium but not phorbol esters could mimic the effect of alpha1-adrenergic stimulation; and we show that protein kinase C is not involved as an upstream signal to AMPK by alpha1-adrenergic stimulation and that the AMP-to-ATP ratio is unaltered after alpha1-adrenergic stimulation. We further show that glucose uptake mediated by alpha1- but not by beta-adrenoceptors can be inhibited by AMPK inhibition. Acetyl-CoA carboxylase (ACC) is phosphorylated at Ser218 by AMPK, and alpha1- but not beta-adrenoceptor stimulation results in phosphorylation of ACC at this residue. These results suggest a novel pathway where alpha1-adrenoceptor activation, independent of protein kinase C, leads to activation of AMPK in skeletal muscle, which contributes to alpha1-adrenoceptor-mediated increases in glucose uptake.     

Test–retest variability for standard automated perimetry and short‐wavelength automated perimetry in diabetic patients

Purpose: To assess limits for significant improvement or deterioration of visual fields in diabetic patients based on short‐term test–retest variability in subjects with different degrees of retinopathy. Methods: Fifty patients with diabetic retinopathy ranging from level 10 to 75 [according to the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale] were tested repeatedly with both standard automated perimetry (SAP) and short‐wavelength automated perimetry (SWAP) with short intervals. The association between visual field loss and degree of retinopathy outside fovea was analysed. Test–retest variability of global and local visual field indices and prediction limits for significant change were calculated. Results: The amount of visual field loss was significantly associated to the degree of retinopathy, with a correlation coefficient of ?0.51 for SAP (P = 0.0003) and ?0.45 for SWAP (P = 0.002). Global test–retest variability was smaller with SAP than with SWAP (P < 0.0001). For both SAP and SWAP, local test–retest variability was considerably smaller at test points with normal sensitivity than at test points with reduced sensitivity (P < 0.0001). Paracentral test points within 10° of eccentricity had less variability than peripheral points (P < 0.0001), implying that smaller change is required to reach statistically significant improvement or deterioration at initially normal and paracentral points than at depressed points and peripherally located test points. Conclusion: Our results propose that SAP, as well as SWAP, can be useful for monitoring visual function outside fovea in diabetic patients with various degrees of retinopathy. We report a preference for SAP because of less variability generally. Limits for significant improvement or deterioration have been assessed but need future validation in a longitudinal study.     

The activity of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system in relation to waist/hip circumference ratio in men

OBJECTIVE: To investigate possible differences, between generally and abdominally obese men, in activity and regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. RESEARCH METHODS AND PROCEDURES: Fifty non-diabetic, middle-aged men were selected to obtain two groups with similar body mass index (BMI) but different waist/hip circumference ratio (WHR). Measurements were performed of the activity of the HPA axis and the sympathetic nervous system, as well as metabolic and endocrine variables. RESULTS: Men with a high WHR, in comparisons with men with a low WHR, had higher insulin, glucose, and triglyceride values in the basal state and higher glucose and insulin after an oral glucose tolerance test. Men with high WHR had elevated diurnal adrenocorticotropic hormone (ACTH) values but similar cortisol values, except lower cortisol values in the morning. Diurnal growth hormone concentrations showed reduced peak size. Stimulation of the HPA axis with corticotropin-releasing hormone (CRH) and laboratory stress showed no difference in ACTH values between groups, but cortisol values were lower in men with high WHR. In comparison with men with a low WHR, men with a high WHR had elevated pulse pressure and heart rate in the basal state and after challenges by CRH and laboratory stress. They also had increased urinary excretion of catecholamine metabolites. DISCUSSION: These results suggest a mild dysregulation of the HPA axis, occurring with elevated WHR independent of the BMI. The results also indicate a central activation of the sympathetic nervous system, such as in the early phases of hypertension, correlating with insulin resistance.     

Autologous bone marrow transplantation in children with acute lymphoblastic leukemia

We report 25 children with acute lymphoblastic leukemia (ALL) treated with purged autologous bone marrow transplantation (ABMT) at a single center. Two children with high-risk ALL were transplanted in first remission and 23 with relapsing ALL were transplanted in second (n = 21) or third (n = 2) remission. There was no procedure-related mortality. The median time to engraftment (i.e. to reach a polymorphonuclear cell count of 0.5 x 10(9)/l) was 25 days (range 16-45 days). Seven children relapsed, four within five months after ABMT: 18 of 25 children (72%) are in continuous complete remission after a median follow-up period of 50 months (range 5-71 months). The predicted long-term disease-free survival is 65% in the whole group and 61% in those transplanted after relapse. Relapse-free children returned to normal activities within three months after ABMT. The major side effects were development of cataract and gonadal insufficiency. We consider the results promising, but our data do not allow comparison with results reported from treatment with chemotherapy alone, since some of our patients were referred from other centers and represent a selected patient group. Long-term follow-up of well-defined patient populations is necessary to evaluate the effect of ABMT.     

Optic disc hemorrhages and generalized vascular disease

PURPOSE: To study the relationship between optic disc hemorrhages and four different groups of medications used in general vascular disease and diabetes. METHODS: The authors screened citizens of the city of Malm?, Sweden who were between 57 and 79 years old (32,918 subjects), in order to find individuals with undetected glaucoma. One set of optic disc photographs was taken of each participant and examined for optic disc hemorrhages. Logistic regression was used, with platelet aggregation inhibitors, antihypertensive agents, cholesterol-lowering medication, and antidiabetic agents as independent variables that were tested in isolation as well as in various combinations and adjusted for age and gender. RESULTS: Optic disc hemorrhages were significantly more common in individuals taking platelet aggregation inhibitors (OR 3.16, P < 0.0001). There was no significant association between ODH and the other three groups of medications. CONCLUSIONS: The significant relationship between platelet aggregation inhibitors and optic disc hemorrhages is a new and interesting finding that could indicate an association between optic disc hemorrhages and generalized vascular disease. Alternatively, it could mean that platelet aggregation inhibitors prolong resorption of or predispose to optic disc hemorrhages.