Effect of Acute Negative and Positive Energy Balance on Basal Very-Low Density Lipoprotein Triglyceride Metabolism in Women

Background

Acute reduction in dietary energy intake reduces very low-density lipoprotein triglyceride (VLDL-TG) concentration. Although chronic dietary energy surplus and obesity are associated with hypertriglyceridemia, the effect of acute overfeeding on VLDL-TG metabolism is not known.

Objective

The aim of the present study was to investigate the effects of acute negative and positive energy balance on VLDL-TG metabolism in healthy women.

Design

Ten healthy women (age: 22.0±2.9 years, BMI: 21.2±1.3 kg/m²) underwent a stable isotopically labeled tracer infusion study to determine basal VLDL-TG kinetics after performing, in random order, three experimental trials on the previous day: i) isocaloric feeding (control) ii) hypocaloric feeding with a dietary energy restriction of 2.89±0.42 MJ and iii) hypercaloric feeding with a dietary energy surplus of 2.91±0.32 MJ. The three diets had the same macronutrient composition.

Results

Fasting plasma VLDL-TG concentrations decreased by ∼26% after hypocaloric feeding relative to the control trial (P = 0.037), owing to decreased hepatic VLDL-TG secretion rate (by 21%, P = 0.023) and increased VLDL-TG plasma clearance rate (by ∼12%, P = 0.016). Hypercaloric feeding increased plasma glucose concentration (P = 0.042) but had no effect on VLDL-TG concentration and kinetics compared to the control trial.

Conclusion

Acute dietary energy deficit (∼3MJ) leads to hypotriglyceridemia via a combination of decreased hepatic VLDL-TG secretion and increased VLDL-TG clearance. On the other hand, acute dietary energy surplus (∼3MJ) does not affect basal VLDL-TG metabolism but disrupts glucose homeostasis in healthy women.     

Lifestyle intervention leading to moderate weight loss normalizes postprandial triacylglycerolemia despite persisting obesity

Obesity is associated with impaired postprandial triacylglycerolemia, an independent risk factor for cardiovascular disease. Given that obesity is hard to treat, efforts should focus on treating its comorbidities. We aimed to investigate whether moderate weight loss normalizes postprandial triacylglycerol (TAG) concentrations, in the absence of the acute effects of negative energy balance. For this purpose, postprandial lipemia was investigated in eight obese but otherwise healthy, sedentary men (age: 41.3 ± 4.1 years, BMI: 36.5 ± 1.6 kg·m(-2)), once before and again after a 10% weight loss followed by ≥4 weeks of weight maintenance, and was compared with that of eight age-matched healthy lean men (BMI: 24.7 ± 0.6 kg·m(-2)). Dietary intervention consisted of reduced carbohydrate and saturated fat intake and increased monounsaturated fat intake. Obese volunteers were advised to increase physical activity using pedometers to record daily activity. Postprandial triacylglycerolemia after weight loss was reduced by 27-46% (P < 0.05), and became similar to that of lean men despite persisting obesity (BMI after weight loss: 32.9 ± 1.5 kg·m(-2)). Reduction in postprandial TAG responses was inversely correlated with the decrease in postprandial insulin sensitivity index (ISI) after weight loss (r = -0.714, P = 0.047). We conclude that moderate weight loss induced by a low-carbohydrate and saturated fat diet and a slight increase in daily physical activity normalizes postprandial triacylglycerolemia in obese men, independently of acute diet-induced negative energy balance, and possibly through enhancement of insulin action.     

The inhibition of tryptophan hydroxylase, not protein synthesis, reduces the brain trapping of α-methyl-l-tryptophan: an autoradiographic study

The effects of the tryptophan hydroxylase (TPH) inhibitor p-chlorophenylalanine (PCPA; 200mg/kg; 3 days), and of the protein synthesis inhibitor cycloheximide (CXM, 2mg/kg), on regional serotonin (5-HT) synthesis were studied using the alpha-[14C]methyl-L-tryptophan (alpha-[14C]MTrp) autoradiographic method. The objectives of these investigations were to evaluate the changes, if any, on 5-HT synthesis, as measured with alpha-MTrp method, following the inhibition of TPH by PCPA, or the inhibition of proteins synthesis by CXM. The rats were used in the tracer experiment approximately 24h after the last dose of PCPA was administered, and in the CXM experiments, they were used 30 min following a single injection of CXM. In both experiments, the control rats were injected with the same volume of saline (0.5 ml/kg; s.c.) and at the same times as the drug injections. The results demonstrate that trapping of alpha-MTrp, which is taken to be related to brain 5-HT synthesis, is drastically reduced (40-80%) following PCPA treatment. The inhibition of protein synthesis with CXM did not have a significant effect on the global brain trapping of alpha-MTrp and 5-HT synthesis. These findings suggest that the brain trapping of alpha-[14C]MTrp relates to brain 5-HT synthesis, but not to brain protein synthesis.     

Sexual risk behaviour of Canadian participants in the first efficacy trial of a preventive HIV-1 vaccine

Background

Phase I and phase II HIV-1 vaccine trials have revealed increases in risky sexual activity among study subjects during the trials, perhaps because the subjects believe that the vaccine being tested is efficacious; subjects may thus suffer harm from their participation. We evaluated the sexual behaviour of Canadian men who have sex with men (MSM) who participated in the phase III Vax004 trial of an HIV-1 vaccine.

Methods

Using self-reports of sexual behaviours during the 6 months before trial entry as a baseline, we determined changes in reported sexual behaviour after 6, 12 and 18 months of participation in the trial.

Results

Of 291 HIV-seronegative MSM enrolled from July to October 1999, 260 (89%) completed 18 months of follow-up, 19 (7%) experienced seroconversion, and 12 (4%) did not complete follow-up. Unprotected receptive anal intercourse during the previous 6 months with partners whose HIV-1 serostatus was positive or unknown was reported by 21% of men at enrolment and by 27% at any point during 18 months of follow-up. No increase in this behaviour from baseline was reported by participants, including among men who were motivated to enrol because of expected protection from HIV-1 infection, men who believed they had received the vaccine, men who believed that the vaccine had greater than 50% efficacy, or men who believed that they had received the vaccine and that vaccine efficacy was greater than 50%.

Interpretation

MSM can be successfully enrolled in HIV-1 vaccine efficacy trials without evident increases in those sexual behaviours most associated with HIV-1 risk.Development of preventive HIV-1 vaccines requires clinical trials that effectively recruit, enrol and retain high-risk subjects, including men who have sex with men (MSM). Since candidate vaccines may prove to have little or no efficacy, these trials must also strive to minimize harms associated with participation. A major concern has been that trial participants might believe vaccination affords some protection and therefore increase their sexual risk-taking.^1,2 This concern derives in part from increases in unprotected anal intercourse observed during phase I and phase II vaccine trials. For example, self-reports of unprotected insertive anal intercourse during the previous 6 months increased among 44 gay men enrolled in San Francisco trials, from 9% at enrolment to 20% at the 12-month assessment; however, the HIV status of sexual partners was not assessed.¹ The world''s first phase III trial to evaluate a candidate preventive HIV-1 vaccine was recently completed in North America and Europe.² A consortium sponsored by the Canadian Network for Vaccines and Immunotherapeutics of Cancer and Chronic Viral Diseases (CANVAC) was formed to assess participation, retention and change in sexual risk behaviour at trial sites in this country. We report here the Canadian experience in this trial through 18 months of follow-up and assess trends in high-risk sexual behaviour reported by participants.     

Effects of Proportions of Dietary Macronutrients on Glucocorticoid Metabolism in Diet-Induced Obesity in Rats

Tissue glucocorticoid levels in the liver and adipose tissue are regulated by regeneration of inactive glucocorticoid by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and inactivation by 5α- and 5β-reductases. A low carbohydrate diet increases hepatic 11β-HSD1 and reduces glucocorticoid metabolism during weight loss in obese humans. We hypothesized that similar variations in macronutrient proportions regulate glucocorticoid metabolism in obese rats. Male Lister Hooded rats were fed an obesity-inducing ad libitum ‘Western’ diet (37% fat, n = 36) for 22 weeks, then randomised to continue this diet (n = 12) or to switch to either a low carbohydrate (n = 12) or a moderate carbohydrate (n = 12) diet for the final 8 weeks. A parallel lean control group were fed an ad libitum control diet (10% fat, n = 12) throughout. The low and moderate carbohydrate diets decreased hepatic 11β-HSD1 mRNA compared with the Western diet (both 0.7±0.0 vs 0.9±0.1 AU; p<0.01), but did not alter 11β-HSD1 in adipose tissue. 5α-Reductase mRNA was increased on the low carbohydrate compared with the moderate carbohydrate diet. Compared with lean controls, the Western diet decreased 11β-HSD1 activity (1.6±0.1 vs 2.8±0.1 nmol/mcg protein/hr; p<0.001) and increased 5α-reductase and 5β-reductase mRNAs (1.9±0.3 vs 1.0±0.2 and 1.6±0.1 vs 1.0±0.1 AU respectively; p<0.01) in the liver, and reduced 11β-HSD1 mRNA and activity (both p<0.01) in adipose tissue. Although an obesity-inducing high fat diet in rats recapitulates the abnormal glucocorticoid metabolism associated with human obesity in liver (but not in adipose tissue), a low carbohydrate diet does not increase hepatic 11β-HSD1 in obese rats as occurs in humans.     

High Uptake of HIV Testing in Pregnant Women in Ontario,Canada

In 1999, Ontario implemented a policy to offer HIV counseling and testing to all pregnant women and undertook measures to increase HIV testing. We evaluated the effectiveness of the new policy by examining HIV test uptake, the number of HIV-infected women identified and, in 2002, the HIV rate in women not tested during prenatal care. We analyzed test uptake among women receiving prenatal care from 1999 to 2010. We examined HIV test uptake and HIV rate by year, age and health region. In an anonymous, unlinked study, we determined the HIV rate in pregnant women not tested. Prenatal HIV test uptake in Ontario increased dramatically, from 33% in the first quarter of 1999 to 96% in 2010. Test uptake was highest in younger women but increased in all age groups. All health regions improved and experienced similar test uptake in recent years. The HIV rate among pregnant women tested in 2010 was 0.13/1,000; in Toronto, the rate was 0.28 per 1,000. In the 2002 unlinked study, the HIV rate was 0.62/1,000 among women not tested in pregnancy compared to 0.31/1,000 among tested women. HIV incidence among women who tested more than once was 0.05/1,000 person-years. In response to the new policy in Ontario, prenatal HIV testing uptake improved dramatically among women in all age groups and health regions. A reminder to physicians who had not ordered a prenatal HIV test appeared to be very effective. In 2002, the HIV rate in women who were not tested was twice that of tested women: though 77% of pregnant women had been tested, only 63% of HIV-infected women were tested. HIV testing uptake was estimated at 98% in 2010.     

The inhibition of tryptophan hydroxylase, not protein synthesis, reduces the brain trapping of alpha-methyl-L-tryptophan: an autoradiographic study

The effects of the tryptophan hydroxylase (TPH) inhibitor p-chlorophenylalanine (PCPA; 200mg/kg; 3 days), and of the protein synthesis inhibitor cycloheximide (CXM, 2mg/kg), on regional serotonin (5-HT) synthesis were studied using the alpha-[14C]methyl-L-tryptophan (alpha-[14C]MTrp) autoradiographic method. The objectives of these investigations were to evaluate the changes, if any, on 5-HT synthesis, as measured with alpha-MTrp method, following the inhibition of TPH by PCPA, or the inhibition of proteins synthesis by CXM. The rats were used in the tracer experiment approximately 24h after the last dose of PCPA was administered, and in the CXM experiments, they were used 30 min following a single injection of CXM. In both experiments, the control rats were injected with the same volume of saline (0.5 ml/kg; s.c.) and at the same times as the drug injections. The results demonstrate that trapping of alpha-MTrp, which is taken to be related to brain 5-HT synthesis, is drastically reduced (40-80%) following PCPA treatment. The inhibition of protein synthesis with CXM did not have a significant effect on the global brain trapping of alpha-MTrp and 5-HT synthesis. These findings suggest that the brain trapping of alpha-[14C]MTrp relates to brain 5-HT synthesis, but not to brain protein synthesis.     

Factors Influencing Non-<Emphasis Type="Italic">albicans</Emphasis> Candidemia: A Case–Case–Control Study

The study identified factors predisposing to non-albicans candidemia with special interest to prior antimicrobial treatment. A retrospective, case–case–control study was performed at the University Hospital of Heraklion, Greece, from November 2007 through September 2011 including adult patients. The study had three groups. The first included 58 patients with non-albicans candidemia, the second 48 with C. albicans candidemia, while the third (control) 104 without candidemia. Each of the two candidemia groups was compared with the control using multivariate logistic regression model. The mean (SD) age of the non-albicans, the albicans and the control patients was 67 (12), 67 (18) and 59 (19) years, respectively. The most common non-albicans Candida spp. isolated were C. parapsilosis in 19 patients (33%), C. glabrata in 17 (29%) and C. tropicalis in 15 (26%). Independent risk factors for non-albicans candidemia were prior treatment with quinolones (p < 0.001), b-lactam-b-lactamase inhibitors (p = 0.011) and presence of central venous catheter (p = 0.05), while for C. albicans candidemia were prior treatment with quinolones (p < 0.001), carbapenems (p = 0.003) along with cardiac disease (p < 0.001). Neither duration of hospitalization nor in-hospital mortality [41% for the non-albicans vs 29% for C. albicans group (p = 0.192)] was significantly different between the two candidemia groups. The study reveals the role of antimicrobial exposure as a risk factor for candidemia caused by different species. Prior treatment with b-lactam-b-lactamase inhibitors was associated with non-albicans, while with carbapenems with C. albicans candidemia. Prior use of quinolones was associated with candidemia in general.     

Both acute and subchronic treatments with pindolol,a 5-HT1A and β1 and β2 adrenoceptor antagonist,elevate regional serotonin synthesis in the rat brain: An autoradiographic study

Antidepressant treatments, including those that increase serotonin (5-HT) neurotransmission, require several weeks or months until the onset of the therapeutic effect in depressed patients. The negative feedback on 5-HT transmission exhibited by the 5-HT_1A and 5-HT_1B autoreceptors has been postulated as a possible delaying factor. The aim of the present study was to assess the effect of the acute and subchronic treatment with pindolol, a 5-HT_1A/1B, β₁ and β₂ adrenoceptor antagonist, on 5-HT synthesis, one of the key parameters of 5-HT neurotransmission. Male Sprague–Dawley (SPD) rats (180–220 g) were treated with pindolol or an adequate volume of saline, administered either acutely (15 mg/kg i.p.; SPD-AC-SAL, SPD-AC-TR) or subchronically (15 mg/kg day i.p. for 7 days; SPD-SUBCHR-SAL, SPD-SUBCHR-TR). Thirty minutes following the single i.p. injection (acute experiment) or at the 8th day following the commencement of the subchronic treatment (subchronic experiment), 5-HT synthesis was measured using α-[¹⁴C]methyl-l-tryptophan autoradiography. The analysis of variance (ANOVA), followed by the Benjamini–Hochberg correction for multiple comparisons, revealed: (1) a significant increase of 5-HT synthesis in the SPD-AC-TR rats, relative to the SPD-AC-SAL rats in all brain regions examined except the substantia nigra – pars reticularis, dorsal subiculum, inferior olive, raphe magnus and raphe obscurus and (2) a significant increase of 5-HT synthesis in the SPD-SUBCHR-TR rats, relative to the SPD-SUBCHR-SAL rats in all brain regions except the median raphe, hypothalamus and raphe pontine. On the basis of these results, we hypothesized that the antagonism of the 5-HT_1A/1B receptors prevents the negative feedback mediated by these receptors on 5-HT synthesis, resulting in a persistent increase of 5-HT synthesis. The results accord with clinical reports on the utility of pindolol in the augmentation of antidepressant treatment.