Obesity Reduction Black Intervention Trial (ORBIT): 18‐Month Results

Obesity is a chronic condition that is prevalent in black women. The Obesity Reduction Black Intervention Trial (ORBIT) was a randomized controlled weight loss and weight‐loss maintenance (WLM) trial. Participants (N = 213) were randomized to the intervention or control groups in August 2005 and September 2006. Follow‐up data were collected 6 and 18 months after randomization. The main outcome was change in weight and BMI from baseline to 18 months. The mean weight at baseline was 104.9 kg, and the mean weight loss in the intervention group at 6 months was 3.0 kg and a gain of 0.2 kg in the control group (mean difference between groups in weight change at 6 months, adjusting for baseline weight and cohort, ?3.27 kg; 95% confidence interval (CI), ?4.50 to ?2.05 kg; P < 0.001). Both groups gained weight between 6 and 18 months (mean 1.0 kg in the intervention group and 0.1 kg in the control group). However, intervention participants lost significantly more weight than control participants during the 18‐month intervention (adjusted mean difference between groups at 18 months, ?2.83 kg; 95% CI, ?4.71 to ?0.95; P = 0.003). At 18 months, intervention participants were more likely than control participants to have lost at least 5% of baseline weight (24% vs. 12%, P < 0.04). Our results indicate that the ORBIT program did promote weight loss and weight‐loss maintenance. However, the results also clearly illustrate there is more to learn about what will contribute to meaningful weight loss and maintenance in this population.     

RNA processing: new mutants that affect endonucleolytic processing of RNA

A strain of Escherichia coli carrying the rne-3071 mutation that affects the RNA processing enzyme ribonuclease E, was mutagenized, and double mutants deficient in RNA processing were isolated. The isolation was based on the appearance of a particular RNA precursor molecule upon infection of an rne mutant with a specific bacteriophage T4 deletion strain. From one of the double mutants the rne mutation was removed, and the new single mutant, designated rng, was examined. In this mutant the maturation of host RNA as well as of bacteriophage T4 RNA is affected. The effect of the rng mutation on RNA synthesis is unique and can be distinguished from the effects of the other established mutations in RNA processing. The effects of the rng mutation can be recognized in vivo and in vitro.     

Wait times in the emergency department for patients with mental illness

Background:

It has been suggested that patients with mental illness wait longer for care than other patients in the emergency department. We determined wait times for patients with and without mental health diagnoses during crowded and noncrowded periods in the emergency department.

Methods:

We conducted a population-based retrospective cohort analysis of adults seen in 155 emergency departments in Ontario between April 2007 and March 2009. We compared wait times and triage scores for patients with mental illness to those for all other patients who presented to the emergency department during the study period.

Results:

The patients with mental illness (n = 51 381) received higher priority triage scores than other patients, regardless of crowding. The time to assessment by a physician was longer overall for patients with mental illness than for other patients (median 82, interquartile range [IQR] 41–147 min v. median 75 [IQR 36–140] min; p < 0.001). The median time from the decision to admit the patient to hospital to ward transfer was markedly shorter for patients with mental illness than for other patients (median 74 [IQR 15–215] min v. median 152 [IQR 45–605] min; p < 0.001). After adjustment for other variables, patients with mental illness waited 10 minutes longer to see a physician compared with other patients during noncrowded periods (95% confidence interval [CI] 8 to 11), but they waited significantly less time than other patients as crowding increased (mild crowding: −14 [95% CI −12 to −15] min; moderate crowding: −38 [95% CI −35 to −42] min; severe crowding: −48 [95% CI −39 to −56] min; p < 0.001).

Interpretation:

Patients with mental illness were triaged appropriately in Ontario’s emergency departments. These patients waited less time than other patients to see a physician under crowded conditions and only slightly longer under noncrowded conditions.In a 2008 report, the Schizophrenia Society of Ontario recommended adding a psychiatric wait times component to the Ontario government’s Emergency Room Wait Times Strategy.¹ They suggested that patients who present to the emergency department in psychiatric distress wait longer for care than other patients and that they are given a low priority triage score² (all patients are assigned a triage score when they first arrive at the emergency department, which may determine when and where they are seen by a physician).³ The Kirby Report, a senate report on mental illness and addiction in Canada, also decried differential emergency care for patients with mental illness.⁴A recent study found that patients with acute myocardial infarction are given lower priority care in the emergency department if they have a charted history of depression.⁵ However, whether patients who present to the emergency department for mental illness receive slower care than other patients is not known. In this study, we compared the emergency department wait times and triage scores for patients with affective and psychotic disorders to those for other patients, both in noncrowded conditions and during periods of crowding. Because we believe that triage nurses apply triage principles consistently to all emergency patients while physicians may be less likely to adhere to the guidelines, we hypothesized that there would be no “down-triage” (assigning a lower priority triage score) of these patients, but that patients with mental illness would have longer delays to see a physician, relative to other patients.     

Levels of 25-hydroxyvitamin D in familial longevity: the Leiden Longevity Study

Background:

Low levels of 25(OH) vitamin D are associated with various age-related diseases and mortality, but causality has not been determined. We investigated vitamin D levels in the offspring of nonagenarians who had at least one nonagenarian sibling; these offspring have a lower prevalence of age-related diseases and a higher propensity to reach old age compared with their partners.

Methods:

We assessed anthropometric characteristics, 25(OH) vitamin D levels, parathyroid hormone levels, dietary vitamin D intake and single nucleotide polymorphisms (SNPs) associated with vitamin D levels. We included offspring (n = 1038) of nonagenarians who had at least one nonagenarian sibling, and the offsprings’ partners (n = 461; controls) from the Leiden Longevity Study. We included age, sex, body mass index, month during which blood sampling was performed, dietary and supplemental vitamin D intake, and creatinine levels as possible confounding factors.

Results:

The offspring had significantly lower levels of vitamin D (64.3 nmol/L) compared with controls (68.4 nmol/L; p = 0.002), independent of possible confounding factors. There was no difference in the levels of parathyroid hormone between groups. Compared with controls, the offspring had a lower frequency of a genetic variant in the CYP2R1 gene (rs2060793) (p = 0.04). The difference in vitamin D levels between offspring and controls persisted over the 2 most prevalent genotypes of this SNP.

Interpretation:

Compared with controls, the offspring of nonagenarians who had at least one nonagenarian sibling had a reduced frequency of a common variant in the CYP2R1 gene, which predisposes people to high vitamin D levels; they also had lower levels of vitamin D that persisted over the 2 most prevalent genotypes. These results cast doubt on the causal nature of previously reported associations between low levels of vitamin D and age-related diseases and mortality.Vitamin D plays a critical role in bone formation,¹ immune cell differentiation, and in the inhibition of proliferation and angiogenesis in cancer.² Low serum levels of 25-hydroxyvitamin D3 (25[OH] vitamin D) are associated with increased mortality, cardiovascular disease, diabetes mellitus, cancer, multiple sclerosis, allergy, asthma, infection, depression, mental illness and musculoskeletal pain.^3–6 However, because of design limitations, previous studies have not been able to infer causality.⁷ A meta-analysis that included 51 studies and more than 30 000 individuals in each treatment group showed no reduction in all-cause or cardiovascular mortality with vitamin D supplementation,⁸ suggesting that low serum levels of vitamin D are a consequence rather than a cause of disease.Vitamin D status is routinely assessed by measurement of serum concentration of the prohormone 25(OH) vitamin D, which is the most stable and abundant metabolite of vitamin D in circulation. In the current study, we investigated the association between serum levels of 25(OH) vitamin D and familial longevity. We assessed vitamin D levels in the offspring of nonagenarian siblings whom we have previously shown to have a lower prevalence of cardiovascular diseases and lower mortality compared to age- and environmental-matched controls.^9,10 We also assessed whether genetic variation in 3 genes¹¹ was associated with 25(OH) vitamin D levels among the offspring of nonagenarians who had at least 1 nonagenarian sibling, and their partners.     

Epicutaneous immunization with DNP-BSA induces CD4(+) CD25(+) Treg cells that inhibit Tc1-mediated CS

As we have shown previously that protein antigen applied epicutaneously (EC) in mice inhibits TNP-specific Th1-mediated contact sensitivity (CS), we postulated that the maneuver of EC immunization might also suppress Tc1-dependent CS response. Here we showed that EC immunization of normal mice with 2,4-dinitrophenylated bovine serum albumin (DNP-BSA) applied on the skin in the form of a patch induces a state of subsequent unresponsiveness due to regulatory T cells (Treg) that inhibited sensitization and elicitation of effector T-cell responses. Suppression is transferable in vivo by TCRαβ(+) CD4(+) CD25(+) lymphocytes harvested from lymph nodes (LNs) of skin-patched animals. Flow cytometry revealed that EC immunization with DNP-BSA increased TCRαβ(+) CD4(+) CD25(+) FoxP3(+) lymphocytes in subcutaneous LNs, suggesting that observed suppression was mediated by Treg cells. Further, in vitro experiments showed that EC immunization with DNP-BSA prior to 1-fluoro-2,4-dinitrobenzen sensitization suppressed LN cell proliferation and inhibited production of TNF-α, IL-12 and IFN-γ. Using a transwell system or anti-CTLA-4 mAb, we found that EC induced suppression required direct Treg-effector cell contact and is CTLA-4-dependent.     

Chromenones as potent bradykinin B1 antagonists

A series of fused 6,6-bicyclic chromenones was investigated for activity against the bradykinin B1 receptor. SAR studies based on a pharmacophore model revealed compounds with high affinity for both human and rabbit B1. These compounds demonstrated favorable pharmacokinetic properties and 5-chlorochromenone 15 was efficacious in a carrageenan-induced mechanical hyperalgesia model for chronic pain.