Secular trends in cardiovascular risk factors with a 36-year perspective: observations from 38- and 50-year-olds in the Population Study of Women in Gothenburg

Objectives

To study secular trends in cardiovascular risk factors in four different cohorts of women examined in 1968–1969, 1980–1981, 1992–1993 and 2004–2005.

Design

Comparison of four representative cohorts of 38- and 50-year-old women over a period of 36 years.

Setting

Gothenburg, Sweden with ∼450 000 inhabitants.

Subjects

Four representative samples of 38- and 50-year-old women were invited to free health examinations (participation rate 59–90%, n =1901).

Main outcome measures

Body mass index (BMI), systolic and diastolic blood pressure (SBP, DBP), leisure time exercise, use of antihypertensive medication, smoking, levels of haemoglobin, b-glucose, s-cholesterol, s-triglycerides and HDL-cholesterol.

Results

There was no significant difference in mean BMI from 1968–1969 versus 2004–2005. Mean leisure time exercise was significantly higher in later born cohorts; in 1968, around 15% were physically active compared with 40% in 2004. SBP and DBP, mean s-cholesterol and s-triglyceride levels were significantly lower in both 38- and 50-year-old cohorts in 2004–2005 versus 1968–1969. HDL-cholesterol (not measured until 1992–1993), showed a significantly higher mean level in 2004–2005. Reduction of risk factors was apparent in women with a high as well as low level of physical activity. Smoking declined most in women with high levels of physical activity.

Conclusions

Several cardiovascular risk factors related to lifestyle have improved in middle-aged women from the 1960s until today. Most of the positive trends are observed in women with both low and high physical activity.     

Utilizing current diagnostic criteria and treatment algorithms for managing type 2 diabetes mellitus

Within the past 2 years, the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) and the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) have revised their guidelines for the diagnosis and treatment of type 2 diabetes mellitus (T2DM). Both organizations recommend a diagnostic glycated hemoglobin (HbA1c) of >6.5% (based on a new appreciation of the relationship between glycemia and complications) and fasting plasma glucose levels or an oral glucose tolerance test. Findings from major trials of glucose control in patients with T2DM and the approval of novel medications have prompted revised treatment algorithms from both organizations. While both treatment guidelines recommend starting metformin in most patients on diagnosis of T2DM, they differ in terms of the "trigger" for treatment intensification (HbA1c≥7% and >6.5%, respectively) and which agents are preferred as second-line therapies. The ADA/EASD recommends a tiered approach to treatment, starting with well-validated second-line agents, such as sulfonylureas and basal insulin for patients unable to achieve target glucose levels with metformin. The AACE/ACE recommendations are based on the patient's HbA1c level and include a broader range of first- and second-line therapies and combinations. In addition to metformin, the ACCE/ACE treatment algorithm includes dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones, α-glucosidase inhibitors, sulfonylureas, and glinides. Both organizations advocate individualizing therapy to meet patient needs. This review highlights recent changes in the guidelines and uses a case-based format to illustrate how the current guidelines may be tailored to fit individual patient characteristics and circumstances.     

Mitochondrial and Nuclear Genes Suggest that Stony Corals Are Monophyletic but Most Families of Stony Corals Are Not (Order Scleractinia, Class Anthozoa, Phylum Cnidaria)

Modern hard corals (Class Hexacorallia; Order Scleractinia) are widely studied because of their fundamental role in reef building and their superb fossil record extending back to the Triassic. Nevertheless, interpretations of their evolutionary relationships have been in flux for over a decade. Recent analyses undermine the legitimacy of traditional suborders, families and genera, and suggest that a non-skeletal sister clade (Order Corallimorpharia) might be imbedded within the stony corals. However, these studies either sampled a relatively limited array of taxa or assembled trees from heterogeneous data sets. Here we provide a more comprehensive analysis of Scleractinia (127 species, 75 genera, 17 families) and various outgroups, based on two mitochondrial genes (cytochrome oxidase I, cytochrome b), with analyses of nuclear genes (ß-tubulin, ribosomal DNA) of a subset of taxa to test unexpected relationships. Eleven of 16 families were found to be polyphyletic. Strikingly, over one third of all families as conventionally defined contain representatives from the highly divergent “robust” and “complex” clades. However, the recent suggestion that corallimorpharians are true corals that have lost their skeletons was not upheld. Relationships were supported not only by mitochondrial and nuclear genes, but also often by morphological characters which had been ignored or never noted previously. The concordance of molecular characters and more carefully examined morphological characters suggests a future of greater taxonomic stability, as well as the potential to trace the evolutionary history of this ecologically important group using fossils.     

Frustrated and invisible--younger stroke patients' experiences of the rehabilitation process

PURPOSE: This study aimed to get knowledge of the younger stroke patient's viewpoint and to describe how young stroke patients experience the rehabilitation process. The purpose was also to develop hypotheses about the relationship between young stroke patients and the rehabilitation process. METHOD: Thematised in-depth interviews were performed with two women and three men who suffered from stroke (37 - 54 years). The analysis used was the Grounded Theory method of constant comparison. RESULTS: The analyses resulted in the core category 'Frustration' which was derived from the categories labelled 'The paralysed everyday' and 'Outside and invisible'. 'The paralysed everyday' category involved different aspects of everyday life after a stroke. Because of their fatigue they were unable to work and their family and social life were negatively affected. They found it difficult to engage in daily life activities and felt indifferent. The three women expressed frustration over the demands they experienced as being mothers and housekeepers, whereas the two men emphasised economic responsibility of the family as problematic. The category 'Outside and invisible' describes the lack of participation the informants experienced regarding the rehabilitation process. The informants felt they lacked information and age-adapted interventions. Their needs were not provided for and they felt distant from the other patients. Their remaining symptoms were probably on a cognitive basis and therefore invisible. This was a source of frustration. CONCLUSION: The hypotheses generated indicated that young stroke patients are frustrated and invisible due to the fact that the rehabilitation setting does not acknowledge the different needs of young stroke patients compared with older patients.     

Pharmacokinetic Interaction between Ritonavir and Indinavir in Healthy Volunteers

The pharmacokinetic interaction between indinavir and ritonavir was evaluated in five groups of healthy adult volunteers to explore the potential for twice-daily (b.i.d.) dosing of this combination. All subjects received 800 mg of indinavir every 8 h (q8h) on day 2. In addition, subjects in group I received one dose of 800 mg of indinavir on day 1 and 800 mg of indinavir q8h on day 17. Subjects in Groups II and IV each received one dose of 600 mg of indinavir on days 1 and 17, and subjects in groups III and V each received one dose of 400 mg of indinavir on days 1 and 17. During days 3 to 17, ritonavir placebo or ritonavir at 200, 300, 300, or 400 mg q12h was given to groups I, II, III, IV, and V, respectively. Ritonavir at steady state probably inhibited the cytochrome P-450 3A metabolism of indinavir and substantially increased plasma indinavir concentrations, with the area under the plasma concentration-time curve (AUC) increasing up to 475% and the peak concentration in serum (C_max) increasing up to 110%. The C_max/trough concentration ratio decreased from 50 in standard q8h regimens to less than 14 when indinavir was administered with ritonavir. For a constant indinavir dose, an increase in the ritonavir dose yielded similar indinavir AUCs, C_maxs, and concentrations at 12 h (C₁₂s). For a constant ritonavir dose, an increase in the indinavir dose resulted in approximately proportional increases in the indinavir AUC, less than proportional increases in C_max, and slightly more than proportional increases in C₁₂. Ritonavir reduced between-subject variability in the indinavir AUC and trough concentrations and did not affect indinavir renal clearance. With the altered pharmacokinetic profile, indinavir likely could be given as a b.i.d. combination regimen with ritonavir. This could potentially improve patient compliance and thereby reduce treatment failures.     

RSV604, a novel inhibitor of respiratory syncytial virus replication

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease.     

Virtual inhibitory quotient predicts response to ritonavir boosting of indinavir-based therapy in human immunodeficiency virus-infected patients with ongoing viremia

Depending on the degree of underlying resistance present, optimization of the pharmacokinetics of protease inhibitors may result in improved virologic suppression. Thirty-seven human immunodeficiency virus (HIV)-infected subjects who had chronic detectable viremia and who were receiving 800 mg of indinavir three times a day (TID) were switched to 400 mg of indinavir BID with 400 mg of ritonavir two times a day (BID) for 48 weeks. Full pharmacokinetic evaluations were obtained for 12 subjects before the switch and 3 weeks after the switch. Combination therapy increased the indinavir predose concentrations in plasma by 6.47-fold, increased the minimum concentration in serum by 3.41-fold, and reduced the maximum concentration in serum by 57% without significantly changing the area under the plasma concentration-time curve at 24 h. At week 3, 58% (21 of 36) of the subjects for whom postbaseline measurements were available achieved a viral load in plasma of <50 copies/ml or a reduction from the baseline load of > or =0.5 log(10) copies/ml. Of these subjects, 82% (14 of 17) whose viruses had three or fewer protease inhibitor mutations and 88% (14 of 16) whose viruses had an indinavir virtual phenotypic susceptibility test of more than sixfold less than that for the baseline isolate were considered virologic responders. The indinavir virtual inhibitory quotient, which is a function of baseline indinavir phenotypic resistance (estimated by virtual phenotype) and the indinavir predose concentration in plasma achieved with indinavir-ritonavir combination therapy, was the best predictor of a viral load reduction. Sixteen subjects discontinued the study by week 48 due to adverse events, predominantly related to hyperlipidemia. Pharmacokinetic intensification of indinavir-based therapy with ritonavir reduced the viral loads in subjects but added toxicity. The virtual inhibitory quotient, which incorporates both baseline viral resistance and the level of drug exposure in plasma, was superior to either baseline resistance or drug exposure alone in predicting the virologic response.     

Type I interferon inhibits antibody responses induced by a chimpanzee adenovirus vector.

Recent studies have indicated that type I interferon (IFN) enhances antibody responses and promotes isotype switching. In this study, we analyzed the role of type I IFN signaling during the generation of transgene product-specific antibody responses elicited by recombinant adenovirus (Ad) vectors. A vector derived from a human Ad serotype (AdHu5) induced low levels of type I IFN following infection of dendritic cells (DCs) and stimulated normal transgene product-specific antibody responses in mice that have a defective type I IFN receptor (IFNAR(-/-)). A vector derived from a chimpanzee Ad serotype (AdC68) induced very high levels of type I IFN following infection of DCs, and surprisingly, primed stronger transgene product-specific antibody responses in IFNAR(-/-) mice compared to wild-type mice. The increased antibody response in IFNAR(-/-) mice vaccinated with the AdC68 vector was mainly due to the generation of IgG1 antibodies that were not elicited in wild-type mice. The induction of IgG1 antibodies correlated with an increase in transgene product expression in IFNAR(-/-) mice and was not associated with an increase in T helper 2 responses. We conclude that type I IFN, when induced at high levels, can downregulate transgene product expression of Ad vectors and inhibit the formation of optimal antibody responses.