Age and risk of stroke in atrial fibrillation: evidence for guidelines?

AIM: Guidelines for the clinical management of patients with atrial fibrillation suggest that treatment strategies for prescribing oral anticoagulant therapy should implicate change at age 60, 65 and 75 years. We examined if there is any threshold concerning risk of stroke by age. METHODS: We identified 141,493 subjects, aged 40-89 years, with an incident hospital diagnosis of nonvalvular atrial fibrillation or flutter and no previous or concomitant diagnosis of stroke in the Danish National Registry of Patients from January 1, 1980, to December 31, 2002. The subjects were followed in the Danish National Registry of Patients for the occurrence of an incident diagnosis of stroke of any nature and in the Danish Civil Registration System for emigration and vital status. We examined the risk of stroke by age in men and women using Cox regression models, which included age categorized in intervals, linear splines of age with cut points at age 60 and 75 years, or at age 65 and 75 years. We also analyzed age as a continuous variable in linear and polynomial regression models. RESULTS: During follow-up 15,964 incident strokes were reported to the Danish National Registry of Patients. The risk of stroke increased by increasing age at baseline. We did not find any evidence for a threshold concerning risk of stroke by age, and the best model fit was obtained in a third-order polynomial regression model. CONCLUSION: The risk of stroke increased gradually by increasing age, and we could not detect any threshold concerning risk of stroke by age.     

Influence of chronic cocaine treatment and sleep deprivation on sexual behavior and neurogenesis of the male rat

The present study investigated the influence of chronic cocaine treatment on genital reflexes associated with paradoxical sleep deprivation (PSD), and possible alterations in hippocampus neurogenesis of the male rat. At 21 days of age, the rats were distributed into two groups and injected with saline or cocaine (7 mg/kg, three times a week for 12 weeks). At age 90 days, they were submitted to a four-day period of PSD (PSD groups) or maintained in home-cages (control groups), challenged with saline or cocaine administration, and placed in observation cages to assess genital reflexes. Two additional groups were used to quantify neurogenesis. PSD rats treated chronically with cocaine and challenged with saline did not differ from their respective control groups. The association of PSD with cocaine potentiated penile erection (PE) when compared to PSD-saline (saline challenged) rats, and these effects were similar to those observed in long-term cocaine treated rats. The bromodeoxyuridine (BrdU) assay indicated a reduction in BrdU-positive cells in the adult hippocampus after chronic cocaine treatment. These findings show that long-term cocaine treatment from brain development through adulthood had a marked effect on sexual responses and neuronal proliferation.     

Distress reduction from a psychological intervention contributes to improved health for cancer patients

PURPOSE: Psychological interventions are efficacious in reducing emotional distress for cancer patients. However, it is not clear whether psychological improvements are, in turn, related to improved health. A clinical trial tests whether a psychological intervention for cancer patients can do so, and also tests two routes to achieve better health: (a) reducing patients' Emotional Distress, and/or (b) enhancing their functional immunity. METHODS: Post-surgery, 227 breast cancer patients were randomized to intervention or assessment only Study Arms. Conducted in small groups, intervention sessions were offered weekly for 4 months and followed by monthly sessions for 8 months. Measures included psychological (distress), biological (immune), and health outcomes (performance status and evaluations of patient's symptomatology, including toxicity from cancer treatment, lab values) collected at baseline, 4 months, and 12 months. RESULTS: A path model revealed that intervention participation directly improved health (p<.05) at 12 months. These effects remained when statistically controlling for baseline levels of distress, immunity, and health as well as sociodemographic, disease, and cancer treatment variables. Regarding the mechanisms for achieving better health, support was found for an indirect effect of distress reduction. That is, by specifically lowering intervention patients' distress at 4 months, their health was improved at 12 months (p<.05). Although the intervention simultaneously improved patients' T-cell blastogenesis in response to phytohemagglutinin (PHA), the latter increases were unrelated to improved health. CONCLUSION: A convergence of biobehavioral effects and health improvements were observed. Behavioral change, rather than immunity change, was influential in achieving lower levels of symptomatology and higher functional status. Distress reduction is highlighted as an important mechanism by which health can be improved.     

Behavioral and neurochemical effects of cocaine and diphenhydramine combinations in rhesus monkeys

Rationale  Diphenhydramine (DPH) is an over-the-counter medication used in the treatment of allergic symptoms. While DPH abuse is infrequent, recent preclinical evidence suggests that DPH and cocaine combinations may have enhanced reinforcing properties. Objective  The aims were to assess the reinforcing effectiveness of cocaine and DPH alone or in combination under a second-order schedule of reinforcement and to examine the neurochemical basis of this interaction using in vivo microdialysis in awake rhesus monkeys. Materials and methods  Cocaine (0.03–0.3 mg/kg per injection), DPH (0.3–3.0 mg/kg per injection), or a combination was available under a second-order schedule of intravenous drug reinforcement (n = 3). In microdialysis studies, noncontingent cocaine (0.1–1.0 mg/kg, iv), DPH (1.7 and 3.0 mg/kg, iv), or a combination was administered and changes in extracellular dopamine levels in the caudate nucleus were examined (n = 3–5). Results  Cocaine and DPH dose-dependently maintained operant responding. Dose combinations of 1.0 or 1.7 mg/kg per injection DPH and 0.03 mg/kg per injection cocaine maintained greater rates of operant responding than 0.03 mg/kg per injection cocaine alone in the second component of the behavioral session. In microdialysis studies, cocaine dose-dependently increased extracellular dopamine levels, but no dose of DPH tested significantly increased dopamine levels above baseline. Moreover, combining DPH with cocaine did not enhance cocaine-induced dopamine increases. Conclusions  The results support previous evidence of enhanced reinforcement with cocaine and DPH combinations and extend this finding to operant behavior maintained under a second-order schedule. However, the reinforcing effects of DPH alone or in combination with cocaine do not appear to be mediated via changes in dopamine overflow. Banks and Andersen contributed equally to this work.     

Hereditary iron and copper deposition: diagnostics, pathogenesis and therapeutics

Hereditary deposition of iron (primary haemochromatosis) or copper (Wilson's disease) are autosomal recessive metabolic disease characterized by progressive liver pathology and subsequent involvement of various other organs. The prevalence of primary haemochromatosis is approximately 0.5%, about 200 times higher than the prevalence of Wilson's disease. The two diseases are characterized by homozygous occurrences of mutations in the HFE gene on chromosome 6 (primary haemochromatosis) and the ATP7B gene on chromosome 13 (Wilson's disease). Unlike most other inherited conditions, these diseases can be successfully treated, emphasizing the importance of early diagnosis. Serum ferritin values, transferrin saturation and genetic analysis are used when diagnosing haemochromatosis. The diagnostics of Wilson's disease depends on the use of urinary copper values, serum ceruloplasmin and liver biopsy. If untreated, both of these genetic diseases result in rapidly progressing multiorgan damage and early death. The key treatment for haemochromatosis is phlebotomy, for Wilson's disease chelation or Zn treatment. Although the present treatments considerably improve the prognosis of patients, they may be inadequate in patients diagnosed so late that extensive body deposits of metal have been developed. The main research needs in this field are to further clarify molecular mechanisms of disease progression and to develop new chelators that are more effective and less toxic than those presently available.     

Alloantigen-enhanced accumulation of CCR5+ 'effector' regulatory T cells in the gravid uterus

Regulatory T cells play an essential role in preventing fetal rejection by the maternal immune system. Here we show that, based on the expression of CCR5, regulatory T cells can be divided into a highly suppressive CCR5+ and a far less suppressive CCR5- subpopulation, suggesting that the former represent the effector arm of regulatory T cells. Although regulatory T cells from CCR5-/- gene deletion mutants still suppress, they are less effective mediators of maternal-fetal tolerance. The accumulation of CCR5+ regulatory T cells at this site appears to be enhanced by alloantigen. This finding is in stark contrast to the systemic expansion of regulatory T cells during pregnancy, which appears to be alloantigen-independent. The fact that CCR5+ regulatory T cells preferentially accumulate in the gravid uterus and that expression of CCR5 on regulatory T cells can be induced by activation lead us to propose that CCR5 is responsible for the accumulation of those regulatory T cells that have been activated by paternal antigens.     

The influence of dietary intake and meal pattern on blood glucose control in children and adolescents using intensive insulin treatment

AIMS/HYPOTHESIS: We studied dietary factors and their association with blood glucose control in type 1 diabetic children and adolescents using intensive insulin treatment. MATERIALS AND METHODS: A total of 550 children and adolescents with type 1 diabetes mellitus (age 2-19 years) recorded their diet for 4 days in pre-coded food diaries. Of the study group, 34% used insulin pumps, 43% used four or more injections and 16% three injections per day. HbA(1c) was related to targets of optimal blood glucose control defined by the International Society for Pediatric and Adolescent Diabetes (ISPAD). RESULTS: Adolescents with optimal glucose control (HbA(1c) < or = 7.5%) had a lower intake of added sugar (7.7 vs 9.1% of energy intake, p = 0.004), a higher intake of fibre (19.3 vs 17.0 g/day, p = 0.01) and a higher intake of fruits and vegetables (257 vs 227 g/day, p = 0.04) than those with suboptimal metabolic control (HbA(1c) > 7.5%). Multiple regression analysis in adolescents showed that fibre and meal pattern were significantly associated with blood glucose control (effect fibre intake = -0.02, p = 0.04, effect having breakfast regularly = -0.89, p = 0.009). In children meal pattern was associated with blood glucose control (effect having dinner regularly = -0.66, p = 0.02, effect having supper regularly = -0.78, p = 0.03). CONCLUSIONS/INTERPRETATION: In diabetic adolescents both intake of fibre and having a regular meal pattern are associated with blood glucose control. Lower intake of added sugar and sugar-sweetened soft drinks and higher intake of fruits and vegetables are observed among those with optimal compared with those with suboptimal blood glucose control. Dietary guidance should be intensified during adolescence to improve dietary intake and blood glucose control.     

Circulating sex hormones and gene expression of subcutaneous adipose tissue oestrogen and alpha-adrenergic receptors in HIV-lipodystrophy: implications for fat distribution

OBJECTIVE: Circulating oestradiol and testosterone, which have been shown to increase in human immunodeficiency virus (HIV)-infected patients following highly active antiretroviral therapy (HAART), may influence fat distribution and insulin sensitivity. Oestradiol increases subcutaneous adipose tissue in humans possibly through binding to oestrogen-receptor-alpha, which in turn activates anti-lipolytic alpha2A-adrenergic-receptor. DESIGN AND METHODS: To address these issues circulating pituitary-gonadal-axis hormones and gene expression of receptors in subcutaneous adipose tissue were determined in 31 nondiabetic HIV-infected male patients receiving HAART (16 with lipodystrophy), in whom measures of fat distribution (CT and DEXA-scans) and insulin sensitivity (hyperinsulinaemic euglycaemic clamp) were available. RESULTS: Total and free oestradiol and testosterone were decreased in lipodystrophic patients compared to nonlipodystrophic patients, whereas luteinizing hormone, follicle-stimulating hormone and prolactin were similar and normal in both study groups. Ratio of subcutaneous to total abdominal fat mass, limb fat, and insulin sensitivity, which were all decreased in lipodystrophic patients, correlated positively with both plasma oestradiol and testosterone (n = 31). Glycerol concentration during clamp (a marker of lipolysis) correlated inversely with expression of alpha2A-adrenergic-receptor, ratio of subcutaneous to total abdominal fat mass, and limb fat, respectively. Expression of alpha2A-adrenergic-receptor correlated positively with expression of oestrogen-receptor-alpha. CONCLUSIONS: The results fit the hypothesis that sex hormones play a role in altered fat distribution and insulin sensitivity of male patients with HIV-lipodystrophy. The effect of oestradiol on the subcutaneous fat depot and lipolysis may be mediated in part through binding to the oestrogen-receptor-alpha, in turn activating anti-lipolytic alpha2A-adrenergic-receptor.