AIDS Risk Reduction Strategies Among United States and Swedish Heterosexual University Students

Attitudes toward sex and condoms in the U.S. are more negative and less monolithic than in Sweden. We investigated the possible effect of this on AIDS prevention strategies by comparing women and men who were heterosexual university students in the two countries (Sweden: n = 570; U.S.: n = 407). Using self-administered questionnaires, subjects were asked about their sexual activities, safer sex practices, numbers of partners, and condom use. American students took a more multifaceted approach to safer sex — combining changes in sexual activities, reductions in casual sex, and increased condom use with both steady and nonsteady partners. Swedish students took a more singular approach — consistently using condoms with nonsteady partners. It is suggested that the difference in Swedish practices results from fundamental differences in sexual attitudes between the countries.     

A sensitive LC/MS/MS bioanalysis assay of orally administered lipoic acid in rat blood and brain tissue

A sensitive liquid chromatography tandem mass spectrometry (LC/MS/MS) bioanalytical method was developed and validated to analyze lipoic acid (LA) in rat blood and brain samples. Ten mobile phase combinations were investigated during method development. Mobile phase combination of 0.1% acetic acid (pH 4 adjusted with ammonia solution)/acetonitrile was most optimum in terms of sensitivity and peak shape of LA and the internal standard, valproic acid. Sample extraction method was explored using liquid–liquid extraction and protein precipitation methods. Protein precipitation yielded the highest recovery of the analytes from blood and brain ranging from 92 to 115%. The lower limit of quantitation (LLOQ) of LA was 0.1 ng/mL (0.485 nM) in both blood and brain while on-column lower limit of detection (LLOD) was 0.03 pg. The precision (% R.S.D.) ranged from 1.49 to 26.39% and 1.49 to 10.89% for intra- and inter-day assays, respectively. The accuracy ranged from 91.2 to 116.17% for intra-day assay and 102.68 to 114.33% for inter-day assay.     

Osteocalcin-insulin relationship in obese children: a role for the skeleton in energy metabolism

Objective Osteocalcin is a bone‐specific protein secreted by osteoblasts and often used as a bone formation biomarker. Rodent studies have reported a hormonal role of osteocalcin on glucose metabolism, increasing insulin secretion and sensitivity and increasing energy expenditure. However, it is unknown whether osteocalcin fulfils the same function in humans. Methods We investigated the relationship between serum osteocalcin and insulin concentrations in 27 prepubertal obese children (9–12 years old) randomly divided into two groups, one of which entered a physical training programme, and 16 nonobese control children. Whole body bone mineral density (WB‐BMD), serum osteocalcin, circulating insulin and adiponectin were measured at baseline and after 6 months. Results Trained and untrained obese children had higher WB‐BMD than controls at baseline. Trained children also displayed a significant insulin increase and a significant adiponectin decrease while osteocalcin was increased compared to untrained obese children. Significant linear correlations between WB‐BMD and adiponectin, delta BMD (variation between baseline and after‐training values) and delta adiponectin, insulin and osteocalcin, delta insulin and delta osteocalcin, delta insulin and delta under‐carboxylated osteocalcin were found only in trained obese children with no significant relationship in control and untrained obese children. Conclusions In trained obese children, correlations indicate that when BMD is increased, osteocalcin is increased and insulin lowered. This suggests that increased BMD is associated with increased energy metabolism and a decreased level of insulin. We thus report statistically significant relationships between the skeleton (osteocalcin) and energy metabolism (insulin), suggesting a regulatory hormonal loop including osteocalcin and insulin.     

Morphine-induced analgesic tolerance, locomotor sensitization and physical dependence do not require modification of mu opioid receptor, cdk5 and adenylate cyclase activity

Acute morphine administration produces analgesia and reward, but prolonged use may lead to analgesic tolerance in patients chronically treated for pain and to compulsive intake in opioid addicts. Moreover, long-term exposure may induce physical dependence, manifested as somatic withdrawal symptoms in the absence of the drug. We set up three behavioral paradigms to model these adaptations in mice, using distinct regimens of repeated morphine injections to induce either analgesic tolerance, locomotor sensitization or physical dependence. Interestingly, mice tolerant to analgesia were not sensitized to hyperlocomotion, whereas sensitized mice displayed some analgesic tolerance. We then examined candidate molecular modifications that could underlie the development of each behavioral adaptation. First, analgesic tolerance was not accompanied by mu opioid receptor desensitization in the periaqueductal gray. Second, cdk5 and p35 protein levels were unchanged in caudate-putamen, nucleus accumbens and prefrontal cortex of mice displaying locomotor sensitization. Finally, naloxone-precipitated morphine withdrawal did not enhance basal or forskolin-stimulated adenylate cyclase activity in nucleus accumbens, prefrontal cortex, amygdala, bed nucleus of stria terminalis or periaqueductal gray. Therefore, the expression of behavioral adaptations to chronic morphine treatment was not associated with the regulation of micro opioid receptor, cdk5 or adenylate cyclase activity in relevant brain areas. Although we cannot exclude that these modifications were not detected under our experimental conditions, another hypothesis is that alternative molecular mechanisms, yet to be discovered, underlie analgesic tolerance, locomotor sensitization and physical dependence induced by chronic morphine administration.     

Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia

Opioid receptors are major actors in pain control and are broadly distributed throughout the nervous system. A major challenge in pain research is the identification of key opioid receptor populations within nociceptive pathways, which control physiological and pathological pain. In particular, the respective contribution of peripheral vs. central receptors remains unclear, and it has not been addressed by genetic approaches. To investigate the contribution of peripheral delta opioid receptors in pain control, we created conditional knockout mice where delta receptors are deleted specifically in peripheral Na_V1.8-positive primary nociceptive neurons. Mutant mice showed normal pain responses to acute heat and to mechanical and formalin stimuli. In contrast, mutant animals showed a remarkable increase of mechanical allodynia under both inflammatory pain induced by complete Freund adjuvant and neuropathic pain induced by partial sciatic nerve ligation. In these 2 models, heat hyperalgesia was virtually unchanged. SNC80, a delta agonist administered either systemically (complete Freund adjuvant and sciatic nerve ligation) or into a paw (sciatic nerve ligation), reduced thermal hyperalgesia and mechanical allodynia in control mice. However, these analgesic effects were absent in conditional mutant mice. In conclusion, this study reveals the existence of delta opioid receptor-mediated mechanisms, which operate at the level of Na_V1.8-positive nociceptive neurons. Delta receptors in these neurons tonically inhibit mechanical hypersensitivity in both inflammatory and neuropathic pain, and they are essential to mediate delta opioid analgesia under conditions of persistent pain. This delta receptor population represents a feasible therapeutic target to alleviate chronic pain while avoiding adverse central effects.     

Macrolide-resistant Shigella sonnei

Shigella sonnei UCN59, isolated during an outbreak of S. sonnei in January 2007, was resistant to azithromycin (MIC 64 mg/L). The isolate contained a plasmid-borne mph(A) gene encoding a macrolide 2 -phosphotransferase that inactivates macrolides. Emergence of the mph(A) gene in S. sonnei may limit usefulness of azithromycin for treatment of shigellosis.     

Surviving ejection from military aircraft: Psychological reactions modifying factors and intervention

Surviving ejection from a military aircraft is a stressful experience. A retrospective study of 175 Royal Air Force ejectees showed that 40 per cent had significant adverse emotional reactions and that the rate of return to operational flying was significantly reduced in this group. Composite vignettes of a satisfactory and a poor outcome are presented, and the role of the psychotherapist in alleviating the commonly encountered emotional reactions is described. Confidential counselling is most helpful. Attention must be paid to the nature, personal meaning and social context of the ejection experience.     

Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts

Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand these potentially opposing functions by interrogating functional relationships among CAF subtypes, their mediators, desmoplasia, and tumor growth in a wide range of tumor types metastasizing to the liver, the most common organ site for metastasis. Depletion of hepatic stellate cells (HSC), which represented the main source of CAF in mice and patients in our study, or depletion of all CAF decreased tumor growth and mortality in desmoplastic colorectal and pancreatic metastasis but not in nondesmoplastic metastatic tumors. Single-cell RNA-Seq in conjunction with CellPhoneDB ligand-receptor analysis, as well as studies in immune cell–depleted and HSC-selective knockout mice, uncovered direct CAF-tumor interactions as a tumor-promoting mechanism, mediated by myofibroblastic CAF–secreted (myCAF-secreted) hyaluronan and inflammatory CAF–secreted (iCAF-secreted) HGF. These effects were opposed by myCAF-expressed type I collagen, which suppressed tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction by type I collagen opposes the overall tumor-promoting effects of CAF, thus providing a mechanistic explanation for their dual functions in cancer. Therapeutic targeting of tumor-promoting CAF mediators while preserving type I collagen may convert CAF from tumor promoting to tumor restricting.