Unmet needs and opportunities for optimal management of patients with type 2 diabetes and chronic kidney disease.

This brief report utilizes EHR data from a large US health system to summarize unmet needs in patients with type 2 diabetes and chronic kidney disease and identifies areas of opportunity to optimize management within this patient population from treatment, screening and monitoring, and health care resource use perspectives.

Development of clinical prediction models for renal and cardiovascular outcomes and mortality in patients with type 2 diabetes and chronic kidney disease using time-varying predictors.

AIMS: To develop a set of prediction models for end-stage kidney disease (ESKD), cardiovascular outcomes, and mortality in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) using commonly measured clinical variables. METHODS: We studied 1432 participants with T2D and CKD enrolled in the Chronic Renal Insufficiency Cohort, followed for a median period of 7 years. We used Cox proportional-hazards models to model the six outcomes (ESKD, stroke, myocardial infarction (MI), congestive heart failure (CHF), death before ESKD, and all-cause mortality). We internally evaluated these models using concordance and calibration measures. RESULTS: The newly developed six prediction models included 15 predictors: age at diabetes diagnosis, sex, blood pressure, body mass index, hemoglobin A1c, high density lipoprotein cholesterol, urine protein-to-creatinine ratio, estimated glomerular filtration rate, smoking status, and history of stroke, MI, CHF, ESKD, and amputation. The resulting models demonstrated good/strong discrimination (cross-validation C-index range: 0.70 to 0.90) and calibration. CONCLUSIONS: This study provided an internally validated and useful tool for predicting individual adverse outcomes and mortality in patients with T2D and CKD. These models may inform optimal use of targeted health interventions.

Cocaine disrupts pup-induced maternal behavior in juvenile and adult rats.

Impaired onset of maternal behavior in first generation rat dams was previously correlated with rearing by cocaine-treated dams and prenatal cocaine exposure. Pup-induced maternal behavior in non-lactating rats has not been examined with regard to cocaine exposure and rearing conditions. First generation male and female juveniles and young adult males reared by cocaine-treated or control dams and prenatally exposed to either cocaine or control conditions were tested for pup-induced maternal behavior at postnatal days 28 and 60. We now report disruptions in pup-induced maternal behavior in both 28 and 60 day old first generation offspring attributable to rearing condition and prenatal cocaine exposure.

Neurokinin 1 receptor signaling mediates sex differences in mu and kappa opioid-induced enhancement of contact hypersensitivity.

Contact hypersensitivity (CHS) is a type of cutaneous inflammation that is exacerbated by neurogenic factors. Both mu- and kappa-opioids enhance CHS to a greater extent in females than males. It was hypothesized that potentiated neurokinin 1 (NK1) receptor signaling following opioid treatment accounts for sex differences in the magnitude of CHS. Following morphine or spiradoline treatment the NK1 receptor antagonist SR140,333 significantly attenuated the magnitude of CHS in females but not males. By contrast, the NK2 antagonist SR48968 had no effect on morphine modulation of CHS. Taken together, these data indicate that NK1 receptor signaling is a key mediator of sex differences in opioid-induced enhancement of CHS.

Dissociation between sex differences in the immunological, behavioral, and physiological effects of kappa- and delta-opioids in Fischer rats.

RATIONALE: The sex of the individual can have a profound effect on sensitivity to the effects of opioids. Recently, our laboratory provided the first evidence that females may be more sensitive to the immune-altering effects of mu-opioids than males. However, it remains unknown whether kappa- and delta-opioids produce sexually dimorphic effects on immune responses. OBJECTIVE: The present study sought to determine whether kappa- and delta-opioids produce differential immunological effects in males and females using the memory-T-cell-dependent in vivo inflammatory response contact hypersensitivity (CHS). As sex differences in the magnitude of opioid effects can be outcome-specific, additional experiments were conducted to compare the immunological effects of kappa- and delta-opioids with other behavioral and physiological effects. MATERIALS AND METHODS: Contact hypersensitivity was induced in male and female Fischer rats. Prior to elicitation of CHS, animals were administered selected doses of the kappa-opioid spiradoline (0.2-20 mg/kg), delta-opioid SNC80 (1-10 mg/kg), or vehicle. The antinociceptive and diuretic effects of spiradoline were also assessed in males and females, as were the locomotor effects of SNC80. RESULTS: Spiradoline produced significantly greater enhancement of CHS in females than males, but produced comparable antinociceptive and diuretic effects in both sexes. By contrast, SNC80 did not significantly affect the course of CHS in either sex, but females were significantly more sensitive to its locomotor stimulatory effects. CONCLUSIONS: These results demonstrate that females are more sensitive than males to the CHS-altering effects of spiradoline and that sex differences in the magnitude and direction of opioid-induced sex differences are outcome dependent.

Cocaine treatment and prenatal environment interact to disrupt intergenerational maternal behavior in rats.

The link between impaired maternal behavior (MB) and cocaine treatment could result from drug-induced decreases in maternal reactivity to offspring, prenatal drug exposure (PDE) in offspring that could alter their ability to elicit MB, or the interaction of both, which could subsequently impair MB of the 1st-generation dams. Following chronic or intermittent cocaine or saline treatment during gestation, rat dams rearing natural or cross-fostered litters were compared along with untreated dams for MB. Untreated 1st-generation females with differentially treated rearing dams and PDE were tested for MB with their natural litters. The authors report disruptions in MB in dams and their 1st-generation offspring, attributable to main and interaction effects of maternal treatment, litter PDE, and rearing experience.

Sex differences in opioid-induced enhancement of contact hypersensitivity.

Previous research has demonstrated that, in male rats, the magnitude of contact hypersensitivity (CHS) can be enhanced by morphine treatment. The present experiments test the hypothesis that the mu-opioids morphine, etorphine, and buprenorphine would produce significant sex differences in the magnitude of 2,4-dinitrofluorobenzene-induced CHS. During tests conducted over a 192-h period, morphine, etorphine, and buprenorphine administered before elicitation of CHS on the external surface of the ear (pinna) potentiated the CHS response, and the magnitude of this enhancement was significantly greater in females than males. By contrast, morphine had no effect on croton oil-induced irritant contact dermatitis, indicating that morphine's effects on CHS do not generalize to immunologically nonspecific forms of contact dermatitis. Activation of brain mu-opioid receptors is responsible for the effects of morphine on CHS, because intracerebroventricular treatment with the mu-opioid receptor antagonist beta-funaltrexamine blocked morphine potentiation of CHS in females and males. The sex differences in morphine potentiation of CHS appear to be a result of the gonadal hormonal milieu, because castration enhanced the CHS response following vehicle and morphine treatment, whereas ovariectomy significantly attenuated the enhancement of CHS by morphine. Because ovariectomy had no effect on the CHS response following vehicle treatment, the presence of female gonadal hormones may underlie the sex differences in morphine potentiation of CHS in gonadally intact animals. Overall, these results support an increased sensitivity to the modulatory effects of opioids on the CHS response in females that depends on the interaction between gonadal hormones and the central mu-opioid system.

An oxytocin antagonist infused into the central nucleus of the amygdala increases maternal aggressive behavior.

Decreased oxytocin levels in the amygdalas of rat dams following chronic gestational cocaine exposure have been correlated with heightened maternal aggressive behavior. In this experiment, drug-naive dams were implanted with bilateral cannulas into the central nucleus of the amygdala (CNA) or control area and infused with 1,000 or 500 ng of an oxytocin antagonist (OTA) or buffer, 4 hr before testing. Behavior was compared among dams infused with OTA into target areas just outside the CNA and cocaine-treated dams (infused with buffer). Dams infused with 1,000 ng OTA attacked intruders significantly more often than buffer-infused dams. OTA did not affect other behaviors, suggesting that disruption of oxytocin activity in the CNA may be sufficient to selectively alter maternal aggressive behavior.

Cocaine increases inducible nitric oxide synthase expression in rats: effects of acute and binge administration.

The present studies assessed the effects of acute and binge cocaine administration on the in vivo production of inducible nitric oxide synthase in a rat model of endotoxemia. Inducible nitric oxide synthase is a key enzyme involved in host defense and inflammatory responses consequent to infection through its production of nitric oxide. Male Lewis rats received subcutaneous injections of saline or selected doses of cocaine (7.5-30 mg/kg) at the same time as a 50 microg/kg dose of lipopolysaccharide (LPS). Animals in the binge cocaine experiments received two additional injections of cocaine or saline at 2 and 4 h after the initial injections. All animals were sacrificed 6 h after initial drug administration and tissues harvested for determination of iNOS protein levels. Plasma nitrite/nitrate levels were also assayed to assess any treatment-related differences in the degradative by-products of nitric oxide metabolism. Western blot analyses of iNOS expression indicated that both acute and binge cocaine treatment resulted in significant increases in iNOS expression in all tissues assayed. Furthermore, acute and binge cocaine treatment also dose-dependently increased plasma nitrite levels. These data suggest that cocaine may impact resistance to gram-negative infections and severity of these infections via modulation of nitric oxide parameters.

The effect of genistein aglycone on cancer and cancer risk: a review of in vitro, preclinical, and clinical studies.

In Asian epidemiological studies, health benefits, including reduced incidence of breast and prostate cancers, are attributed to soy food and isoflavone consumption. The recent increased intake of soy foods and supplements in the American diet has raised concerns about the possible estrogen-like effects of natural isoflavones and possible promotion or propagation of estrogen-sensitive cancers. These concerns are primarily based on in vitro and rodent data which suggest that genistein aglycone can stimulate tumor cell proliferation and growth in mice having deficient immune systems. In contrast, a recent nested case-control study and meta-analysis of numerous epidemiological studies show an inverse correlation between genistein intake and breast cancer risk. Furthermore, clinical studies in osteopenic and osteoporotic, postmenopausal women support the breast and uterine safety of purified naturally derived genistein administered for up to 3 years. In this review, we summarize the in vitro, preclinical and clinical evidence for the safety of natural genistein.