Using metabolic markers to identify insulin resistance in premenopausal women with and without polycystic ovary syndrome.

BACKGROUND: Insulin resistance (IR) is associated with increased risk for type 2 diabetes mellitus and cardiovascular disease. Quantifying IR is invasive and time-consuming, and thus not routinely used in clinical practice. Simple metabolic markers to predict IR exist, but have not been validated in premenopausal women or women with polycystic ovary syndrome (PCOS). OBJECTIVE: To evaluate the ability of metabolic markers to identify premenopausal women with/without PCOS who are insulin resistant. DESIGN/SETTING: Cross-sectional analysis. PARTICIPANTS: One hundred and seventy-one non-diabetic premenopausal overweight/obese women without PCOS and 71 women with PCOS. METHODS: IR was quantified by the steady-state plasma glucose during the modified insulin-suppression test. Metabolic markers (BMI, lipid/lipoprotein concentrations, and fasting glucose) were evaluated for their discriminative ability to identify IR, using area under the receiver-operating-characteristic curve (AUROC) analysis. Optimal cut-points were evaluated for predictive power. RESULTS: In the non-PCOS group, the triglyceride/HDL cholesterol ratio (TG/HDL-C) was the best marker (AUROC 0.73). Optimal diagnostic cut-point was 1.9. In the PCOS group, the TG/HDL-C ratio, cholesterol/HDL-C ratio (TC/HDL-C), and HDL-C performed well (AUROC > 0.80), with optimal cut-points for TG/HDL-C 1.3, TC/HDL-C 3.4, and HDL-C 52 mg/dL: TG/HDL-C was more sensitive, but HDL-C had a higher PPV for IR. CONCLUSION: TG/HDL-C can identify IR in premenopausal women with and/without PCOS; diagnostic cut-points differ from those of men and postmenopausal women. HDL-C is an alternative predictor in women with PCOS. These simple metabolic markers, which are standardized between labs, inexpensive, and routinely measured, can be used to tailor lifestyle and medical interventions to improve health outcomes in insulin-resistant premenopausal women.

Assessment of the young adult hip joint using plain radiographs.

Radiographic examination remains the mainstay of the initial assessment of the young adult hip; however, common parameters are required to assist in the formation of accurate diagnoses and appropriate management plans. This paper aims to summarise the most important aspects of the assessment of plain radiographs performed on the young adult hip joint.

Collective sensing and collective responses in quorum-sensing bacteria.

Bacteria often face fluctuating environments, and in response many species have evolved complex decision-making mechanisms to match their behaviour to the prevailing conditions. Some environmental cues provide direct and reliable information (such as nutrient concentrations) and can be responded to individually. Other environmental parameters are harder to infer and require a collective mechanism of sensing. In addition, some environmental challenges are best faced by a group of cells rather than an individual. In this review, we discuss how bacteria sense and overcome environmental challenges as a group using collective mechanisms of sensing, known as 'quorum sensing' (QS). QS is characterized by the release and detection of small molecules, potentially allowing individuals to infer environmental parameters such as density and mass transfer. While a great deal of the molecular mechanisms of QS have been described, there is still controversy over its functional role. We discuss what QS senses and how, what it controls and why, and how social dilemmas shape its evolution. Finally, there is a growing focus on the use of QS inhibitors as antibacterial chemotherapy. We discuss the claim that such a strategy could overcome the evolution of resistance. By linking existing theoretical approaches to data, we hope this review will spur greater collaboration between experimental and theoretical researchers.

Effects of endogenous and exogenous estrogen exposures in midlife and late-life women on episodic memory and executive functions.

Cognitive aging affects episodic memory and executive functions, and these vulnerable domains are postulated to be modulated by endogenous and exogenous estrogen exposures. In midlife and late-life women without dementia, estrogen effects on cognition can be examined through associations with concentrations of serum estrone and estradiol and through clinical trials of estrogen-containing hormone therapy. To this end, we reviewed published studies including at least 100 women (larger studies are less prone to publication bias) addressing associations between estrogen levels and performance on neuropsychological tests of episodic memory or executive functions (including working memory; seven studies), or that reported results of placebo-controlled clinical trials of hormone therapy with objective measures within these cognitive domains (eight studies). Results were considered separately for midlife and late-life (age≥65 years) women. There were no consistent associations between endogenous serum estrogen concentrations and episodic memory or executive functions in naturally menopausal midlife women or in older postmenopausal women. Clinical trial findings suggested no substantial impact of exogenous estrogens on episodic memory or executive functions over time frames of up to several years. A quantitative synthesis of clinical trial results supported the inference of absence of effect. This overall conclusion of no substantial effect on episodic memory or executive functions might reassure women concerned by potential adverse cognitive consequences of menopause or of relatively short-term midlife hormone therapy. There was no apparent window of opportunity during which exogenous hormones might benefit near-term cognition, but included studies provided limited power to identify such a window. Conclusions are tempered by small numbers of studies, imprecise estimates of long-term estrogen exposures, and narrow range of neuropsychological tests. Long-term (late-life) cognitive consequence of midlife estrogen exposures are poorly addressed by current data, as are cognitive consequences of surgical menopause and cognitive consequences of exogenous estrogens during the menopause transition. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Association of DRD2 and DRD3 polymorphisms with Parkinson's disease in a multiethnic consortium.

OBJECTIVE: To examine genetic associations of polymorphisms in the dopamine receptor D2 (DRD2) and D3 (DRD3) genes with risk of Parkinson's disease (PD). METHODS: The study included 1325 newly diagnosed patients with PD and 1735 controls from a consortium of five North American case-control studies. We collected risk factor information by in-person or telephone interview. Six DRD2 and two DRD3 polymorphisms were genotyped using a common laboratory. Odds ratios were estimated using logistic regression. RESULTS: Among non-Hispanic whites, homozygous carriers of Taq1A DRD2 (rs1800497) polymorphism had an increased risk of PD compared to homozygous wildtype carriers (OR=1.5, 95% CI 1.0-2.3). In contrast, the direction of association for Taq1A polymorphism was opposite for African-Americans, showing an inverse association with PD risk (OR=0.10, 95% CI 0.2-0.7). Among white Hispanics who carried two alleles, the Ser9Gly DRD3 (rs6280) polymorphism was associated with a decreased risk of PD (OR=0.4, 95% CI 0.2-0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms. CONCLUSIONS: DRD2 polymorphisms are unlikely to be true disease-causing variants; however, three DRD2 polymorphisms (including Taq1A) may be in linkage disequilibrium with possible disease associated variants in the DRD2-ANKK1-NCAM1-TTC12 gene cluster.

Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease.

BACKGROUND AND PURPOSE: In 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine animal models of Parkinson's disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association. METHODS: Parkinson's Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population-based case-control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age- and sex-matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in-person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Two ADORA2A polymorphisms were inversely associated with PD risk - rs71651683, a 5' variant (adjusted allelic OR = 0.51, 95% CI 0.33-0.80, permutation-adjusted P = 0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wild-type genotype were 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively (permutation-adjusted P for trend = 0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee-PD association was strongest among subjects homozygous for either variant allele rs762551 (P(interaction) = 0.05) or rs2470890 (P(interaction) = 0.04). CONCLUSION: In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms.

Effect of reproductive factors and postmenopausal hormone use on the risk of Parkinson disease.

OBJECTIVE: Parkinson disease (PD) is less common in women possibly because of hormonal or reproductive influences. The objective of this study was to evaluate the associations of reproductive factors and postmenopausal hormone use with the risk of PD among postmenopausal women. METHODS: Incident cases (n = 178) and randomly selected age-matched controls (n = 189) who were members of the Kaiser Permanente Medical Care Program (KPMCP) of Northern California participated in the study conducted during the years 1994 to 1995. Statistical analyses were carried out using logistic regression. RESULTS: The association of postmenopausal hormone use with PD risk depended on the type of menopause. Among women with history of a hysterectomy with or without an oophorectomy, estrogen use alone was associated with a 2.6-fold increased risk (adjusted odds ratio (OR) 2.6, 95% CI: 1.1 to 6.1) and significant trends in the risk of PD were observed with increasing duration of estrogen use, but disease risk was not influenced by recency of use. In contrast, among women with natural menopause, no increased risk of PD was observed with hormone use (estrogen alone or a combined estrogen-progestin regimen). Early age at final menstrual period (44 years or younger) was associated with reduction in risk (adjusted OR 0.5, 95% CI: 0.3 to 1.0). Age at menarche and parity were not associated with the risk of PD. CONCLUSION: Postmenopausal use of estrogen alone may increase the risk of Parkinson disease (PD) among women with a hysterectomy. Among women with natural menopause for whom the usual treatment is combined estrogen-progestin therapy, no increased risk of PD was observed.

Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity.

PURPOSE: Botulinum neurotoxin type A (BoNT/A) is effective in the treatment of intractable detrusor overactivity (DO). In addition to its known inhibitory effect on presynaptic release of acetylcholine by motor terminals, there is increasing evidence that BoNT/A may affect sensory fibers. We investigated a possible effect of BoNT/A on human bladder afferent mechanisms by studying the sensory receptors P2X3 and TRPV1 in biopsies from patients with neurogenic or idiopathic DO. MATERIALS AND METHODS: A total of 38 patients (22 with neurogenic DO, 16 with idiopathic DO) with intractable DO were treated with intradetrusor BoNT/A, and bladder biopsies were taken at 4 and 16 weeks. Urodynamics and voiding diary were also recorded. Specimens were studied immunohistochemically for P2X3, TRPV1 and the pan-neuronal marker PGP9.5, in comparison with controls. RESULTS: P2X3-immunoreactive and TRPV1-immunoreactive (-IR) fibers were decreased at 4 weeks after BoNT/A, and more significantly at 16 weeks (paired t test p=0.0004 and p=0.0008, respectively), when significant improvements were observed in clinical and urodynamic parameters. P2X3-IR fiber decrease was significantly correlated with reduction of urgency episodes at 4 and 16 weeks (p=0.0013 at 4 weeks and p=0.02 at 16 weeks), but not maximum cystometric capacity or detrusor pressures. TRPV1-IR fiber decrease showed a similar trend. PGP9.5-IR suburothelial fibers remained unchanged after treatment at both followups (p=0.85 and p=0.21 at 4 and 16 weeks, respectively). Urothelial cell P2X3-IR and TRPV1-IR also appeared unchanged. CONCLUSIONS: Decreased levels of sensory receptors P2X3 and/or TRPV1 may contribute to the clinical effect of BoNT/A in detrusor overactivity.

The relationship between mucosal cyclooxygenase-2 (COX-2) expression and experimental radiation-induced mucositis.

Although cycloooxygenase-2 (COX-2) is upregulated by factors associated with oral mucositis, its role in the pathogenesis of mucositis has not been studied. We investigated the kinetics of mucosal COX-2 expression following radiation exposure, and assessed its relationship to the development of oral mucositis in an established animal model using immunohistochemical endpoints. While little or no COX-2 expression was observed in unirradiated mucosa or in tissue taken 2 days after radiation, COX-2 expression was dramatic on days 10 and 16, especially in submucosal fibroblasts and endothelium. The kinetics of COX-2 expression paralleled mucositis severity. A burst of angiogenic activity was seen on day 21 following peak COX-2 expression. The kinetics of COX-2 expression relative to mucositis progression suggests that COX-2 is not a primary driver of radiation injury, but instead plays an amplifying role.

Rehabilitation of balance in two patients with cerebellar dysfunction.

The treatment of two patients with cerebellar dysfunction is described. One patient was a 36-year-old woman with a 7-month history of dizziness and unsteadiness following surgical resection of a recurrent pilocystic astrocytoma located in the cerebellar vermis. The other patient was a 48-year-old man with cerebrotendinous xanthomatosis (CTX) and diffuse cerebellar atrophy, and a 10-year history of progressive gait and balance difficulties. Each patient was treated with a 6-week course of physical therapy that emphasized the practice of activities that challenged stability. The patient with the cerebellar tumor resection also performed eye-head coordination exercises. Each patient had weekly therapy and performed selected balance retraining exercises on a daily basis at home. Measurements taken before and after treatment for each patient included self-perception of symptoms, clinical balance tests, and stability during selected standing and gait activities; for the patient with the cerebellar tumor resection, vestibular function tests and posturography were also performed. Both patients reported improvements in symptoms and demonstrated similar improvements on several kinematic indicators of stability during gait. The patient with the cerebellar tumor resection improved on posturography following treatment, whereas the patient with CTX improved on clinical balance tests. This case report describes two individualized treatment programs and documents functional improvements in two patients with different etiologies, durations, and clinical presentations of cerebellar dysfunction. The outcomes suggest that patients with cerebellar lesions, acute or chronic, may be able to learn to improve their postural stability.

12(S)-HETE increases the motility of prostate tumor cells through selective activation of PKC alpha.

Prostate carcinoma has become the second most fatal cancer in American men. In rat Dunning prostate adenocarcinoma cells, increased cellular motility has been associated positively with their increased metastatic potential. However, the mechanism(s) responsible for regulation of tumor cell motility is poorly understood. We have reported that a lipoxygenase metabolite of arachidonic acid 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] augments tumor cell metastatic potential through activation of protein kinase C (PKC). We report here that 12(S)-HETE increased the motility of AT2.1 cells and this 12(S)-HETE increased motility was inhibited by PKC inhibitor calphostin C. Western blot analysis revealed that AT2.1 cells expressed the Ca(2+)-dependent PKC isoform alpha and Ca(2+)-independent PKC isoform delta. Pretreatment of cells with a Ca2+ chelator BAPTA blocked the 12(S)-HETE increased motility. Further, the motility of AT2.1 cells was increased in a dose dependent manner by thymelea toxin, a selective PKC alpha activator. Our data demonstrate that 12(S)-HETE augments the motility of AT2.1 cells via its selective activation of PKC alpha which may serve as a key target for the development of antimetastatic drugs useful for combating prostate cancers.

Biomechanical analysis of failed sit-to-stand.

Background sit-to-stand (STS) failure is a transient loss of balance that can engender falls among elders. The purpose of this paper is to describe the mechanisms whereby failed STS differs from successful STS. The authors compared successful STS from 11 normal elders to 20 "sitback" and 20 "step" type failed STS's in 13 subjects. Kinematic and kinetic data were incorporated into our 11-segment whole body model to estimate the net joint forces and torques and body segment momenta. Significant between group differences in the magnitude and timing of momentum generation and dissipation, knee extensor torques and the magnitude of the vertical ground reaction force were identified. Both types of failed sit-to-stand maneuvers are less energetic than successful rises. STS failures might result from either weakness or balance control and coordination impairment, or both, resulting in an insufficiently energetic effort. Further research is required to differentiate between these two possible sources of impairment. Determining the root cause of functional limitations is necessary to develop effective interventions.

Quantitative assessment of four men using above-elbow prosthetic control.

We studied the relationship between kinematically unconstrained activities of daily living (ADL) tasks and a kinematically constrained task in above-elbow (AE) amputee subjects using myoelectrically controlled prostheses. Four men, 24 to 49 years old, with unilateral AE amputation wore a prosthesis interfaced to a programmable controller to emulate two different elbow control schemes, conventional velocity and a new "natural" controller. Subjects were timed during three ADL tasks--cutting meat, donning socks, and rolling dough--with both controllers. The prosthesis emulator was then connected to a crank device with a handle, and the subjects turned the crank from bottom to top positions in a vertical plane using each controller. Synergistic shoulder-elbow joint coordination required for crank turning was quantified as the maximum slope of the change in elbow torque versus the change in crank-angle. Performance between the two controllers differed significantly for the crank test but not for ADL tasks. One subject did not complete all crank turning tests. Positive canonical correlation of 0.77 was found between time and crank domain measures. We conclude that biomechanical assessments should be integrated with time-based clinical tests to comprehensively evaluate performance of AE amputee subjects with a myoelectric device.

Mode of action of dl-norgestrel and ethinylestradiol combination in postcoital contraception. II. Effect of postovulatory administration on ovarian function and endometrium.

A combination of 1.0 mg dl-norgestrel and 0.1 mg ethinylestradiol (EE) was administered orally at 36 hours after the detection of the luteinizing hormone peak and again at 48 hours in 12 healthy volunteers with normal menstrual cycles. The effects on ovarian function were studied by comparing the daily serum levels of progesterone (P), 17 alpha-hydroxyprogesterone, and estradiol (E2) in control (placebo) and treatment cycles. Five subjects showed no significant change in the levels of these steroids but had a shortened luteal phase. The treatment significantly decreased both P and E2 levels in three subjects, while two subjects showed diminished E2 levels only. The remaining two subjects had lower P levels and fluctuating E2 patterns. Endometrial biopsies from both study cycles indicated asynchronous development of the epithelial and stromal components in the treatment cycle. These findings (abnormal luteal phase steroid levels and duration and outphased endometrial development) indicate that corpus luteum function was variously affected by the action of norgestrel-EE treatment.

PIP: A combination of 1.0 mg dl-norgestrel and 0.1 mg ethinyl estradiol (EE) was administered orally at 36 hours after detection of the luteinizing hormone peak and again at 48 hours in 12 healthy volunteers with normal menstrual cycles. The effects on ovarian functions were studied by comparing the daily serum levels of progesterone (P), 17alpha-hydroxyprogesterone, and estradiol (E2) in control (placebo) and treatment cycles. 5 subjects showed no significant changes in the levels of these steroids but had a shortened luteal phase. The treatment significantly decreased both P and E2 levels in 3 subjects, while 2 subjects showed diminished E2 levels only. The remaining 2 subjects had lower P levels and fluctuating E2 patterns. Endometrial biopsies from both study cycles indicated asynchronous development of the epithelial and stromal components in the treatment cycle. These findings (abnormal luteal phase steroid levels and duration and outphased endometrial development) indicate that corpus luteum function was variously affected by the action of norgestrel-EE treatment.

The effect of estrogen priming on induction of labor with prostaglandins.

A double-blind, randomized study was designed to determine whether estrogen "priming" of the unripe cervix followed by prostaglandin induction of labor would have a synergistic effect on cervical ripening and improve the success rate of induction. One hundred near-term patients with Bishop scores less than or equal to 4 received an intramuscular injection of either 10 mg of estradiol valerate or a placebo 48 hours prior to induction of labor with oral prostaglandin E2. The serial changes in Bishop scores were very similar in both groups. The success rate of induction in the study group (69.8%) was not statistically different from that in the control group (61.9%). The duration of labor was 9.9 +/- 4.1 hours in the study group versus 9.1 +/- 3.7 hours in the control group (not significant). This study showed that 10 mg of estradiol valerate had no detectable effect on the unripe cervix near term and did not show a synergistic effect with prostaglandins during induction of labor.

Influence of maternal oxygen administration on the term fetus before labor.

Thirty-two healthy pregnant women at term who were to undergo cesarean section following epidural anesthesia were randomly assigned to receive preoperatively, by face mask, room air or oxygen for more than 10 minutes. Patients were kept at a left lateral tilt position of 15 degrees and were unaware which gas was administered. Oxygenation significantly increased (p less than 0.05) maternal PO2 to 283 mm Hg (SD 67). The cord vein PO2 of the group receiving oxygen was 34 mm Hg (SD 6), significantly higher (p less than 0.01) than the value of 26 mm Hg (SD 7) in the group receiving room air. The cord artery PO2 of the oxygen group was also significantly higher (p less than 0.05) at 20 mm Hg (SD 6) versus 15 mm Hg (SD 6). No other cord gas values were significantly different. There was no significant difference in the cord vein-artery PO2 differential. There was no significant difference in the infants' hematocrits determined at 4 hours of age in the two groups. All infants were in excellent condition (1-minute Apgar score greater than or equal to 8).