Thermoregulatory cutaneous vasodilatation (VD) is attenuated in aged skin. While acetylcholine (ACh) plays a role in thermally mediated VD, the precise mechanisms through which ACh-mediated VD acts and whether those downstream mechanisms change with ageing are unclear. We tested the hypotheses that both nitric oxide (NO)- and prostanoid-mediated pathways contribute to exogenous ACh-mediated VD, and that both are attenuated with advanced age. Twelve young (Y: 23 +/- 1 years) and 10 older (O: 69 +/- 1 years) subjects underwent infusions of 137.5 mum ACh at four intradermal microdialysis sites: control (C, Ringer solution), NO synthase inhibited (NOS-I, 10 mm l-NAME), cyclooxygenase inhibited (COX-I, 10 mm ketorolac) and NOS-I + COX-I. Red blood cell flux was monitored using laser-Doppler flowmetry, and cutaneous vascular conductance (CVC) was calculated (laser-Doppler flux/mean arterial pressure) and normalized to maximal CVC (%CVC(max)) (28 mm sodium nitroprusside + local heating to 43 degrees C). Baseline %CVC(max) was increased in the O at COX-I sites (COX-I 16 +/- 1, NOS-I + COX-I 16 +/- 2 versus C 10 +/- 1%CVC(max); P < 0.001) but not in the young, suggesting an age-related shift toward COX vasoconstrictors contributing to basal cutaneous vasomotor tone. There was no difference in peak %CVC(max) during ACh infusion between age groups, and the response was unchanged by NOS-I (O: NOS-I 35 +/- 5 versus C 38 +/- 5%CVC(max); P = 0.84) (Y: NOS-I 41 +/- 4 versus C 39 +/- 4%CVC(max); P = 0.67). COX-I and NOS-I + COX-I attenuated the peak CVC response to ACh in both groups (COX-I O: 29 +/- 3, Y: 22 +/- 2%CVC(max) versus C; P < 0.001 both groups; NOS-I + COX-I O: 32 +/- 3 versus Y: 29 +/- 2%CVC(max); versus C; P < 0.001 both groups). ACh mediates cutaneous VD through prostanoid and non-NO-, non-prostanoid-dependent pathways. Further, older subjects have a diminished prostanoid contribution to ACh-mediated VD.

The present study examined the time and frequency structure of force output in adult humans to determine whether the changes in complexity with age are dependent on external task demands. Healthy young (20-24 yr), old (60-69 yr), and older-old (75-90 yr) humans produced isometric force contractions to constant and sine wave targets that also varied in force level. First, force variability on each force task increased with advancing age. Second, both time and frequency analysis showed that the structure of the force output in the old and older-old adults was less complex in the constant-force level task and more complex in the sine wave force task. Third, the alterations in force output with aging were primarily due to low-frequency bands <4 Hz. These results support the postulation that the observed increase or decrease in physiological complexity with aging is influenced by the relatively fast time scale of external task demands (Vaillancourt DE and Newell KM. Neurobiol Aging 23: 1-11, 2002).

We tested the hypothesis that differences in sympathetic reflex responses to head-up tilt (HUT) between males (n = 9) and females (n = 8) were associated with decrements in postural vasomotor responses in women. Muscle sympathetic nerve activity (MSNA; microneurography), heart rate, stroke volume (SV; Doppler), and blood pressure (Finapres) were measured during a progressive HUT protocol (5 min at each of supine, 20 degrees, 40 degrees, and 60 degrees ). MSNA and hemodynamic responses were also measured during the cold pressor test (CPT) to examine nonbaroreflex neurovascular control. SV was normalized to body surface area (SV(i)) to calculate the index of cardiac output (Q(i)), and total peripheral resistance (TPR). During HUT, heart rate increased more in females versus males (P < 0.001) and SV(i) and Q(i) decreased similarly in both groups. Mean arterial pressure (MAP) increased to a lesser extent in females versus males in the HUT (P < 0.01) but increases in TPR during HUT were similar. MSNA burst frequency was lower in females versus males in supine (P < 0.03) but increased similarly during HUT. Average amplitude/burst increased in 60 degrees HUT for males but not females. Both males and females demonstrated an increase in MAP as well as MSNA burst frequency, mean burst amplitude, and total MSNA during the CPT. However, compared with females, males demonstrated a greater neural response (DeltaTotal MSNA) due to a larger increase in mean burst amplitude (P < 0.05). Therefore, these data point to gender-specific autonomic responses to cardiovascular stress. The different MSNA response to postural stress between genders may contribute importantly to decrements in blood pressure control during HUT in females.

OBJECTIVE

The purpose of this study was to examine whether television viewing (TVV) provides a context for patterns of snacking fostering overweight in young girls from overweight and non-overweight families.

METHODS

Participants were 173 non-Hispanic white girls and their parents from central Pennsylvania, assessed longitudinally when girls were 5, 7, and 9 years old. Path analysis was used to test patterns of relationships among girls' TVV, snacking while watching television, snacking frequency, fat intake from energy-dense snack food, and girls' increase in body mass index (BMI) from age 5 to 9.

RESULTS

In both overweight and non-overweight families, girls who watched more television consumed more snacks in front of the television. In families where neither parent was overweight, television viewing was the only significant predictor of girls' increase in BMI. In families where one or both parents were overweight, girls who watched more television snacked more frequently, and girls who snacked more frequently had higher intakes of fat from energy-dense snacks, which predicted their increase in BMI from age 5 to 9. TVV did not directly predict girls' increase in BMI in girls from overweight families.

CONCLUSIONS

The results of this study support and extend previous findings that have shown that excessive television viewing and snacking patterns are risk factors for the development of overweight in children; however, patterns of relationships may differ based on parental weight status. For overweight families, TVV may provide a context for excessive snack consumption, in addition to inactivity.

Recent magnetic resonance imaging studies suggest an increased transverse relaxation rate and reduced diffusion tensor imaging fractional anisotropy values in the substantia nigra in Parkinson's disease. The transverse relaxation rate and fractional anisotropy changes may reflect different aspects of Parkinson's disease-related pathological processes (ie, tissue iron deposition and microstructure disorganization). This study investigated the combined changes of transverse relaxation rate and fractional anisotropy in the substantia nigra in Parkinson's disease. High-resolution magnetic resonance imaging (T2-weighted, T2*, and diffusion tensor imaging) were obtained from 16 Parkinson's disease patients and 16 controls. Bilateral substantia nigras were delineated manually on T2-weighted images and coregistered to transverse relaxation rate and fractional anisotropy maps. The mean transverse relaxation rate and fractional anisotropy values in each substantia nigra were then calculated and compared between Parkinson's disease subjects and controls. Logistic regression, followed by receiver operating characteristic curve analysis, was employed to investigate the sensitivity and specificity of the combined measures for differentiating Parkinson's disease subjects from controls. Compared with controls, Parkinson's disease subjects demonstrated increased transverse relaxation rate (P<.0001) and reduced fractional anisotropy (P=.0365) in the substantia nigra. There was no significant correlation between transverse relaxation rate and fractional anisotropy values. Logistic regression analyses indicated that the combined use of transverse relaxation rate and fractional anisotropy values provides excellent discrimination between Parkinson's disease subjects and controls (c-statistic=0.996) compared with transverse relaxation rate (c-statistic=0.930) or fractional anisotropy (c-statistic=0.742) alone. This study shows that the combined use of transverse relaxation rate and fractional anisotropy measures in the substantia nigra of Parkinson's disease enhances sensitivity and specificity in differentiating Parkinson's disease from controls. Further studies are warranted to evaluate the pathophysiological correlations of these magnetic resonance imaging measurements and their effectiveness in assisting in diagnosing Parkinson's disease and following its progression.

We have studied human melanoma cell (C8161) adhesion and migration in response to stimulation by soluble collagen IV (CIV) using a modified Boyden chamber. In this modified chamber, shear flow can be introduced over the cell-substrate interface, affecting tumor cell chemotactic migration through a microporous filter. A relatively high level of intercellular adhesion molecule-1 (ICAM-1) was found on C8161 cells. In contrast, levels of beta(2)-integrins (e.g., LFA-1 and Mac-1), the molecules that would be necessary for C8161 stable adhesion to the endothelium substrate, were found to be very low on these melanoma cells. As a result, C8161 transendothelial migration under a flow condition of 4 dyn/cm(2) decreased by 70% as compared to static migration. When human neutrophils (PMNs) were present in the tumor cell suspension, C8161 migration recovered by 85% over C8161 cells alone under the 4 dyn/cm(2) flow condition. Blocking ICAM-1 on C8161 cells or Mac-1 on PMNs significantly inhibited C8161-PMN adhesion and subsequent C8161 migration through the endothelium under flow conditions. In addition, increased interleukin-8 production and Mac-1 expression by PMNs were detected when they were co-cultured with C8161 melanoma cells. These results suggest that transmigration of C8161 cells under flow conditions can be influenced by PMNs, mediated by Mac-1/ICAM-1 adhesive interactions and enhanced by altered cytokine production.

In this study, we tested several hypotheses related to changes in finger interaction and multifinger synergies during multifinger force production tasks in Parkinson's disease. Ten patients with Parkinson's disease, mostly early stage, and 11 healthy control subjects participated in the study. Synergies were defined as covaried adjustment of commands to fingers that stabilized the total force produced by the hand. Both Parkinson's disease patients and control subjects performed accurate isometric force production tasks with the fingers of both the dominant and nondominant hands. The Parkinson's disease patients showed significantly lower maximal finger forces and higher unintended force production (enslaving). These observations suggest that changes in supraspinal control have a major effect on finger individuation. The synergy indexes in the patients were weaker in both steady-state and cyclic force production tasks compared with the controls. These indexes also were stronger in the left (nondominant) hand in support of the dynamic-dominance hypothesis. Half of the patients could not perform the cyclic task at the highest frequency (2 Hz). Anticipatory adjustments of synergies prior to a quick force pulse production were delayed and reduced in the patients compared with the controls. Similar differences were observed between the asymptomatic hands of the patients with symptoms limited to one side of the body and matched hands of control subjects. Our study demonstrates that the elusive changes in motor coordination in Parkinson's disease can be quantified objectively, even in patients at a relatively early stage of the disease. The results suggest an important role of the basal ganglia in synergy formation and demonstrate a previously unknown component of impaired feedforward control in Parkinson's disease reflected in the reduced and delayed anticipatory synergy adjustments.

BACKGROUND

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is believed to have a genetic basis. However, no specific susceptibility gene or region has been conclusively identified.

OBJECTIVE

The objective of this study was to duplicate a previous study that localized a PCOS susceptibility region to chromosome 19p13.2 and to narrow the susceptibility region.

METHODS

This study was designed to test for genetic linkage and association between PCOS and short tandem repeat polymorphisms in 367 families, by analysis of linkage and family-based association.

METHODS

The study was conducted at academic medical centers.

METHODS

We studied 367 families of predominantly European origin with at least one PCOS patient. Families included 107 affected sibling (sister) pairs (ASPs) in 83 families, and 390 trios with both parents and an affected daughter. The data set comprises two independent groups. Set 1 consists of 44 ASPs and 163 trios. Set 2 consists of 63 ASPs and 227 trios.

METHODS

The intervention was the drawing of blood for DNA extraction.

METHODS

We employed measures of evidence for linkage and association between PCOS and 19 STRs.

RESULTS

Linkage with PCOS was observed over a broad region of chromosome 19p13.2. The strongest evidence for association was observed with D19S884 (chi2 = 11.85; nominal P < 0.0006; permutation P = 0.034) and duplicated our earlier findings.

CONCLUSIONS

The present analysis suggests that a PCOS susceptibility locus maps very close to D19S884. Additional studies that systematically characterize DNA sequence variation in the immediate area of D19S884 are required to identify the PCOS susceptibility variant.

In this study, food-deprived (18 h) control rats and rats with alloxan-induced diabetes were orally administered saline or the amino acid leucine to assess whether it regulates protein synthesis independently of a change in serum insulin concentrations. Immediately after leucine administration, diabetic rats were infused with insulin (0.0, 4.0, or 20 pmol small middle dot min(-1) small middle dot kg(-1)) for 1 h to examine the role of the hormone in the protein synthetic response to leucine. In control rats, leucine stimulated protein synthesis by 58% and increased phosphorylation of the translational repressor, eukaryotic initiation factor (eIF) 4E-binding protein (BP)-1, 4E-BP1, fivefold. Consequently, association of the mRNA cap-binding protein eukaryotic initiation factor (eIF)4E with 4E-BP1 was reduced to 50% of control values, and eIF4G*eIF4E complex assembly was increased 80%. Furthermore, leucine increased the phosphorylation of the 70-kDa ribosomal protein S6 (rp S6) and the ribosomal protein S6 kinase (S6K1). Diabetes attenuated protein synthesis compared with control rats. Nonetheless, in diabetic rats, leucine increased protein synthesis by 53% without concomitant changes in the phosphorylation of 4E-BP1 or S6K1. Skeletal muscle protein synthesis was stimulated in diabetic rats infused with insulin, but rates of synthesis remained less than values in nondiabetic controls that were administered leucine. Phosphorylation of 4E-BP1 and S6K1 was increased in diabetic rats infused with insulin in a dose-dependent manner, and the response was enhanced by leucine. The results suggest that leucine enhances protein synthesis in skeletal muscle through both insulin-dependent and -independent mechanisms. The insulin-dependent mechanism is associated with increased phosphorylation of 4E-BP1 and S6K1. In contrast, the insulin-independent effect on protein synthesis is mediated by an unknown mechanism.

The pattern of dopamine cell loss in Parkinson's disease (PD) is known to be prominent in the ventrolateral and caudal substantia nigra (SN), but less severe in the dorsal and rostral region. Both diffusion tensor imaging (DTI) and R2* relaxometry of the SN have been reported as potential markers for PD, but their relative ability to mark disease progression and differences in pathophysiological bases remains unclear. High-resolution T2-weighted, R2*, and DTI were obtained from 28 controls and 40 PD subjects [15 early stage [disease duration ≤1 year], 14 mid stage [duration 2-5 years], and 11 late stage [duration >5 years]). Fractional anisotropy and R2* values in both rostral and caudal SN were obtained for all subjects, and clinical measures (e.g., disease duration, levodopa-equivalent daily dosage, and "off"-drug UPDRS motor score) were obtained for Parkinson's subjects. There was no correlation between fractional anisotropy and clinical measures, whereas R2* was strongly associated with disease progression. Compared to controls, fractional anisotropy in caudal SN was significantly decreased in PD patients of all stages, whereas in rostral SN, it was decreased significantly only in the late-stage group. R2* in both SN regions was significantly increased in the mid- and late-stage, but not early-stage, of PD subjects. These findings suggest that fractional anisotropy changes may mark early pathological changes in caudal SN, whereas the changes in R2* may more closely track PD's clinical progression after symptom onset.

OBJECTIVE

A priority for research is to identify individuals early in development who are particularly susceptible to weight gain in the current, obesogenic environment. This longitudinal study investigated whether early individual differences in inhibitory control, an aspect of temperament, predicted weight outcomes and whether parents' restrictive feeding practices moderated this relation.

METHODS

Participants included 197 non-Hispanic white girls and their parents; families were assessed when girls were 5, 7, 9, 11, 13, and 15 years old. Measures included mothers' reports of girls' inhibitory control levels, girls' reports of parental restriction in feeding, girls' body mass indexes (BMIs), and parents' BMIs, education, and income.

RESULTS

Girls with lower inhibitory control at age 7 had higher concurrent BMIs, greater weight gain, higher BMIs at all subsequent time points, and were 1.95 times more likely to be overweight at age 15. Girls who perceived higher parental restriction exhibited the strongest inverse relation between inhibitory control and weight status.

CONCLUSIONS

Variability in inhibitory control could help identify individuals who are predisposed to obesity risk; the current findings also highlight the importance of parenting practices as potentially modifiable factors that exacerbate or attenuate this risk.

The pathogenesis of acne has been linked to multiple factors such as increased sebum production, inflammation, follicular hyperkeratinization, and the action of Propionibacterium acnes within the follicle. In an attempt to understand the specific genes involved in inflammatory acne, we performed gene expression profiling in acne patients. Skin biopsies were obtained from an inflammatory papule and from normal skin in six patients with acne. Biopsies were also taken from normal skin of six subjects without acne. Gene array expression profiling was conducted using Affymetrix HG-U133A 2.0 arrays comparing lesional to nonlesional skin in acne patients and comparing nonlesional skin from acne patients to skin from normal subjects. Within the acne patients, 211 genes are upregulated in lesional skin compared to nonlesional skin. A significant proportion of these genes are involved in pathways that regulate inflammation and extracellular matrix remodeling, and they include matrix metalloproteinases 1 and 3, IL-8, human beta-defensin 4, and granzyme B. These data indicate a prominent role of matrix metalloproteinases, inflammatory cytokines, and antimicrobial peptides in acne lesions. These studies are the first describing the comprehensive changes in gene expression in inflammatory acne lesions and are valuable in identifying potential therapeutic targets in inflammatory acne.

OBJECTIVE

To report the baseline characteristics and racial differences in the polycystic ovary syndrome (PCOS) phenotype from a large multicenter clinical trial (PPCOS).

METHODS

Double-blind, randomized trial of three treatment regimens (with extended release metformin or clomiphene citrate).

METHODS

Academic medical centers.

METHODS

Six hundred twenty-six infertile women with PCOS, aged 18-39 years, with elevated T levels and oligomenorrhea (exclusion of secondary causes), seeking pregnancy, with>> or = 1 patent fallopian tube, normal uterine cavity, and a partner with sperm concentration>> or = 20 x 10(6)/mL in>> or = 1 ejaculate.

METHODS

Baseline characterization.

METHODS

Historical, biometric, and biochemical measures of PCOS.

RESULTS

There were no significant differences in baseline variables between treatment groups. The overall mean (+/-SD) age of the subjects was 28.1 +/- 4.0 years, and the mean body mass index was 35.2 kg/m2 (+/-8.7). Polycystic ovaries (PCOs) were present in 90.3% of the subjects, and the mean volume of each ovary was 10 cm3 or more. Of the subjects, 7% had ovaries that were discordant for PCO morphology. At baseline, 18.3% of the subjects had an abnormal fasting glucose level >> 100 mg/dL). Asians tended to have a milder phenotype, and whites and African Americans were similar in these measures.

CONCLUSIONS

The treatment groups were well matched for baseline parameters, and we have added further information to the PCOS phenotype.

Previous studies have shown that neutrophils (PMNs) facilitate melanoma cell extravasation [M.J. Slattery, C. Dong, Neutrophils influence melanoma adhesion and migration under flow conditions, Intl. J. Cancer 106 (2003) 713-722] Little is known, however, about the specific interactions between PMNs, melanoma and the endothelium (EC) or the molecular mechanism involved under flow conditions. The aim of this study is to investigate a "two-step adhesion" hypothesis that involves initial PMN tethering on the EC and subsequent melanoma cells being captured by tethered PMNs. Different effects of hydrodynamic shear stress and shear rate were analyzed using a parallel-plate flow chamber. Results indicate a novel finding that PMN-facilitated melanoma cell arrest on the EC is modulated by shear rate, which is inversely-proportional to cell-cell contact time, rather than by the shear stress, which is proportional to the force exerted on formed bonds. Beta2 integrins/ICAM-1 adhesion mechanisms were examined and the results indicate LFA-1 and Mac-1 cooperate to mediate the PMN-EC-melanoma interactions under shear conditions. In addition, endogenously produced IL-8 contributes to PMN-facilitated melanoma arrest on the EC through the CXC chemokine receptors 1 and 2 (CXCR1 and CXCR2) on PMN. These results provide new evidence for the complex role of hemodynamic forces, secreted chemokines and PMN-melanoma adhesion in the recruitment of metastatic cancer cells to the EC.

Breast cancer preferentially metastasizes to the skeleton, a hospitable environment that attracts and allows breast cancer cells to thrive. Growth factors released as bone is degraded support tumor cell growth, and establish a cycle favoring continued bone degradation. While the osteoclasts are the direct effectors of bone degradation, we found that osteoblasts also contribute to bone loss. Osteoblasts are more than intermediaries between tumor cells and osteoclasts. We have presented evidence that osteoblasts contribute through loss of function induced by metastatic breast cancer cells. Metastatic breast cancer cells suppress osteoblast differentiation, alter morphology, and increase apoptosis. In this study we show that osteoblasts undergo an inflammatory stress response in the presence of human metastatic breast cancer cells. When conditioned medium from cancer cells was added to human osteoblasts, the osteoblasts were induced to express increased levels of IL-6, IL-8, and MCP-1; cytokines known to attract, differentiate, and activate osteoclasts. Similar findings were seen with murine osteoblasts and primary murine calvarial osteoblasts. Osteoblasts are co-opted into creating a microenvironment that exacerbates bone loss and are prevented from producing matrix proteins for mineralization. This is the first study implicating osteoblast produced IL-6, IL-8 (human; MIP-2 and KC mouse), and MCP-1 as key mediators in the osteoblast response to metastatic breast cancer cells.

OBJECTIVE

Hyperandrogenia and insulin resistance are heritable family traits, likely to cluster in children of polycystic ovary syndrome (PCOS) mothers.

METHODS

We performed a case control study of PCOS children (n = 32) compared with children from control women (n = 38) for reproductive and metabolic abnormalities, stratifying results by three Tanner stage groupings. The children underwent history and physical examinations, a 3-h timed urine collection, a 2-h oral glucose tolerance test, and abdominal ultrasound examination (females only). Serum was obtained in older children (age>> 8 yr) who consented.

RESULTS

Urine LH levels were significantly lower in the Tanner IV-V PCOS girls compared with controls (P = 0.04). Urine testosterone levels were significantly elevated in Tanner II-III PCOS boys compared with controls (P = 0.007). There were no significant differences in dehydroepiandrosterone levels. We validated the correlation between salivary and serum levels of insulin (insulin areas under the curve) in an adult population [n =30, Pearson correlation coefficient (r) = 0.67; P < 0.0001], which also replicated in the children (2-h insulin r = 0.57; P = 0.0004). Mean area under the curve salivary insulin levels were significantly higher in the Tanner IV-V PCOS girls in the later stages of puberty when compared with controls (3625 +/- 1372 vs. 1766 +/- 621 min x muU/ml, 95% confidence interval 475-3242; P < 0.02).

CONCLUSIONS

Hyperinsulinism may be a familial characteristic of PCOS children (or at least girls) but does not appear until the later stages of puberty. Other reproductive abnormalities that characterize PCOS may develop later.

OBJECTIVE

The objective of the study was to examine the effects of an exercise/diet lifestyle intervention on free fatty acid (FFA)-induced hepatic insulin resistance in obese humans.

METHODS

Obese men and women (n = 23) with impaired glucose tolerance were randomly assigned to either exercise training with a eucaloric (EU; approximately 1800 kcal; n = 11) or hypocaloric (HYPO; approximately 1300 kcal; n = 12) diet for 12 wk. Hepatic glucose production (HGP; milligrams per kilogram fat-free mass(-1) per minute(-1)) and hepatic insulin resistance were determined using a two-stage sequential hyperinsulinemic (40 mU/m(2) . min(-1)) euglycemic (5.0 mm) clamp with [3-(3)H]glucose. Measures were obtained at basal, during insulin infusion (INS; 120 min), and insulin plus intralipid/heparin infusion (INS/FFA; 300 min).

RESULTS

At baseline, basal HGP was similar between groups; hyperinsulinemia alone did not completely suppress HGP, whereas INS/FFA exhibited less suppression than INS (EU, 4.6 +/- 0.8, 2.0 +/- 0.5, and 2.6 +/- 0.4; HYPO, 3.8 +/- 0.5, 1.2 +/- 0.3, and 2.3 +/- 0.4, respectively). After the intervention the HYPO group lost more body weight (P < 0.05) and fat mass (P < 0.05). However, both lifestyle interventions reduced hepatic insulin resistance during basal (P = 0.005) and INS (P = 0.001) conditions, and insulin-mediated suppression of HGP during INS was equally improved in both groups (EU: -42 +/- 22%; HYPO: -50 +/- 20%, before vs. after, P = 0.02). In contrast, the ability of insulin to overcome FFA-induced hepatic insulin resistance and HGP was improved only in the HYPO group (EU: -15 +/- 24% vs. HYPO: -58 +/- 19%, P = 0.02).

CONCLUSIONS

Both lifestyle interventions are effective in reducing hepatic insulin resistance under basal and hyperinsulinemic conditions. However, the reversal of FFA-induced hepatic insulin resistance is best achieved with a combined exercise/caloric-restriction intervention.

Previous research has shown that early maturing girls at age 11 have lower subsequent physical activity at age 13 in comparison to later maturing girls. Possible reasons for this association have not been assessed. This study examines girls' psychological response to puberty and their enjoyment of physical activity as intermediary factors linking pubertal maturation and physical activity. Participants included 178 girls who were assessed at age 11, of whom 168 were reassessed at age 13. All participants were non-Hispanic white and resided in the US. Three measures of pubertal development were obtained at age 11 including Tanner breast stage, estradiol levels, and mothers' reports of girls' development on the Pubertal Development Scale (PDS). Measures of psychological well-being at ages 11 and 13 included depression, global self-worth, perceived athletic competence, maturation fears, and body esteem. At age 13, girls' enjoyment of physical activity was assessed using the Physical Activity Enjoyment Scale and their daily minutes of moderate-to-vigorous physical activity (MVPA) were assessed using objective monitoring. Structural Equation Modeling was used to assess direct and indirect pathways between pubertal development at age 11 and MVPA at age 13. In addition to a direct effect of pubertal development on MVPA, indirect effects were found for depression, global self-worth and maturity fears controlling for covariates. In each instance, more advanced pubertal development at age 11 was associated with lower psychological well-being at age 13, which predicted lower enjoyment of physical activity at age 13 and in turn lower MVPA. Results from this study suggest that programs designed to increase physical activity among adolescent girls should address the self-consciousness and discontent that girls' experience with their bodies during puberty, particularly if they mature earlier than their peers, and identify activities or settings that make differences in body shape less conspicuous.

Shear rate is significantly lower in the superficial femoral compared with the brachial artery in the supine posture. The relative shear rates in these arteries of subjects in the upright posture (seated and/or standing) are unknown. The purpose of this investigation was to test the hypothesis that upright posture (seated and/or standing) would produce greater shear rates in the superficial femoral compared with the brachial artery. To test this hypothesis, Doppler ultrasound was used to measure mean blood velocity (MBV) and diameter in the brachial and superficial femoral arteries of 21 healthy subjects after being in the supine, seated, and standing postures for 10 min. MBV was significantly higher in the brachial compared with the superficial femoral artery during upright postures. Superficial femoral artery diameter was significantly larger than brachial artery diameter. However, posture had no significant effect on either brachial or superficial femoral artery diameter. The calculated shear rate was significantly greater in the brachial (73 +/- 5, 91 +/- 11, and 97 +/- 13 s(-1)) compared with the superficial femoral (53 +/- 4, 39 +/- 77, and 44 +/- 5 s(-1)) artery in the supine, seated, and standing postures, respectively. Contrary to our hypothesis, our current findings indicate that mean shear rate is lower in the superficial femoral compared with the brachial artery in the supine, seated, and standing postures. These findings of lower shear rates in the superficial femoral artery may be one mechanism for the higher propensity for atherosclerosis in the arteries of the leg than of the arm.

OBJECTIVE

Physical activity has been shown to enhance quality of life (QOL); however, few investigations of these effects exist in women undergoing the menopausal transition. The present study examined the long-term effects of physical activity on menopause-related QOL and tested the mediating effects of physical self-worth and positive affect in this relationship.

METHODS

Middle-aged women previously enrolled in a 4-month randomized controlled trial involving walking and yoga, and a control group completed a follow-up mail-in survey 2 years after the end of the trial. The survey included a battery of psychological and physical activity measures, including measures of menopausal symptoms and menopause-related QOL. Longitudinal linear panel analysis was conducted within a covariance modeling framework to test whether physical self-worth and positive affect mediated the physical activity-QOL relationship over time.

RESULTS

At the end of the trial, physical activity and menopausal symptoms were related to physical self-worth and positive affect, and in turn, greater levels of physical self-worth and positive affect were associated with higher levels of menopause-related QOL. Analyses indicated that increases in physical activity and decreases in menopausal symptoms over the 2-year period were related to increases in physical self-worth (betas = 0.23 and -0.52, physical activity and menopausal symptoms, respectively) and, for symptoms, also to decreased positive affect (beta = -0.47), and both physical self-worth (beta = 0.34) and affect (beta = 0.43) directly influenced enhancements in QOL (R = 0.775).

CONCLUSIONS

The findings support the position that the effects of physical activity on QOL are mediated, in part, by intermediate psychological outcomes and that physical activity can have long-term benefits for women undergoing the menopausal transition.

During their passage through the circulatory system, tumor cells undergo extensive interactions with various host cells including endothelial cells. The capacity of tumor cells to form metastasis is related to their ability to interact with and extravasate through endothelial cell layers, which involves multiple adhesive interactions between tumor cells and endothelium (EC). Thus it is essential to identify the adhesive receptors on the endothelial and melanoma surface that mediate those specific adhesive interactions. P-selectin and E-selectin have been reported as adhesion molecules that mediate the cell-cell interaction of endothelial cells and melanoma cells. However, not all melanoma cells express ligands for selectins. In this study, we elucidated the molecular constituents involved in the endothelial adhesion and extravasation of sialyl-Lewis(x/a)-negative melanoma cell lines under flow in the presence and absence of polymorphonuclear neutrophils (PMNs). Results show the interactions of alpha(4)beta(1) (VLA-4) on sialyl-Lewis(x/a)-negative melanoma cells and vascular adhesion molecule (VCAM-1) on inflamed EC supported melanoma adhesion to and subsequent extravasation through the EC in low shear flow. These findings provide clear evidence for a direct role of the VLA-4/VCAM-1 pathway in melanoma cell adhesion to and extravasation through the vascular endothelium in a shear flow. PMNs facilitated melanoma cell extravasation under both low and high shear conditions via the involvement of distinct molecular mechanisms. In the low shear regime, beta(2)-integrins were sufficient to enhance melanoma cell extravasation, whereas in the high shear regime, selectin ligands and beta(2)-integrins on PMNs were necessary for facilitating the melanoma extravasation process.

OBJECTIVE

To review the evidence that polycystic ovary syndrome is a genetic disease.

METHODS

Review of published literature.

RESULTS

The existing literature provides a strong basis for arguing that PCOS clusters in families. However, the mode of inheritance of the disorder is still uncertain, although the majority of studies are consistent with an autosomal dominant pattern, modified perhaps by environmental factors. In addition, studies on PCOS cells (theca, muscle, and adipocytes) in culture have documented a persistent biochemical and molecular phenotype that distinguishes them from normal cells. Although several loci have been proposed as PCOS genes including CYP11A, the insulin gene, and a region near the insulin receptor, the evidence supporting linkage is not overwhelming. The strongest case can be made for the region near the insulin receptor gene, as it has been identified in two separate studies. However, the responsible gene at chromosome 19p13.3 remains to be identified. Association studies have provided a number of potential loci with genetic variants that may create or add to a PCOS phenotype, including Calpain 10, IRS-1 and -2, and SHBG.

CONCLUSIONS

Collectively, these findings are consistent with the concept that a gene or several genes are linked to PCOS susceptibility. Because the mutations/genotypes associated with PCOS are rare, and their full impact on the phenotype incompletely understood, routine screening of women with PCOS or stigmata of PCOS for these genetic variants is not indicated at this time. Currently the treatment implications for individually identified genetic variants is uncertain and must be addressed on a case by case basis.

Humans are known to show anticipatory adjustments in the grip force prior to a self-generated or predictable action or perturbation applied to a hand-held object. We investigated whether humans can also adjust covariation of individual finger forces (multi-finger synergies) prior to self-triggered perturbations. To address this issue, we studied adjustments in multi-digit synergies associated with applied load/torque perturbations while the subjects held a customized handle steadily. The main hypothesis was that the subjects would be able to demonstrate the phenomenon of anticipatory covariation, that is changes in covariation patterns among digit forces and moments of force in anticipation of a perturbation, but only when the perturbation was triggered by the subjects themselves. Based on the principle of superposition (decoupled grasping force and resultant torque control), we also expected to see different adjustments in indices of multi-digit synergies stabilizing the total gripping force and the total moment of force. The task for the subjects (n = 8) was to return the initial handle position as quickly as possible after a perturbation, which consisted of removing one of three loads hanging from the handle. There were six experimental conditions: two types of perturbations (self-triggered and experimenter-triggered) by three positions of the load (left, center, and right). Three-dimensional forces and moments of force recorded from each digit contact were used for the analysis. Indices of covariation among digit forces and among moments of force, previously employed for studying motor synergies, were computed across trials. Positive values of the indices reflected negative covariations of individual digit forces and moments of force (their inter-compensatory changes) to stabilize the total force and moment acting on the handle. In steady-state conditions, subjects showed strong positive indices for both digit forces and digit moments. Under the self-triggered conditions, changes in the indices of digit force and moment covariation were seen about 150 ms prior to the perturbation, while such changes were observed only after the perturbation under the experimenter-triggered conditions. Immediately following a perturbation, the indices of force and moment covariation rapidly changed to negative revealing the lack of inter-compensation among the individual digit forces and moments. Later, both indices showed a recovery to positive values; the recovery was faster in the self-triggered conditions than in the experimenter-triggered ones. During the steady-state phase after the perturbation, the indices of force and moment covariation decreased and increased, respectively, as compared to their values during the steady-state phase prior to the perturbation. We conclude that humans are able to adjust multi-digit synergies involved in prehensile tasks in anticipation of a self-triggered perturbation. These conclusions speak against hypotheses on the organization of multi-element actions based on optimal control principles. Different changes in the indices of force and moment covariation after a perturbation corroborate the principle of superposition. We discuss relations of anticipatory covariation to anticipatory postural adjustments.

BACKGROUND

Aging is associated with decreased manual dexterity. Recent findings have identified changes in multi-finger synergies in elderly individuals. The purpose of current work was to study age-related changes in adjustments of multi-finger synergies in preparation to a quick targeted force pulse production task.

METHODS

Right-handed elderly and young subjects produced quick force pulses by pressing on individual force sensors with the four fingers of the right hand. Prior to the force pulse, the subjects produced a constant low level of the total force. An index of multi-finger synergies was computed across trials for each time sample for each subject and each condition.

RESULTS

During steady-state force production, subjects showed co-variation of commands to fingers that stabilized the total force. An index of this co-variation started to decrease prior to the initiation of the force pulse (anticipatory synergy adjustment). Anticipatory synergy adjustments in young subjects started earlier and were larger than in elderly subjects. In particular, young and elderly subjects showed significant anticipatory synergy adjustments starting about 150ms and about 50ms prior to the force pulse initiation, respectively. There were no significant differences between the two groups in other indices of performance such as reaction time, time to peak force, and magnitude of the peak force.

CONCLUSIONS

We conclude that healthy aging is associated with decreased feed-forward adjustments of multi-finger synergies in preparation to action. This may contribute to the age-related decline in the hand function. Based on similarities in age-related changes in anticipatory postural adjustments and anticipatory synergy adjustments we suggest a hypothesis that the two phenomena may share common mechanisms.