A single dose of dietary nitrate supplementation protects against endothelial ischemia-reperfusion injury in early postmenopausal women.

The onset of menopause and accompanying changes to ovarian hormones often precedes endothelial dysfunction in women. In particular, accelerated impairments in macrovascular and microvascular function coincide with the loss of estrogen, as does impaired endothelial responses to ischemia-reperfusion (IR) injury. In healthy, early postmenopausal women (n = 12; 3.9 ± 1.5 years since menopause) we tested the hypothesis that acute dietary nitrate (NO3-) supplementation would improve endothelial function and attenuate the magnitude of endothelial dysfunction following whole-arm IR in comparison with placebo. In this randomized, double-blind, placebo-controlled, crossover study we tested participants before and after NO3--rich (BRnitrate) and NO3--depleted (BRplacebo) beetroot juice (BR) consumption, as well as following IR injury, and 15 min after IR to assess recovery. Analyses with repeated-measures general linear models revealed a condition × time interaction for brachial artery flow-mediated dilation (FMD; P = 0.04), and no interaction effect was found for the near-infrared spectroscopy-derived reperfusion slope (P = 0.86). Follow-up analysis showed a significant decline in FMD following IR injury with BRplacebo in comparison with all other timepoints (all, P < 0.05), while this decline was not present with BRnitrate (all, P > 0.05). Our findings demonstrate that a single dose of dietary NO3- minimizes IR-induced macrovascular endothelial dysfunction in healthy, early postmenopausal women, but does not improve resting macrovascular and microvascular function. Trial registration number: NCT03644472. Novelty: In healthy, early postmenopausal women, a single dose of NO3--rich BR can protect against IR-induced endothelial dysfunction. This protection may be due to nitric oxide bioactivity during IR rather than improved endothelial function prior to the IR protocol per se.

Facial and autonomic activity in depression: social context differences during imagery.

Previous research indicates that depressed patients show reduced facial expression as well as a lack of social context differences in frowning in response to sad imagery. The present study examined social context differences in facial electromyogram (EMG), self-reported emotion, skin conductance level and heart rate in 21 depressed and 22 non-depressed women assessed by the Beck Depression Inventory. Subjects were asked to imagine happy and sad situations both with and without visualizing other people. Depressed subjects showed a lack of social context differences in EMG-brow activity during sad imagery while heart rate was increased during sad-social compared to sad-solitary imagery. In contrast, non-depressed subjects showed increased EMG-brow activity during sad-social compared to sad-solitary imagery but no social context differences in heart rate. EMG-cheek activity and heart rate were increased during happy-social compared to happy-solitary imagery in depressed and non-depressed subjects. Skin conductance level was reduced in depressed compared to non-depressed subjects during baseline but failed to respond to imagery. Social context differences in heart rate and a lack thereof of frowning during sad imagery may indicate an altered psychosocial functioning in depression.

Stress management in medical education: a review of the literature.

PURPOSE: To review systematically clinical studies providing empirical data on stress-management programs in medical training. METHOD: The authors searched Medline and PSYCHINFO from 1966 to 1999. Studies were included if they evaluated stress-management programs for medical trainees (medical students, interns, or residents); reported empirical data; and had been conducted at allopathic medical schools. RESULTS: Although the search yielded over 600 articles discussing the importance of addressing the stress of medical education, only 24 studies reported intervention programs, and only six of those used rigorous scientific method. Results revealed that medical trainees participating in stress-management programs demonstrated (1) improved immunologic functioning, (2) decreases in depression and anxiety, (3) increased spirituality and empathy, (4) enhanced knowledge of alternative therapies for future referrals, (5) improved knowledge of the effects of stress, (6) greater use of positive coping skills, and (7) the ability to resolve role conflicts. Despite these promising results, the studies had many limitations. CONCLUSION: The following considerations should be incorporated into future research: (1) rigorous study design, including randomization and control (comparison) groups, (2) measurement of moderator variables to determine which intervention works best for whom, (3) specificity of outcome measures, and (4) follow-up assessment, including effectiveness of future patient care.

Reduced facial expression and social context in major depression: discrepancies between facial muscle activity and self-reported emotion.

The expression of emotion is determined by emotion and the presence and absence of others, i.e. social context. The present study examined social context differences in facial muscle activity and self-reported emotion of 11 major depressed and 11 non-depressed patients. Subjects were asked to imagine happy and sad situations with and without visualizing other people. Facial muscle activity over the brow and cheek region was reduced in depressed compared to non-depressed patients during happy and sad imagery whereas self-reported emotion showed no group differences. In both subject groups, happy imagery induced increased smiling and self-reported happiness whereas sad imagery induced increased frowning and self-reported sadness. Smiling and self-reported happiness were increased during happy-social compared to happy-solitary imagery in both groups. In contrast, frowning showed a lack of social context differences, although self-reported sadness was increased during sad-social vs. sad-solitary imagery in both groups. Reduced facial muscle activity in depression may indicate psychomotor retardation whereas the lack of social context differences in frowning may suggest social disengagement and an inhibition of sad facial expression in the presence of others.

Canine carotid allograft changes after photochemotherapy and external polyester sheathing.

BACKGROUND: The purpose of this study is to define and refine the changes in canine carotid allografts after photochemotherapy and polyester sheathing. Photochemotherapy with 8-methoxy psoralen (8MOP) and UVA (PUVA) was given alone or combined with intraluminal visible light (VL) 450 nm in proper dosages to speed the depopulation of endothelial (EC) and smooth muscle cells (SMC) and to modulate the immune response. METHODS: Novel apparati were made for photochemotherapy of 19 right canine carotid arterial allografts with 19 paired untreated controls in the left carotid. External UVA and internal visible light (VL 450 nm) were used with 8-methoxy psoralen (8-MOP) as a sensitizer. RESULTS: With moderate dosage of 8-MOP (1 microg/cc) and 2-4 J/cm2 of external UVA (PUVA), smooth muscle cells (SMC) disappeared faster from the media and fibroblasts (FB) appeared earlier in the adventitia of the treated right allografts, reducing but not eliminating the immune response. Intraluminal VL did not enhance the PUVA effect. At 68 days, treated and control allografts showed similar dimensions with subsided immune reactions. The media thickness was reduced from 0.38 mm to 0.18 mm and the host adventitia increased from 0.22 to 0.60 mm. Variable reactions peaked between two and three weeks and subsided after one month. All allografts remained open with canine carotid i.d.s of 2-3 mm and 80 to 100 cc/ minute arterial flows. Although the UVA dosage was moderate) similar doses sterilized log 7 of staph aureus cultures in saline. The allografts without smooth muscle showed moderate but stable cylindrical dilatation without spasm or stenosis and with an adequate adventitial buttress for a small vessel. A polyester sleeve around four treated grafts was inseparable from the allograft in less than 3 weeks and tolerated well over a 70-day period. CONCLUSIONS: Biodegradable graft sheaths with bioerodible hydrogels with growth factors (FGF) for local delivery may provide a faster and more complete matrix remodeling for a superior conduit in the future.

The incidence of T2-weighted MR imaging signal abnormalities in the brain of cocaine-dependent patients is age-related and region-specific.

BACKGROUND AND PURPOSE: Cocaine and its metabolites can produce vasospasm, and cocaine-dependent patients are at increased risk for stroke. Based on previous case reports, we hypothesized that the incidence of hyperintense brain lesions observed on T2-weighted MR images would also be increased in asymptomatic cocaine-dependent individuals. METHODS: Sixty-two male "crack" (smoked) cocaine-dependent participants ranging in age from 25 to 66 years were compared with 116 normal male control participants ranging in age from 25 to 80 years. Those with histories of neurologic symptoms or illnesses were excluded. The severity of hyperintense lesions was rated on a 0- to 3-point scale, and ratings of 3 were used in the data analysis as an indicator of a probable pathologic process. Three regions were separately rated: the cerebral white matter, insular subcortex white matter, and subcortical gray matter (basal ganglia and thalamus region). RESULTS: Significantly increased risk of severe lesions was observed in the two white matter regions of the cocaine-dependent group (odds ratio of 16.7 and 20.3) but not in the subcortial gray matter region (odds ratio of 1.4). In the insula subcortex white matter, the risk of lesions increased with age in the cocaine-dependant sample, but remained essentially absent among normal controls through the age of 80 years. In the cerebral white matter, the relationship of age and risk of lesion among normal participants was similar in shape to that in cocaine-dependent participants, but equivalent risk was seen 20 years earlier among cocaine-dependent participants. CONCLUSIONS: Cocaine-dependent participants had a significantly increased age-related risk of white matter damage. The possible clinical implications of this damage are discussed.

The construct of control in mind-body medicine: implications for healthcare.

Research suggests that one of the principal reasons patients are attracted to alternative medicine is that they find many of these therapies more congruent with their philosophical orientation toward health. Many mind-body approaches, which are some of the most frequently used classifications of complementary and alternative therapies, grow out of research demonstrating the important role of psychological factors in treating and preventing illness. This article reviews research on one such factor--control--and its importance in health. Studies demonstrating the following are highlighted: (1) illness frequently results in feelings of loss of control; (2) gaining a sense of control can help patients to cope with illness; (3) whereas control may influence physiological function and health outcomes, the amount of active control we can exercise over physical functioning and health is limited; and (4) it is important to match control strategies to patient control styles and preferences. The implications of mind-body studies are also discussed.

In simple synthetic promoters YY1-induced DNA bending is important in transcription activation and repression.

Depending on promoter context, YY1 can activate or repress transcription, or provide a site for transcription initiation. To investigate whether the ability of YY1 to induce DNA bending influenced its ability to activate and repress transcription, simple synthetic promoters were constructed in which the YY1 binding site was inserted between the TATA box and either the NF1 or AP1 recognition sequences. In transient transfections of COS cells, the NF1YY1TATA and NF1RYY1TATA promoters exhibited a dramatic 15-20-fold increase in correctly initiated transcription. These promoters exhibited even larger 60-80-fold increases in transcription in HeLa cells. Neither multiple copies of the YY1 binding site alone, nor placement of a YY1 site upstream of the NF1 site activated transcription. Deletion of 4 bp between the NF1 and YY1 sites, which changes the phase of the DNA bends, abolished the 16-fold activation of transcription by NF1YY1TATA. Insertion of the YY1 site between the AP1 site and the TATA box decreased transcription approximately 3-fold. Replacing the YY1 binding site with an intrinsic DNA bending sequence mimicked this transcription repression. Sequences of similar length which do not bend DNA fail to repress AP1-mediated transcription. Gel mobility shift assays were used to show that binding of YY1 to its recognition sequence did not repress binding of AP1 to its recognition sequences. Our data indicate that YY1-induced DNA bending may activate and repress transcription by changing the spatial relationships between transcription activators and components of the basal transcription apparatus.

Steroidogenic factor-1 as a positive regulator of rat granulosa cell differentiation and a negative regulator of mitosis.

Ovarian follicles contain small nonaromatase-expressing and large aromatase-expressing granulosa cells (GCs). The present studies were designed to determine whether small GCs can differentiate into large GCs and/or express aromatase. Additional studies were conducted to assess the role of steroidogenic factor-1 (SF-1), an orphan nuclear receptor, in regulating GC differentiation and proliferation. For these studies, small GCs were isolated from immature rats by Percoll gradient centrifugation and cultured for up to 48 h with FSH and/or 8-bromo-cAMP (8-br-cAMP). FSH/8-br-cAMP induced a 2-fold increase in SF-1 messenger RNA levels within 4 h. This increase was maintained throughout the culture period. By 24 h culture, FSH/8-br-cAMP increased the percentage of large GCs. It was not until 48 h of culture with FSH and 8-br-cAMP that aromatase expression increased. This increase was detected by both Western blot and quantitative immunocytochemistry. 8-br-cAMP alone did not promote GC differentiation. Small GCs were then cultured with FSH/8-br-cAMP in the presence or absence of an antisense oligonucleotide complementary to the putative SF-1 ligand-binding site (SF-1 AS). As a control, small GCs were cultured with FSH/8-br-cAMP and an 18-mer nonsense oligonucleotide (SF-1 NS). The SF-1 AS, but not the SF-1 NS, prevented FSH/8-br-cAMP from increasing 1) SF-1 messenger RNA levels, 2) transcription of a SF-1(x2) promoter/luciferase construct, 3) GC size, and 4) aromatase expression. In a third series of experiments, small GCs were cultured for 24 h in 1) control media supplemented with 2) a mitogen, phorbol ester [12-O-tetraphorbol acetate (TPA)], 3) FSH/8-br-cAMP, or 4) both. TPA increased the number of GCs by 51 +/- 9%. FSH/8-br-cAMP completely blocked TPA-induced mitosis. When small GCs were cultured with FSH/cAMP, TPA, and SF-1 AS, the number of GCs increased by 50 +/- 7%. This increase was not observed with SF-1 NS. Taken together, these data demonstrate that SF-1 is expressed in both small and large GCs, and enhanced SF-1 expression is part of the molecular mechanism associated with GC differentiation. Interestingly, SF-1 not only regulates differentiation, but also inhibits TPA-induced GC mitosis.

Autogenic-feedback training: a potential treatment for orthostatic intolerance in aerospace crews.

Postflight orthostatic intolerance has been identified as a serious biomedical problem associated with long-duration exposure to microgravity in space. High priority has been given to the development of countermeasures for this disorder that are both effective and practical. A considerable body of clinical research has demonstrated that people can be taught to increase their own blood pressure voluntarily, and that this is an effective treatment for chronic orthostatic intolerance in paralyzed patients. The current pilot study was designed to examine the feasibility of adding training in control of blood pressure to an existing preflight training program designed to facilitate astronaut adaptation to microgravity. Using an operant conditioning procedure, autogenic-feedback training (AFT), three men and two women participated in four to nine training (15-30-minute) sessions. At the end of training, the average increase in systolic and diastolic pressure, as well as mean arterial pressures, that the subjects made ranged between 20 and 50 mm Hg under both supine and 45 degrees head-up tilt conditions. These findings indicate that AFT may be a useful alternative treatment or supplement to existing approaches for preventing postflight orthostatic intolerance. Furthermore, the use of operant conditioning methods for training cardiovascular responses may contribute to the general understanding of the mechanisms of orthostatic intolerance.

Factors affecting the development of skin cancer after scalp irradiation.

A nested case control study of persons who developed skin cancer after scalp irradiation in childhood revealed two risk factors for the appearance of radiation-induced skin cancer: (a) an apparently higher radiation dose delivered inadvertently, manifested by a higher prevalence of alopecia and radiation dermatitis (RR = 3.4; CI 1.3-8.8); (b) a more frequent exposure to the sun, manifested by summer sunbathing (RR = 2.6; CI 1.1-6.1). These findings may have certain implications with regard to the understanding of radiation-induced cancer, after low-dose radiation exposure, in general.

Measuring the psychological construct of control. Discriminant, divergent, and incremental validity of the Shapiro Control Inventory and Rotter's and Wallstons' Locus of Control Scales.

The psychological construct of control is increasingly thought to be an important variable in psychosomatic medicine, but there are limitations with how it has been measured by previous instruments. The current study details four limitations of previous instruments as a rationale for developing a new multi-faceted, multi-dimensional instrument to measure control, the Shapiro Control Inventory (SCI). Discriminant, divergent, and incremental validity of the SCI is compared with the Rotter's Internal/External Locus of Control Scale and Wallstons' Multidimensional Health Locus of Control Scales on five groups, one normal and four clinical groups (depression, generalized anxiety disorder, borderline personality, and panic disorder). Analysis of variance showed significant differences among populations on each of the nine SCI scales. The majority of these results were highly significant, whereas for Rotter's scale the results were barely significant, and for Wallstons' three scales, not at all significant. Correlations of the SCI scales with Rotter's and Wallstons' scales were small to moderate, but in no case explained more than 15% of the variance. The SCI also provided incremental validity over Rotter's and Wallstons' scales both for sensitivity (clinical versus normal) and specificity (between clinical groups). The discussion section provides suggestions for future research.

Adverse effects of meditation: a preliminary investigation of long-term meditators.

Adverse effects of meditation were assessed in twenty-seven long term meditators (average 4.27 years) both retrospectively (time one) and prospectively at one month (time two) and six months (time three) following a meditation retreat. At both time one and time three subjects reported significantly more positive effects than negative from meditation. However, of the twenty-seven subjects, seventeen (62.9%) reported at least one adverse effect, and two (7.4%) suffered profound adverse effects. When subjects at time one were divided into three groups based on length of practice (16.7 months; 47.1 months; 105 months) there were no significant differences in adverse effects. How the data should be interpreted, and their implications both for the clinical and psychotherapeutic use of meditation as a relaxation/self-control strategy, and as a technique for facilitating personal and spiritual growth, are discussed. Limitations of the study and suggestions for future research are also offered.

Blood pressure response to the "second cup of coffee".

Twenty young male coffee-drinkers consumed 150 mg of caffeine in decaffeinated coffee three times a day for 8 days. On days 3, 4, 7, and 8, caffeine or a placebo was administered in the laboratory at 11 A.M., 8 A.M., 11 A.M., and 8 A.M., respectively, in a randomized double-blind crossover design. There was a blood pressure increase relative to the placebo 45 min after taking caffeine at 8 A.M. (5.8/6.5 mm Hg). An increase of 2.4/5.2 mm Hg was seen with the second cup of coffee at 11 A.M. The lower the subject's pre-coffee serum caffeine level, the higher the systolic response, both at 8 A.M. (r = -0.60) and at 11 A.M. (r = -0.62). Because of the pressor effect resulting from habitual caffeine intake, the adverse implications of caffeine use should be considered.

A sense of control, health, and illness: exploring the mind-body relationship and the socio-cultural/spiritual context: reflections on Bali.

Research has shown that there is a much more intimate and complex relationship between the "mind" and "body" than heretofore acknowledged within the predominant Western scientific paradigm; and that a "sense of control" may be one of the more important variables mediating that relationship. Furthermore, even when this "mind-body" relationship is studied, it is often done so in a reductionist way--at a psychophysiological level within the individual, thereby ignoring the socio-cultural context within which it is embedded. To address these issues, this article examines the mind-body relationship within the socio-cultural/spiritual context of Bali. Specifically examined are: (1) the culture's underlying assumptions about the mind-body-spirit connection across developmental and life cycle issues (including physical illness, and death); (2) the importance of maintaining a sense of control, harmony, and balance, within oneself, one's community, and the cosmos; and (3) the implications of those views for a control-based model of positive health. The article concludes with: (1) a discussion of why control seems to be such an important "construct" in human evolution; (2) an examination of the costs and benefits of different methods of maintaining a sense of control and orientation; and (3) and a call for efforts toward a unifying theory of human control.