Classical/nonclassical hybrid cannabinoids: southern aliphatic chain-functionalized C-6beta methyl, ethyl, and propyl analogues

The stereoelectronic requirements for interaction of the southern aliphatic hydroxyl of cannabimimetic pharmacophores with the CB1 and CB2 receptors are explored. The stereoselective syntheses of three series of classical/nonclassical hybrid cannabinoids are described. These compounds were designed to investigate the importance of the southern aliphatic hydroxyl (SAH) pharmacophore for cannabimimetic activity. Variation in the chain length of the SAH moiety in these 6beta-(hydroxyalkyl)dihydrobenzopyran analogues, from 6beta-hydroxymethyl to 6beta-(omega-hydroxyethyl) and 6beta-(omega-hydroxypropyl), and the effects of replacing the hydroxyl functionality by hydride and iodide are reported. Our results indicate that the SAH pharmacophore has less pronounced effects than the C-3 aliphatic chain on cannabinoid activity. Furthermore, it appears that this southern molecular component is capable of interacting with two different subsites on the receptor and that the nature of this interaction is determined by the terminal substituent on the C-6beta alkyl group. One of the subsites can accommodate the relatively polar SAH pharmacophore, while the second subsite interacts with more hydrophobic C-6beta substituents and can accommodate large spherical pharmacophores separated by three methylene carbons from the tricyclic cannabinoid template.     

The Australian brushtail possum (Trichosurus vulpecula) gonadotrophin alpha-subunit: analysis of cDNA sequence and pattern of expression

Substantial evidence has accumulated to suggest that in the near future implementation of the veto-cell-suppressor concept in the treatment of kidney allograft recipients might lead to the establishment of life-long specific allograft tolerance in the absence of further immunosuppressive therapy. Veto suppression prevents the generation of antigen-specific T-helper and cytotoxic T lymphocytes in vitro provided that the T-lymphocyte precursors specifically recognize antigenic peptides associated with the major histocompatibility complex molecules class II and class I, respectively, expressed on the surface of the veto-active cell. Data from a large number of experimental and clinical studies strongly indicate that veto-active cells function in vivo and are capable of preventing allograft rejection. Thus, donor-cell-mediated veto activity is the most likely explanation for the well-known graft tolerizing effect of pretransplant donor blood transfusions in kidney graft recipients. A prerequisite for a veto-active environment in vivo is the establishment of lymphoid microchimerism, in which veto-active donor and recipient cells mutually downregulate potential alloaggression.     

Chronobiology and chronotherapy of asthma

There is no doubt that many pathophysiologic conditions change over a 24-hour period and thus therapy needs to be directed at these changes. In particular, asthma has been one of the better-studied disease processes in regard to circadian changes in pathophysiology. As we continue to learn more about circadian changes, better approaches to treating the disease with the same medications will emerge. It should be remembered that many asthmatics do not perceive their degree of bronchoconstriction. This was brought forth in Turner-Warwick's epidemiologic study in that less than one half of the asthmatic individuals who had problems with their asthma every night describe their asthma as being severe. The majority stated they either had mild or moderate asthma. Therefore, it is important that we use objective criteria such as peak flow meters in determining an individual patient's day-to-night changes in lung function. Then, any therapeutic intervention can be objectively determined at home with both the patient and physician gaining knowledge about the ongoing asthmatic process.     

Silencing is golden: negative regulation in the control of neuronal gene transcription

Recent work has identified negative-acting DNA regulatory elements that function to prevent the expression of neuronal genes in non-neuronal cell types or in inappropriate neuronal subtypes. In some cases, the protein factors that interact with these silencer elements have been isolated and characterized. For example, the recently cloned silencer-binding factor NRSF/REST is a novel zinc-finger protein that interacts with silencer elements in a number of neuron-specific genes. These data suggest that negative regulation plays a major role in determining the diverse patterns of gene expression within the nervous system.     

Brief assessments of dietary behavior in field settings

Our research team is involved in ongoing research in both worksites and medical office settings. These settings offer great potential for reaching individuals who would not otherwise participate in health promotion, but they also place considerable constraints on assessment time and efforts, especially if one's goal is to attract a high and representative proportion of employees or patients. This paper reports on our experience with measures of dietary behavior in these two settings. We found it problematic to collect detailed assessments such as 4-day food records or comprehensive food frequency/history checklists in worksites or medical office settings using population-based samples. Instead, we recommend and provide data on the utility of a dietary-fat screening instrument, and on the Food Habits Questionnaire (FHQ-Kristal, Shattuck, & Henry, 1990), a brief measure of dietary behaviors associated with high-fat eating patterns. The FHQ, in particular, was found to correlate well with other more costly and time-consuming methods of assessment, to be reliable and responsive to intervention effects, and to provide behavioral targets for intervention. The strengths and limitations of these measures for tailoring intervention and assessing outcomes are discussed.     

Quantitative analysis of microvascular changes in diffuse astrocytic neoplasms with increasing grade of malignancy

BACKGROUND: Despite concerns about its prevalence and ramifications, harassment has not been well quantified among physicians. Previous published studies have been small, have surveyed only 1 site or a convenience sample, and have suffered from selection bias. METHODS: Our database is the Women Physicians' Health Study, a large (4501 respondents; response rate, 59%), nationally distributed questionnaire study. We analyzed responses concerning gender-based and sexual harassment. RESULTS: Overall, 47.7% of women physicians reported ever experiencing gender-based harassment, and 36.9% reported sexual harassment. Harassment was more common while in medical school (31% of gender-based and 20% for sexual harassment) or during internship, residency, or fellowship (29% for gender-based and 19% for sexual harassment) than in practice (25% for gender-based and 11% for sexual harassment). Respondents more likely to report gender-based harassment were physicians who were now divorced or separated and those specializing in historically male specialties, whereas those of Asian and other (nonwhite, nonblack, non-Asian, non-Hispanic) ethnicity, those living in the East, and those self-characterized as politically very conservative were less likely to report gender-based harassment. Being younger, born in the United States, or divorced or separated were correlated with reporting ever experiencing sexual harassment; those who were Asian or who were currently working in group or government settings were less likely to report it. Those who felt in control of their work environments, were satisfied with their careers, and would choose again to become physicians reported lower prevalences of ever experiencing harassment. Those with histories of depression or suicide attempts were more likely to report ever having been harassed. CONCLUSIONS: Women physicians commonly perceive that they have been harassed. Experiences of and sensitivity to harassment differ among individuals, and there may be substantial professional and personal consequences of harassment. Since reported rates of sexual harassment are higher among younger physicians, the situation may not be improving.     

Factors affecting high-density lipoproteins

Although it is well established that a low-circulating level of high-density lipoprotein (HDL) cholesterol is strongly associated with the likelihood of developing atherosclerotic coronary heart disease (CHD), the causal nature of this association has not been shown. Low levels of HDL cholesterol frequently are associated with other CHD risk factors, whose correction, often by hygienic means, may reduce CHD risk with minimal risk of adverse side-effects. However, other recommended hygienic interventions may lower HDL cholesterol levels. Specific safe and effective drugs for correcting a low HDL cholesterol level are not available and the potential value of specific pharmacologic treatment of this condition in the treatment or prevention of CHD remains unproven. Thus, while HDL measurement should be incorporated routinely in risk-assessment, intervention efforts should focus primarily on lowering low-density lipoprotein cholesterol.