Evidence for the contribution of non-covalent steroid interactions between DNA and topoisomerase in the genotoxicity of steroids

Fifty two steroids and 9 Vitamin D analogs were docked into ten crystallographically-defined DNA dinucleotide sites and two human topoisomerase II ATP binding sites using two computational programs, Autodock and Surflex. It is shown that both steroids and Vitamin D analogs exhibit a propensity for non-covalent intercalative binding to DNA. A higher predicted binding affinity was found, however, for steroids and the ATP binding site of topoisomerase; in fact these drugs exhibited among the highest topo II binding observed in over 1370 docked drugs. These findings along with genotoxicity data from 26 additional steroids not subjected to docking analysis, support a mechanism wherein the long known, but poorly understood, clastogenicity of steroids may be attributable to inhibition of topoisomerase. A “proof of principle” experiment with dexamethasone demonstrated this to be the likely mechanism of clastogenicity of, at least, this steroid. The generality of this proposed mechanism of genotoxicity across the steroids and vitamin-D analogs is discussed.     

Enhanced purification and production of Müllerian inhibiting substance for therapeutic applications

It is almost 60 years since Prof. Alfred Jost reported the seminal observations regarding Müllerian inhibiting substance (MIS). His experiments clearly showed that a testicular product other than testosterone, a Müllerian inhibitor, was responsible for Müllerian duct regression. Twenty-five years later Dr. Picon established an organ culture assay which paved the way for the initial studies into the biochemistry and biology of Müllerian inhibiting substance, also known as Anti-Müllerian hormone (AMH), undertaken first in Dr. Nathalie Josso's Laboratory in Paris then in our own laboratory in Boston. Purification of MIS led to cloning the human gene and production of recombinant human (rhMIS). MIS is a 140 kDa glycoprotein homodimer which is activated by a biosynthetic protease, cleaving MIS into an aminoterminus (110 kDa) and a carboxyterminus (25 kDa). The latter domain is sufficient for biological activities. MIS functions by interacting with two receptors; a type II binds the hormone and at type I that initiates downstream signaling. The MIS type II receptor has been cloned and functionally confirmed as distinct from that of other members of the TGFbeta superfamily. MIS can employ a number of type I receptors (ALK2, ALK3, ALK6) and BMP receptor specific SMADS 1, 5, and 8 in various tissue specific contexts. Cell lines derived from human ovarian, breast, and prostate tumors, and from rodent Leydig cell tumors, which respond to MIS in growth inhibition assays, all express the MIS type II receptor. A variety of signal transduction pathways are associated with the grown inhibition mediated by MIS. For example, breast and prostate cancer cell lines use a MIS-mediated NFkappaB pathway leading to G1 arrest and apoptosis. The ovarian cancer cell lines employ a pathway which enhances p16, modulates the E2Fs, and induces apoptosis. These signal transduction events can establish new rational treatment strategies to complement the growth inhibitory effects mediated by MIS. These combination strategies are being tested in vitro, and where appropriate will be tested in vivo using the highly purified MIS preparations, prior to use in early human clinical trials.     

Eating disorder diagnosis and the female athlete: A longitudinal analysis from college sport to retirement

ObjectivesFemale athletes experience eating disorders (EDs) at clinical, and subclinical, levels; most studies have determined point-prevalence rates through cross-sectional methodologies. To date, few studies have examined the long-term stability of EDs in female athletes; none extend into retirement.DesignA longitudinal investigation of ED classification (i.e., Clinical ED, Subclinical ED, Healthy) and weight control behaviors (e.g., vomiting, laxative use) from when athletes actively competed (T1) into their retirement (T2).MethodsParticipants included U.S. female athletes (N = 193) who were collegiate competitors (T1) and eventually were retired from their collegiate sports six years later (T2).ResultsAt T2, athletes were classified as Healthy (69.9%), Subclinical ED (26.9%), and Clinical ED (3.1%). Overall percentage of Subclinical EDs increased from 18.7% (T1) to 26.9% (T2); 52.8% of T1 Subclinical ED athletes continued to meet criteria for either Subclinical or Clinical ED at T2. Of the 13 Clinical ED athletes at T1, six (46.2%) continued to meet criteria for either a subclinical or clinical ED at T2. Though exercising (2+ hours/day; n = 8, 4.1%) and dieting/fasting (4+ times/year; n = 14, 7.3%) were the most frequently used weight control behaviors at T2, rates were substantially lower than at T1.ConclusionsRetirement does not result in immediate remittance of eating concerns among female athletes; many continue or develop Subclinical and Clinical ED symptoms. Thus, addressing healthy body image and nutrition when athletes are competing is imperative to assist prevention and intervention efforts that may alleviate ED symptoms as athletes transition from sport.     

Transmesenteric hernia: A rare cause of bowel ischaemia in adults

INTRODUCTIONTransmesenteric herniae are a rare cause of bowel ischaemia in adults with few reported cases in published literature.PRESENTATION OF CASEWe report a rare case of a 26-year-old female with spontaneous transmesenteric hernia of jejunum and proximal ileum due to a congenital mesenteric defect resulting in bowel gangrene, presenting initially with no haemodynamic or biochemical abnormalities. The hernia was reduced, small bowel resected and primary side to side anastomosis performed, following which the patient made a good recovery and was discharged 5 days later.DISCUSSIONThe insidious onset of transmesenteric herniae and lack of specific radiological or laboratory investigations reaffirms the importance of surgeons maintaining a high index of suspicion for this critical surgical emergency.CONCLUSIONClose monitoring of the patient's general condition in cases of non-specific abdominal pain is essential to identify the rare deteriorating patient for early surgical intervention and optimal outcome.     

Personality and Psychological Factors as Predictors of Disordered Eating Among Female Collegiate Athletes

This article examined the relationship of perfectionism, psychological well-being (self-esteem and optimism), reasons for exercising and appearance orientation to eating disorder classification among 204 female collegiate athletes. Multivariate analyses showed that only self-esteem, exercising to improve appearance and be more attractive, and appearance orientation differentiated significantly between the symptomatic/eating disordered athletes and those who were asymptomatic. No differences existed between the two groups of athletes on perfectionism, optimism, or exercising for fitness/health. For athletes, self-esteem, appearance orientation and exercising to be attractive and improve appearance were most important for understanding their level of disordered eating.     

Prevalence of Disordered Eating and Pathogenic Weight Control Behaviors Among Male Collegiate Athletes

The aim of this study was to determine the prevalence of disordered eating and pathogenic weight control behaviors in male collegiate athletes. Male collegiate athletes (N?=?732) from the across the U.S. completed questionnaires online. Results suggested that (a) most eating disturbances occur at the subclinical level, (b) exercising and dieting were the most commonly used weight control practices, and (c) athletes who participate in weight class sports are more likely to be classified as symptomatic and engage in pathogenic eating and weight control behaviors compared to endurance sport or ball game athletes. Implications for professionals working with athletes and recommendations for future research are discussed.