Tissue culture studies of possible uremic neurotoxins: myoinositol

Organotypic cultures of dorsal root ganglion cells revealed neuronal toxicity when exposed to myoinositol at doses of 1090 to 109 micrometer (500 to 50 microgram/ml). The ultrastructural changes consisted of membranous cytoplasmic bodies at high concentrations and dense bodies at lower concentrations. There were no changes at 0 to 22 micrometer (0 to 10 microgram/ml). This range of neurotoxicity parallels the levels of myoinositol found in the serum of uremic patients. Myelin loss occurred in a pattern suggesting "secondary demyelination," similar to the pattern seen in uremic neuropathy. The relevance as a possible model for uremic neuropathy is discussed.     

Interactions between the stimulated hypothalamic-pituitary-adrenal axis and leptin in humans

Leptin, produced by adipocytes, has homeostatic effects on body fat mass through inhibition of appetite and stimulation of the sympathetic nervous system. Several studies have reported that high-dose exogenous glucocorticoids increase circulating leptin concentrations in humans. Conversely, leptin has inhibitory effects on the hypothalamic-pituitary-adrenal (HPA) axis, both at the hypothalamic and adrenal levels. We hypothesized that acute hypercortisolism, in the physiological range, may not alter leptin secretion. Four stimuli of the HPA axis were administered to eight healthy male volunteers in a placebo-controlled study. On separate afternoons, in a randomised order, fasting subjects received i.v. injections of saline, naloxone (125 microg/kg); vasopressin (0.0143 IU/kg); naloxone and vasopressin in combination; or insulin (0.15 U/kg; a dose sufficient to induce hypoglycaemia). Plasma concentrations of adrenocorticotrophic hormone (ACTH), cortisol and leptin were measured before and for 120 min after the injection. The cortisol secretory response was greatest after insulin-hypoglycaemia, this response was significantly greater than that following naloxone, naloxone/vasopressin, or vasopressin alone. Despite the cortisol release, leptin concentrations were not increased after any stimulus. Insulin-hypoglycaemia was associated with a decrease in leptin concentration at 60 and 90 min, while naloxone did not alter leptin concentrations. However, basal leptin concentrations were positively correlated with integrated ACTH and cortisol responses to naloxone, but did not correlate with ACTH or cortisol responses to the other stimuli. Thus acute elevations of plasma cortisol, in the physiological range, do not appear to influence plasma leptin concentrations. The fall in plasma leptin concentration after insulin-induced hypoglycaemia may reflect catecholamine secretion after this stimulus.     

Vestibulodynia-A subset of vulvar vestibulitis or a novel syndrome?

OBJECTIVE: Our purpose was to recognize special features of women with both vestibulitis and constant vulvar pain (vestibulodynia) and to determine whether vestibulodynia is a separate disease entity or a subset of vestibulitis. STUDY DESIGN: Ninety-one women with severe vulvar vestibulitis underwent perineoplasty by a single surgeon during 1992 to 1995. Twenty-five (27%) of them who had vestibulodynia were compared with 66 (73%) who had dyspareunia alone. With univariate and then multivariate analysis, the two groups were compared with regard to demographic, social, and medical variables, the presence of human papillomavirus deoxyribonucleic acid, physical findings in the vestibule, and surgical outcome. RESULTS: The vestibulodynia and vestibulitis groups differed in age (30.5 ± 10.6 years vs 24.7 ± 6.2 years respectively), as well as in marital status (married, 44% vs 18%, respectively), nonuse of contraception (20% vs 1%, respectively), presence of human papillomavirus deoxyribonucleic acid in the vestibule (80% vs 48%, respectively), and failure of surgical treatment (incomplete response rate, 64% vs 2%, respectively). With multivariate analysis, patients with human papillomavirus deoxyribonucleic acid present in the vestibule have an odds ratio of 5.44 (95% confidence interval, 1.45 to 20.33) of belonging to the group with vestibulodynia, whereas dysuria and age have odds ratios of 3.70 (95% confidence interval 1.09 to 12.55) and 1.14 (95% confidence interval 1.04 to 1.24), respectively. CONCLUSIONS: Vestibulodynia is a unique syndrome in that it affects women who are older than those who have vestibulitis alone and it is associated with human papillomavirus deoxyribonucleic acid, dysuria, and a higher surgical failure rate than that for vestibulitis.(Am J Obstet Gynecol 1997;177:43)     

Judicial stress: the roles of gender and social support

Because judges experience a myriad of occupational stressors, they are at risk of experiencing secondary trauma, burnout, negative mental/physical health, poor job performance and low job satisfaction. These experiences might not be uniform, however, as gender and social support might mitigate such stress-related outcomes. Judges from two states in the United States completed a variety of stress and subjective performance measures. Social support was related to less perceived stress, less burnout, and more job satisfaction, but only for males. This suggests that males and females might receive qualitatively different types of social support. Different types of social support could differ in their ability to buffer judges from these stress-related outcomes. Further, among judges with high social support, females scored higher than males on subjective job performance; the opposite pattern occurred for judges with low social support. Thus, a lack of social support appears to have a negative effect on performance self-appraisals but only for females. Results have implications for the psychological study of stress and for programs designed to reduce judges’ stress.     

Update in Outpatient General Internal Medicine: Practice-Changing Evidence Published in 2020

In a time of rapidly shifting evidence-based medicine, it is challenging to stay informed of research that modifies clinical practice. To enhance knowledge of practice-changing literature, a group of 7 internists reviewed titles and abstracts in 7 internal medicine journals with the highest impact factors and relevance to outpatient general internal medicine. Coronavirus disease-19 research was purposely excluded to highlight practice changes beyond the pandemic. New England Journal of Medicine (NEJM), The Lancet, Annals of Internal Medicine, Journal of the American Medical Association (JAMA), JAMA Internal Medicine, British Medical Journal (BMJ), and Public Library of Science (PLoS) Medicine were reviewed. The following collections of article synopses and databases were also reviewed: American College of Physicians Journal Club, NEJM Journal Watch, BMJ Evidence-Based Medicine, McMaster/DynaMed Evidence Alerts, and Cochrane Reviews. A modified Delphi method was used to gain consensus based on relevance to outpatient internal medicine, impact on practice, and strength of evidence. Clusters of articles pertaining to the same topic were considered together. In total, 7 practice-changing articles were included.     

Antibody Drug Conjugates: Preclinical Considerations

The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.