Autoimmune blistering diseases treated with glucocorticoids: An international study of steroid-induced myopathy.

BACKGROUND: Patients with autoimmune blistering diseases (AIBDs) are often exposed to chronic glucocorticoid (GC) treatment with many side effects. Glucocorticoid-induced myopathy (GIM) is a well-established side effect, which particularly affects the proximal muscles. The Glucocorticoid Toxicity Index (GTI) is a validated global assessment tool which quantifies GC toxicity over time. OBJECTIVES: This study marks the first study which analyses GIM in patients with AIBDs. The objectives of this study were to utilize the GTI to investigate the nature and prevalence of GIM in AIBD patients and explore potential risk factors. METHODS: This international cohort study was conducted in blistering disease clinics across Australia, China, Greece, Iran, Japan, the Philippines, Turkey and the United States of America between February 2019 and July 2023. The GTI tool was completed by a medical practitioner at each patient visit. Data related to glucocorticoid toxicity were entered into the Steritas GTI 2.0 to generate an aggregate improvement and cumulative worsening score at each visit. RESULTS: The study included 139 patients. There were 132 episodes of myopathy, and 47.5% of patients developed muscle weakness at some point during the study period. Cumulative GC dose correlated positively with myopathy risk, while average dose and treatment duration were not significant. Older age, male gender and obesity more than doubled the likelihood of developing GIM. CONCLUSIONS: GIM is a common side effect experienced by AIBD patients on GC treatment. Muscle weakness is less likely to occur if cumulative GC dose is less than 0.75 mg/kg/day. Studies of exercise programs to mitigate myopathy and newer alternative treatments to reduce cumulative GC dose should be considered.

Regulating the cytoprotective response in cancer cells using simultaneous inhibition of Hsp90 and Hsp70.

Both heat shock protein 90 and 70 (Hsp90, Hsp70) are cytoprotective proteins that regulate cell death by stabilizing and folding proteins. Taking a two-pronged approach, involving simultaneous inhibition of Hsp90 and Hsp70, leads to synergistic cell death, which makes this is an appealing clinical therapy.

C-terminal heat shock protein 90 modulators produce desirable oncogenic properties.

The cellular protection mechanism, the heat shock response, is only activated by classical heat shock 90 inhibitors (Hsp90) that "target" the N-terminus of the protein, but not by those that modulate the C-terminus. Significant differences in cytotoxicity (nanomolar) for classical inhibitors versus their ability to modulate Hsp90 (low micromolar) are discussed. In contrast, molecules that modulate Hsp90's C-terminus show similar IC50 values for cytotoxicity and Hsp90 inhibition. A comparison between the two types of Hsp90 inhibitors suggests that classical inhibitors may be modulating an alternative biological target that stresses the cell rather directly inhibiting Hsp90, whereas C-terminal modulators are most likely acting by directly inhibiting Hsp90.

Combining an Hsp70 inhibitor with either an N- or C-terminal Hsp90 inhibitor produces mechanistically distinct phenotypes.

Blocking the function of both heat shock protein 90 and 70 (Hsp90 and Hsp70) simultaneously limits these chaperones' cytoprotective effects on cancer cells. The unique phenotype associated with modulating Hsp90's C-terminus, when used in combination with Hsp70 inhibitors, produces a synergistic and highly relevant dual chemotherapy regimen.

The first report of direct inhibitors that target the C-terminal MEEVD region on heat shock protein 90.

Sixteen linear and cyclic peptides were designed de novo to target the C-terminus of heat shock protein 90 (Hsp90). Protein binding data indicates that three compounds directly block co-chaperone access to Hsp90's C-terminus and luciferase renaturation assays confirm Hsp90-mediated protein folding is disrupted. This is the first report of an inhibitor that binds directly to the C-terminal MEEVD region of Hsp90.

N-terminal and C-terminal modulation of Hsp90 produce dissimilar phenotypes.

Classic oncogenic heat shock protein 90 (Hsp90) inhibitors target the N-terminus of the protein, triggering a survival mechanism in cancer cells referred to as the heat shock response (HSR). Inhibiting Hsp90 by modulating the C-terminus does not trigger a HSR, making it a highly attractive chemotherapeutic approach.

Nutritional supplementation in older adults: pleasantness, preference and selection of sip-feeds.

OBJECTIVES: Malnourishment is common in older adults, and nutritional supplementation is used to improve body weight and well-being. Clinical reports suggest, however, that patients routinely reject sip-feeds. The present study examined the following questions: whether sip-feeds are less preferred and less likely to be selected than other energy-dense foods in healthy elders; and whether eating alone further reduces intake relative to eating in a social setting. METHODS: Twenty-one healthy older adults (aged 60-79 years) attended the laboratory on three occasions. Subjects rated six different flavours of sip-feed and then rated the pleasantness of the taste of the favoured flavour against five other energy-dense familiar foods/drinks. Intake of these foods was measured when subjects ate alone or in a group of familiar others. RESULTS: Favourite flavour of sip-feed compared well with other more familiar foods and was selected as part of a snack. Snack intake increased by 60% when consumed in a group setting compared with eating alone. CONCLUSIONS: The study suggests that sip-feeds are rated as pleasant and selected by free-living elders. Rejection of sip-feeds in hospitalized elders may relate more to loss of appetite than to the taste preference for sip-feeds, and that eating alone rather than in groups of familiar others is likely to compound eating problems.

Preferences for different high-energy foods in elderly medical in-patients.

Malnourishment is a common finding in hospitalised elderly patients. It is often addressed by the provision of nutritional supplements, in the form of sip-feeds. Patients' intake of these is frequently inadequate. We assessed the palatability of sip-feed nutritional supplements and other high-energy foods to elderly medical in-patients. Using the Lickhert Scale, 49 subjects rated the taste of a previously selected sip-feed supplement and five other high-energy foods, cheese biscuit, plain potato crisps, chocolate, cherry-flavoured cereal bar and stout beer. Subjects rated the taste of sip-feeds as favourably as all other offered foods, with the exception of the lower rated stout beer (p = 0.0001). Taste alone is unlikely to account for the poor intake of sip-feed nutritional supplements by elderly hospital patients.

Late death in tricyclic antidepressant overdose revisited.

We report a late death following the ingestion of amitriptyline. A 46-year-old woman presented to the emergency department with coma, hypotension, tachycardia, and a prolonged QRS interval after the ingestion of a large quantity of Elavil. She was managed with aggressive supportive care, multiple doses of oral charcoal, and charcoal hemoperfusion. The patient's ECG and hemodynamic status returned to normal within 24 hours. Despite an apparent total recovery, she suddenly sustained a cardiorespiratory arrest and died 33 hours after ECG normalization (at 57 hours after admission). This case brings into question the feasibility of ceasing ECG monitoring in tricyclic antidepressant overdoses once the ECG has stabilized, especially in patients with a history of chronic usage. A possible explanation for late sequelae is the myocardial cell binding and depressant effect of preexisting therapeutic TCA medication.

Workers' understanding of chemical risks: electroplating case study.

BACKGROUND: There is limited research concerning how small companies in particular, respond to health and safety messages. AIMS: To understand individuals' knowledge and beliefs about chemical risks and to compare these with those of experts. METHODS: The use of chromic acid in particular, and also other chemicals associated with chrome plating were studied. All chromium plating firms were based in the West Midlands. The methodology involved initial face to face interviews (n = 21) with chromium platers, structured questionnaires (n = 84) to test the prevalence of beliefs identified in the interviews, an expert questionnaire, and a workshop to discuss findings. The responses of platers were compared with those of occupational health and safety experts. RESULTS: Although chromium platers appeared to understand the short term adverse effects of the chemicals to which they are exposed, their understanding of long term, or chronic effects appeared to be incomplete. They had good knowledge of acute effects based primarily on experience. Platers were aware of the hazardous nature of the chemicals with which they work, but did not draw distinction between the terms "hazards" and "risks". They had difficulties articulating the effects of the chemicals and how exposure might occur; although it is inappropriate to equate this with lack of knowledge. A significant minority of platers displayed deficiencies in understanding key technical terms used in Safety Data Sheets. CONCLUSIONS: This study provides a method which can be used to gain some understanding of workers' knowledge and beliefs about risks that they are exposed to in the workplace. The study also identifies gaps between the platers' knowledge and beliefs and those of experts. New risk information needs to be designed which addresses the information needs of platers using language that they understand.

Small airways function in nonsmokers with rheumatoid arthritis.

To evaluate the possible relationship between rheumatoid arthritis (RA) and airways dysfunction independent of cigarette smoking, we studied 19 lifetime nonsmokers with RA and 47 healthy nonsmokers. Ten tests of small airways function were administered to the subjects. In addition, diffusing capacity and static lung compliance were measured, and upstream airway conductance at mid-to-low lung volumes was calculated. Mean values were not significantly lower in the RA group than in the control group in any of the tests of small airways function. Three of the 19 (16%) patients with RA versus 15 of the 47 (32%) control subjects had abnormal findings on greater than 2 tests of small airways function (P greater than 0.1). Although mean diffusing capacity and static lung compliance were both within normal limits in each group, the former tended to be lower, while the latter was significantly lower, in the RA subjects. We conclude that airways dysfunction in RA, if present, is probably related to factors other than the underlying disease; if an association between RA and small airways abnormality is present in some patients, its prevalence is too small to have been detected in our sample.

C32-O-imidazol-2-yl-methyl ether derivatives of the immunosuppressant ascomycin with improved therapeutic potential.

A series of C32-O-aralkyl ether derivatives of the FK-506 related macrolide ascomycin have been prepared based on an earlier reported C32-O-cinnamyl ether design. In the present study, the nature of the aryl tethering group was varied in an attempt to improve oral activity. An imidazol-2-yl-methyl tether was found to be superior among those investigated and has resulted in an ascomycin analog, L-733,725, with in vivo immunosuppressive activity comparable to FK-506 but with an improved therapeutic index.