Metabolic myopathies: evaluation by graded exercise testing

Exertional muscle pain and fatigue are common complaints; some patients with these symptoms have a metabolic myopathy. We have performed graded exercise testing with analysis of expired ventilation on 13 individuals with various kinds of metabolic myopathies. Their results differed from normal and reflected the underlying biochemical abnormality. Patients with disorders of the mitochondrial electron transport chain demonstrated marked limitations in aerobic metabolism and a greatly reduced maximum oxygen consumption. During intense exertion, normal individuals increase carbon dioxide generation due to buffering of lactic acid. This did not occur in patients with McArdle disease, in whom the respiratory exchange ratio (carbon dioxide production/oxygen consumption) did not rise above 1.0 at maximum exercise. These results indicated a deficit in anaerobic metabolism. Pyruvate dehydrogenase complex allows pyruvate produced from carbohydrate metabolism to enter the citric acid cycle. Patients with this enzyme deficiency showed an initially normal pattern followed by an abrupt cessation in carbohydrate dependent aerobic metabolism at higher work loads. During high-intensity exercise, progressive anaerobic metabolism was not accompanied by additional oxygen consumption. Finally, results from a patient with carnitine palmitoyl transferase deficiency revealed an early dependence on carbohydrate metabolism. The ventilatory threshold occurred at a low percentage of maximal oxygen consumption, reflecting the limited availability of lipid substrates for aerobic metabolism. Detection of some muscle metabolic abnormalities can be made on small biopsy specimens. However, definitive diagnosis of the defect nearly always requires studies on fresh or frozen muscle tissue obtained by an open biopsy. The decision on how the tissue should be processed and which metabolic studies should be performed frequently needs to be made before the biopsy is obtained. Thus, a noninvasive method to initially characterize patients with potential metabolic disorders is useful. Exercise testing with expired gas analysis can indicate the presence of a metabolic myopathy and results can then be used to direct the appropriate biochemical evaluations.     

Vascular findings in CTA body and extremity of critically ill COVID-19 patients: commonly encountered vascular complications with review of literature

Emergency Radiology - The purpose of our review is to discuss the role of CT angiography (CTA) in evaluating a variety of vascular complications in critically ill COVID-19 patients. The COVID-19...     

Reassessment of vasodilator therapy in angina: Effects of oral isosorbide dinitrate and hydralazine on exercise tolerance in patients receiving propranolol

Nitrates, predominantly venodilators, are commonly used in the treatment of angina pectoris, whereas hydralazine, a potent systemic and coronary arterial vasodllator, is usually contraindicated. Hydralazine might be useful in therapy of angina H tachycardia could be prevented by beta adrenergic blockade. Consequently, treadmill exercise tolerance was determined in 20 patients with chronic stable angina during treatment with oral propranolol, 60 mg four times daily (control), propranolol plus 20 mg of oral isosorbide dinitrate, propranolol plus 100 mg of oral hydralazine, and all three drugs combined. The mean heart rate at rest in patients recelving propranolol was 54.0 ± 1.7 beats/min (mean ± standerd error of the mean). It increased 6.8 beats/min with the additlon of hydralazine (p < 0.005) and 7.2 beats/min with Isosorbide dlnitrate and hydralazine comblned (p < 0.005), but was unchanged with Isosorbide dinitrarate alone. Systoilc blood pressure decreased 13.5 mm Hg with Isosorbide dinitrate (p < 0.05) and 28.3 mm Hg with Isosorbide dinitrate and hydralazine combined (p < 0.005), but did not change significantly with hydralazine alone (average decrease 4.1 mm Hg). The mean duration of exercise increased by 24.1 seconds with Isosorbide dinitrate (p < 0.05), and almost twice that (42.4 seconds longer than the control value) with Isosorbide dinitrate and hydralazine (p < 0.005). With hydralazine alone, exercise duration was decreased by 24.7 seconds (p < 0.05). Rate-pressure product at symptom-tolerated maximal exercise was unchanged with Isosorbide dinitrarate or hydralazine alone, but lower than the control value with the two agents combined. It Is concluded that Isosorbide dinitrate Improves exercise tolerance in patients with angina who are being treated with propranolol, but hydralazine remains detrlmental despite the use of the beta blocking agent. However, when Isosorbide dinitrate is combined with hydralazine, the detrimental effects of hydralazine on exercise tolerance are reversed.     

Endocannabinoids and liver disease--review.

AIMS: Endocannabinoids are endogenous compounds that bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. They have been found to have many physiological and patho-physiological functions, including mood alteration, control of feeding and appetite, motor and co-ordination activities, analgesia, immune modulation and gut motility. In this review we aim to elucidate current knowledge as to their role in liver physiology and disease. METHODS: The major findings published to date concerning endocannabinoids and liver disease are described, and their implications with regard to understanding disease mechanisms, and the development of new treatments is considered. RESULTS: Recently, endocannabinoids have been implicated in the hemodynamic alterations occurring in cirrhosis. These changes appear to be mediated via specific cannabinoid receptors (CB1) on splanchnic and hepatic vascular endothelium. Plasma levels of endocannabinoids also seem to be elevated in hepatitis, and are involved in apoptosis of hepatocytes by a membrane mechanism not related to a specific receptor. Other studies suggest a beneficial role for cannabinoids in reducing the inflammation of experimental hepatitis. In an animal model of acute hepatic failure, both endocannabinoids and the antagonist to the CB1 receptor have been found to have a beneficial effect on neurological and cognitive function. CONCLUSIONS: Endocannabinoids appear to be involved in several aspects of acute and chronic liver disease, including vascular changes, modulation of inflammatory process and neurological function, Further research may provide new insights into the pathophysiology of liver disease, as well as a basis for novel treatment modalities.     

Duodenal epithelial thymidine uptake in patients with duodenal ulcer or endoscopic duodenitis

To evaluate the relationship between duodenal ulcer disease and duodenitis, duodenal epithelial cell renewal was measured in mucosal biopsies by the incorporation of [³H]thymidine. When 14 patients with duodenal ulcer were compared to 13 control subjects or 7 with endoscopic duodenitis alone, the crypt size was the same in all groups. Similar to other inflammatory processes of the gastrointestinal tract, patients with endoscopic duodenitis showed increased proliferative indices including a greater number of cells incorporating [³H]thymidine. In contrast, the proliferative indices from the duodenal mucosa of patients with duodenal ulcers did not differ from a control group. In a group of 6 patients with both endoscopic duodenitis and duodenal ulcer, the [³H]thymidine incorporation was intermediate between control subjects or patients with duodenal ulcer alone and those with endoscopic duodenitis alone. When subjects were divided according to the histologic appearance of the duodenal mucosa, those having chronic duodenitis demonstrated enhanced [³H]thymidine incorporation in comparison to a control group or patients with chronic active duodenitis (polymorphonuclear leukocytes present). Although there are many possible explanations of these findings, one may speculate that duodenal ulceration does not stimulate duodenal epithelial proliferation. This project was supported by the Yale Digestive Cancer Research Fund. Dr. Gorelick was supported by a Research Fellowship Award from the National Foundation for Ileitis and Colitis during a portion of this study and is currently a recipient of a Clinical Investigator Award (KO8-AM-00659) from the National Institute of Arthritis, Metabolism and Digestive Diseases.     

In vivo metabolism of the designer anabolic steroid hemapolin in the thoroughbred horse

Hemapolin (2α,3α‐epithio‐17α‐methyl‐5α‐androstan‐17β‐ol) is a designer steroid that is an ingredient in several “dietary” and “nutritional” supplements available online. As an unusual chemical modification to the steroid A‐ring could allow this compound to pass through antidoping screens undetected, the metabolism of hemapolin was investigated by an in vivo equine drug administration study coupled with GC‐MS analysis. Following administration of synthetically prepared hemapolin to a thoroughbred horse, madol (17α‐methyl‐5α‐androst‐2‐en‐17β‐ol), reduced and dihydroxylated madol (17α‐methyl‐5α‐androstane‐2β,3α,17β‐triol), and the isomeric enone metabolites 17β‐hydroxy‐17α‐methyl‐5α‐androst‐3‐en‐2‐one and 17β‐hydroxy‐17α‐methyl‐5α‐androst‐2‐en‐4‐one, were detected and confirmed in equine urine extracts by comparison with a library of synthetically derived reference materials. A number of additional madol derivatives derived from hydroxylation, dihydroxylation, and trihydroxylation were also detected but not fully identified by this approach. A yeast cell‐based androgen receptor bioassay of available reference materials showed that hemapolin and many of the metabolites identified by this study were potent activators of the equine androgen receptor. This study reveals the metabolites resulting from the equine administration of the androgen hemapolin that can be incorporated into routine GC‐MS antidoping screening and confirmation protocols to detect the illicit use of this agent in equine sports.