Nocardia asteroides is an acid-fast bacterium that may cause localized or disseminated disease in humans. Malignancies, chronic debilitating disorders, and use of immunosuppressant drugs predispose ...patients to disseminated infection with this organism. However, nocardial infection in patients with AIDS or infection with human immunodeficiency virus (HIV) has been relatively uncommon, with only 41 cases reported in a recent review. We report a case of pneumonia and meningitis due to N. asteroides in a patient with AIDS.
Objectives. The purpose of this study was to determine whether sodium dichloroacetate improves hemodynmic performance and mechanical efficiency in congestive heart failure.
Background. Congestive ...heart failure is associated with impaired hemodynamic performance and reduced mechanical efficiency. Dichloroacetate stimulates pyruvate dehydrogenase activity by inhibition of pyruvate dehydrogenase kinase, which results in inhibition of free fatty acid metabolism and stimulation of high respiratory quotient glucose and lactate consumption by the heart. Facilitation of glucose and lactate consumption with dichloroacetate should improve mechanical efficiency of the failing ventricle.
Methods. Ten patients with New York Heart Association functional class III to IV congestive heart failure were studied. Dichloroacetate (50 mg/kg body weight) was administered intravenously for 30 min, with measurements of hemodynamic variables, coronary sinus blood flow and blood gas, glucose and lactate levels for 2 h. The same patients were also given dobutamine (5 to 12.5 mg/kg per min) for comparison.
Results. Therapeutic levels of dichloroacetate were achieved (100 to 160 μg/liter of plasma). Myocardial consumption of lactate was stimulated from 29% to 37.4%. Forward stroke volumes increased (+5.3 ml/beat, p < 0.02), as did left ventricular stroke work (+1.8 g-m/m2per beat, p < 0.02) and left ventricular minute work (from 1.38 to 1.55 kg-m/m2per min, p < 0.01). Myocardial oxygen consumption decreased (from 19.3 to 16.3 ml/min, p = 0.06) as left ventricular minute work increased. Left ventricular mechanical efficiency thus improved from 15.2% to 20.6% (p = 0.03).
Dobutamine administration resulted in the opposite trend with respect to myocardial lactate extraction (from 34% to 15.3%, p < 0.02). Stroke volume increased (+7.4 ml/beat, p = NS vs. dichloroacetate), as did left ventricular minute work (from 1.29 to 1,59 g-m/m2per min, p < 0.01 vs. dichloroacetate) and myocardial oxygen consumption (from 18.6 to 21.0 ml/min, p = 0.06 vs. dichloroacetate). Left ventricular mechanical efficiency did not change with dobutamine administration (from 16.4% to 15.8%, p = NS).
Conclusions. Dichloroacetate administration stimulates myocardial lactate consumption and improves left ventricular mechanical efficiency. Forward stroke volume and left ventricular minute work increase significantly, with a simultaneous reduction in myocardial oxygen consumption. Dobutamine administration results in similar hemodynamic improvements but with no change in left ventricular mechanical efficiency and with opposite effects on lactate metabolism. The opposing metabolic actions, yet similar hemodynamic responses, of dichloroacetate and dobutamine suggest that these agents may be complementary in the treatment of congestive heart failure.
OBJECTIVE--To assess the importance of 2,3-diphosphoglycerate (2,3-DPG) and oxygen-haemoglobin binding to oxygen transport in patients with congestive heart failure. METHODS--In 30 patients with ...severe congestive heart failure, arterial, mixed venous, and coronary sinus venous blood concentrations of 2,3-DPG were measured and systemic output and coronary sinus blood flow were measured by a thermodilution technique. Oxygen-haemoglobin affinity was expressed as the oxygen tension in mm Hg at which blood is 50% saturated with oxygen (P50). RESULTS--Compared with normal values, 2,3-DPG was high in arterial blood (2.58 mumol/ml, p = 0.01; 20.8 mumol/g haemoglobin, p < 0.0001). Significant gradients between arterial, mixed venous, and coronary sinus blood 2,3-DPG concentrations were also found (mixed venous = 2.40 mumol/ml, p = 0.05 v arterial blood; coronary sinus venous blood = 2.23 mumol/ml, p < 0.04 v arterial blood). P50 was correspondingly high compared with the accepted normal value (mean 29.7 mm Hg, normal 26.6 mm Hg, p < 0.001). Systemic oxygen transport (351 ml O2/min/m2) varied directly with the forward cardiac index (r = 0.89, p < 0.0001). There was no relation between systemic oxygen transport and arterial oxygen content. Similarly, myocardial oxygen transport was found to vary directly with coronary sinus blood flow. Calculations of changes in cardiac index and coronary sinus blood flow at normal oxygen-haemoglobin binding indicate that a considerable increase in cardiac index and coronary blood flow would be required to maintain similar systemic and myocardial oxygen transport. CONCLUSIONS--In patients with severe heart failure increased 2,3-DPG and reduced oxygen-haemoglobin binding may be compensatory mechanisms that maintain adequate systemic and delivery of oxygen to myocardial tissue.
Gonadectomized (gonadex) turtles, Sternotherus odoratus, had significantly elevated plasma FSH, but LH was less consistently affected. Estradiol (E2)-implants suppressed plasma FSH in gonadex females ...but not in males: testosterone (T) partially suppressed FSH in males. In contrast, E2-treatment markedly suppressed pituitary LH content and in vitro LH secretion in gonadex and intact turtles (inhibitory effects of E2 were less in intact than ovariectomized females). These steroid effects were relatively specific for gonadotropin; pituitary TSH content was not altered. In vitro, pituitary LH secretion responded to doses of GnRH greater than or equal to 1 ng/ml and LH output remained elevated for at least 3 hr of continuous superfusion with gonadotropin-releasing hormone (GnRH). In general, gonadectomy elevated pituitary responsiveness to GnRH while E2 and T suppressed this responsiveness; the effects of E2 are greater in gonadectomized than intact turtles. Thus, negative gonadal feedback appears to be involved in the secretion of gonadotropins in turtles, and steroidal actions may be partly due to suppression of pituitary hormone content and responsiveness to GnRH.
Phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt) signaling pathways contribute to the development of several cancers, including multiple myeloma ...(MM). PTEN is a tumor suppressor that influences the PI3K/Akt/mTOR pathway, which in turn impacts vital cellular processes like growth, survival, and treatment resistance. The current study aims to present the role of PTEN and PI3K/Akt/mTOR signaling in the development of MM and its response to treatment. In addition, the molecular interactions in MM that underpin the PI3K/Akt/mTOR pathway and address potential implications for the development of successful treatment plans are also discussed in detail. We investigate their relationship to both upstream and downstream regulators, highlighting new developments in combined therapies that target the PTEN/PI3K/Akt axis to overcome drug resistance, including the use of PI3K and mitogen-activated protein kinase (MAPK) inhibitors. We also emphasize that PTEN/PI3K/Akt pathway elements may be used in MM diagnosis, prognosis, and therapeutic targets.
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