The anesthetic management of ventricular septal defect (VSD) repair in a child with mitochondrial cytopathy

PURPOSE: To present the anesthetic management for the correction of a ventricular septal defect (VSD) in a patient with multiple acyl CoA dehydrogenase deficiency (glutaric aciduria type II; GAII). A review of the literature about anesthetic management of patients with mitochondrial diseases undergoing cardiopulmonary bypass (CPB) is also included. Clinical features: An 11-yr-old girl with GAII manifested as severe hypoglycemia since she was a newborn and generalized muscle weakness. She underwent open-heart surgery for VSD correction with CPB. The anesthetic management avoided inhalational anesthetics, maintained the blood sugar within normal limits and continued normothermia during CPB in order to avoid the stress of hypothermia for her abnormal mitochondria. The patient tolerated the procedure well and experienced a good recovery. CONCLUSION: The anesthetic management of patients with any mitochondrial disease requires normoglycemia, normothermia and the avoidance of metabolic stress in order to preserve energy production by the diseased mitochondria.     

Contractile and endothelium-dependent dilatory responses of cerebral arteries at various extracellular magnesium concentrations

To clarify the effect of extracellular magnesium (Mg2+) on the vascular reactivity of feline isolated middle cerebral arteries, the effects of slight alterations in the Mg2+ concentration on the contractile and endothelium-dependent dilatory responses were investigated in vitro. The contractions, induced by 10(-8)-10(-5) M norepinephrine, were significantly potentiated at low Mg2+ (0.8 mM v. the normal, 1.2 mM). High (1.6 and 2.0 mM) Mg2+ exhibited an inhibitory effect on the contractile responses. No significant changes, however, in the EC50 values for norepinephrine were found. The endothelium-dependent relaxations induced by 10(-8)-10(-5) M acetylcholine were inhibited by high (1.6 and 2.0 mM) Mg2+. Lowering of the Mg2+ concentration to 0.8 mM or total withdrawal of this ion from the medium failed to alter the dilatory potency of acetylcholine. The changes in the dilatory responses also shifted the EC50 values for acetylcholine to the right. The present results show that the contractile responses of the cerebral arteries are extremely susceptible to the changes of Mg2+ concentrations. In response to contractile and endothelium-dependent dilatory agonists, Mg2+ probably affects both the calcium influx into the endothelial and smooth muscle cells as well as the binding of acetylcholine to its endothelial receptor. Since Mg2+ deficiency might facilitate the contractile but not the endothelium-dependent relaxant responses, the present study supports a role for Mg2+ deficiency in the development of the cerebral vasospasm.     

Work stress and hypertension: A call from research into intervention

Annals of Behavioral Medicine -     

GGA1 acts as a spatial switch altering amyloid precursor protein trafficking and processing

The beta-amyloid (Abeta) precursor protein (APP) is cleaved sequentially by beta-site of APP-cleaving enzyme (BACE) and gamma-secretase to release the Abeta peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized gamma-ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from beta-cleavage but surprisingly reduced Abeta. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP beta-cleavage products from becoming substrates for gamma-secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP-GGA1 interactions may have pathophysiological relevance in AD.     

Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer

10-Ethyl-10-deazaaminopterin (10-EDAM) is an analogue of methotrexate with improved preclinical anticancer activity, more selective entry, and greater conversion to polyglutamate forms in neoplastic cells. In this Phase I trial, we have treated 62 adults with advanced solid tumors, giving 10-EDAM i.v. on either a weekly x 3 schedule (35 patients) or a weekly schedule (27 patients). The dosage levels ranged from 5 to 120 mg/m2. The toxicity observed with 10-EDAM was qualitatively similar to that of methotrexate. Oral mucositis was the dose-limiting toxicity; diarrhea, skin rash, leukopenia, thrombocytopenia, and mild elevations of serum glutamic-oxaloacetic transaminase, prothrombin, and partial thromboplastin times were also observed, but were not dose limiting. A weekly dosage of 80 mg/m2 with escalation or attenuation in accordance with patient tolerance, or 100 mg/m2 weekly for 3 weeks, followed by a 2-week "rest period" are recommended for Phase II assessment. 10-EDAM produced partial remissions in three patients with non-small cell lung cancer and one patient with breast cancer lasting 6, 40+, 26+, and 15 months, respectively. Pharmacokinetic studies carried out at the 5, 30, and 100 mg/m2 dosage levels demonstrated the drug to have a triphasic disappearance from plasma. Elimination was independent of dose over the range tested, with mean plasma half-lives of: alpha = 12.9 min, beta = 1.5 h, and gamma = 11.9 h. Cumulative urinary excretion of the drug ranged from 13 to 55% of the administered dose (mean = 33%); 88% of the urinary drug appeared within the first 4 h following drug administration. The pharmacokinetic behavior of the first and second weekly dosages were consistent within a given patient. The metabolites 7-hydroxy-10-EDAM, and 10-ethyl-10-deaza-2,4-diamino-pteroic acid were demonstrated in the plasma and urine of treated patients. In studies of tissue homogenates from two patients with skin metastases, more extensive retention of the drug and of its polyglutamates was observed in the breast cancer metastases than in the metastases from a kidney cancer or in normal skin.