Elevated levels of the NR2C subunit of the NMDA receptor in the locus coeruleus in depression.

Low levels of the intracellular mediator of glutamate receptor activation, neuronal nitric oxide synthase (nNOS) were previously observed in locus coeruleus (LC) from subjects diagnosed with major depression. This finding implicates abnormalities in glutamate signaling in depression. Receptors responding to glutamate in the LC include ionotropic N-methyl-D-aspartate receptors (NMDARs). The functional NMDAR is a hetero-oligomeric structure composed of NR1 and NR2 (A-D) subunits. Tissue containing the LC and a nonlimbic LC projection area (cerebellum) was obtained from 13 and 9 matched pairs, respectively, of depressed subjects and control subjects lacking major psychiatric diagnoses. NMDAR subunit composition in the LC was evaluated in a psychiatrically normal subject. NR1 and NR2C subunit immunoreactivities in LC homogenates showed prominent bands at 120 and 135 kDa, respectively. In contrast to NRI and NR2C, very weak immunoreactivity of NR2A and NR2B subunits was observed in the LC. Possible changes in concentrations of NR1 and NR2C that might occur in depression were assessed in the LC and cerebellum. The overall amount of NR1 immunoreactivity was normal in the LC and cerebellum in depressed subjects. Amounts of NR2C protein were significantly higher (+ 61%, p = 0.003) in the LC and modestly, but not significantly, elevated in the cerebellum (+ 35%) of depressives as compared to matched controls. Higher levels of NR2C subunit implicate altered glutamatergic input to the LC in depressive disorders.     

Effect of oxygen withdrawal on active and passive electrical properties of arterially perfused rabbit ventricular muscle

Oxygen withdrawal from myocardial cells leads to changes of the transmembrane action potential (mainly action potential shortening), to cellular uncoupling, and to changes of vascular permeability. This study was aimed at the simultaneous measurement of electrical activity and passive electrical properties (extracellular and intracellular longitudinal resistance) in arterially perfused rabbit papillary muscles under different conditions of changed oxygen supply. These included 1) complete anoxia (erythrocyte-free perfusate), 2) hypoxia (PO2 between 23-28 mm Hg, erythrocytes present) in the presence and absence of glucose, and 3) normoxia with erythrocyte-free perfusate. Similarly to myocardial ischemia, rapid cellular uncoupling occurred only after an initial stable period of approximately 17 minutes, and it required complete anoxia. The marked shortening of the action potential developed before cellular uncoupling. In six out of eight experiments, the fibers were inexcitable when uncoupling started. In severe hypoxia, no significant change of internal longitudinal resistance was observed over 35-40 minutes. The time course of the extracellular longitudinal resistance was different from the change in intracellular resistance: A marked decrease occurred almost immediately after the onset of oxygen withdrawal. This decrease was followed by a small increase in conduction velocity, which was most likely due to a change in the interstitial compartment (edema). It was observed during anoxic as well as during hypoxic perfusion. We conclude that 1) cellular uncoupling in arterially perfused tissue requires almost complete oxygen lack and occurs with a delay of more than 10 minutes, 2) marked action potential shortening precedes uncoupling, and therefore can not simply be attributed to an increase in free, intracellular calcium, and 3) vascular endothelial function is more sensitive to oxygen withdrawal than the myocyte.     

Monocrotaline-induced cardiopulmonary injury in rats. Modification by the neutrophil elastase inhibitor SC39026

Rats were killed after 6 weeks of continuous ingestion of the pneumotoxic alkaloid monocrotaline (2.2 mg/kg/day), the neutrophil elastase inhibitor SC39026 (60 mg/kg/day), or both. Pulmonary reactions were evaluated by light and electron microscopy. Lung endothelial function was monitored by angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Lung hydroxyproline content was measured as an index of interstitial fibrosis. Cardiac right ventricular hypertrophy was determined by the right ventricle to the left ventricle plus septum weight ratio (RV/LV + S). Rats receiving SC39026 alone did not differ significantly from untreated control animals with respect to any of the quantitative endpoints, although rarefaction of Type I pneumocytes was observed in the electron micrographs of these animals. Monocrotaline-treated rats, in contrast, developed a significant increase in RV/LV + S, and exhibited pulmonary edema, inflammation, fibrosis, and muscularization and occlusive mural thickening of the pulmonary small arteries and arterioles. These monocrotaline-induced structural changes were accompanied by decreased lung ACE and PLA activities, and increased PGI2 and TXA2 production, and by an increase in lung hydroxyproline content. Cotreatment with SC39026 ameliorated the monocrotaline-induced pulmonary vascular wall thickening and the cardiac right ventricular hypertrophy. These data suggest that inappropriate neutrophil elastase activity contributes to monocrotaline pulmonary vasculopathy and hypertension. On the other hand, cotreatment with SC39026 had no significant effect on the severity of the monocrotaline-induced lung inflammatory reaction, the pulmonary endothelial dysfunction, or the increase in lung hydroxyproline content.     

Intact parathyroid hormone, ionized calcium and calcium infusion test in the evaluation of hyperparathyroidism in chronic renal failure

We studied the parathyroid function in patients with advanced renal failure by determining their plasma concentrations of ionized calcium (iCa), intact parathyroid hormone (PTH) and its inactive metabolites (PTH-MM). The suppressibility of the parathyroidism was studied with a calcium infusion test. The intact PTH values of the nondialysis and dialysis patients did not statistically differ from each other. The concentrations of PTH-MM were, however, higher in the dialysis patients than in the nondialysis patients (p less than 0.05). The ratio of PTH-MM to intact PTH was lowest in healthy reference subjects and highest in dialysis patients (p less than 0.01), and did not correlate with the degree of intact PTH elevation in the patient groups. The calcium infusion test was carried out on 15 patients. All showed suppression in the elevated plasma intact PTH concentration and in 6 the intact PTH value normalized. The PTH-MM value did not normalize in any of the patients. During oral calcium treatment the degree of intact PTH suppression at an achieved concentration of plasma iCa was predictable from the infusion test. Three patients were parathyroidectomized after the calcium infusion test. In 2 of these elevated intact PTH normalized within 24 h while in 1 no change took place. In this latter case on clinical improvement was noted. We conclude that the determination of plasma intact PTH concentration especially of combined with plasma iCa value is a reliable means of studying the hyperparathyroidism associated with chronic renal failure.     

The effect of atrial natriuretic peptide on human isolated resistance arteries.

1. The action of (1-28) alpha-human atrial natriuretic peptide (ANP) was studied on human isolated resistance arteries. 2. Renal, skeletal muscle, omental and subcutaneous resistance arteries were taken from tissue removed at surgery and isometric tension responses were measured with a myograph. 3. ANP (10(-9)-10(-6) M) relaxed precontracted segments of renal and skeletal muscle arteries in a concentration-dependent manner. ANP failed to relax isolated omental or subcutaneous arteries. 4. The effect of ANP on human isolated resistance arteries varies depending on the site of origin of the artery.     

Value of approach to the cervical spine by bilateral anterolateral route

The authors report their experience of anterolateral bilateral approach of cervical spine. They underline the advantages and inconvenience of this route and discuss the indications.     

Cancer risk after evaluation for infertility

To evaluate cancer risk by various causes of infertility, the authors conducted a retrospective cohort study among 2,335 women evaluated for infertility at the Mayo Clinic between 1935 and 1964. Most cancers occurred at expected frequencies, with the exception of cancers of the thyroid (standardized incidence ratio (SIR) = 2.6) and other endocrine glands (SIR = 6.7), although analyses were based on small numbers. Patients with progesterone deficiencies (31 per cent of the study subjects) had a 20 per cent higher cancer risk than did those with other causes of infertility, with excesses deriving primarily from cancers of the lung, cervix, ovary, and thyroid and from melanoma. Breast cancer risk, however, was not elevated in either patients with progesterone deficiencies (SIR = 0.9) or patients with other causes of infertility (SIR = 1.0). Examination of other parameters of infertility, including age at evaluation, type of infertility (primary vs. secondary), and years of attempted conception, showed no elevated risks of breast cancer in any subgroup. These results fail to support previous studies that have linked progesterone deficiencies among infertile women to elevated breast cancer risk. However, the data suggest a possible involvement of a progesterone deficiency in the etiology of other cancers, particularly thyroid cancer and melanoma.