The presence of glutamate dehydrogenase is a selective advantage for the Cyanobacterium synechocystis sp. strain PCC 6803 under nonexponential growth conditions

The unicellular cyanobacterium Synechocystis sp. strain PCC 6803 has two putative pathways for ammonium assimilation: the glutamine synthetase-glutamate synthase cycle, which is the main one and is finely regulated by the nitrogen source; and a high NADP-dependent glutamate dehydrogenase activity (NADP-GDH) whose contribution to glutamate synthesis is uncertain. To investigate the role of the latter, we used two engineered mutants, one lacking and another overproducing NADP-GDH. No major disturbances in the regulation of nitrogen-assimilating enzymes or in amino acids pools were detected in the null mutant, but phycobiline content, a sensitive indicator of the nutritional state of cyanobacterial cells, was significantly reduced, indicating that NADP-GDH plays an auxiliary role in ammonium assimilation. This effect was already prominent in the initial phase of growth, although differences in growth rate between the wild type and the mutants were observed at this stage only at low light intensities. However, the null mutant was unable to sustain growth at the late stage of the culture at the point when the wild type showed the maximum NADP-GDH activity, and died faster in ammonium-containing medium. Overexpression of NADP-GDH improved culture proliferation under moderate ammonium concentrations. Competition experiments between the wild type and the null mutant confirmed that the presence of NADP-GDH confers a selective advantage to Synechocystis sp. strain PCC 6803 in late stages of growth.     

Abstinence is not the only answer

Familial inheritance of congenital diaphragmatic hernia is uncommon. We report two siblings with identical bilateral diaphragmatic defects.     

The Sleep Heart Health Study: design, rationale, and methods

The Sleep Heart Health Study (SHHS) is a prospective cohort study designed to investigate obstructive sleep apnea (OSA) and other sleep-disordered breathing (SDB) as risk factors for the development of cardiovascular disease. The study is designed to enroll 6,600 adult participants aged 40 years and older who will undergo a home polysomnogram to assess the presence of OSA and other SDB. Participants in SHHS have been recruited from cohort studies in progress. Therefore, SHHS adds the assessment of OSA to the protocols of these studies and will use already collected data on the principal risk factors for cardiovascular disease as well as follow-up and outcome information pertaining to cardiovascular disease. Parent cohort studies and recruitment targets for these cohorts are the following: Atherosclerosis Risk in Communities Study (1,750 participants), Cardiovascular Health Study (1,350 participants), Framingham Heart Study (1,000 participants), Strong Heart Study (600 participants), New York Hypertension Cohorts (1,000 participants), and Tucson Epidemiologic Study of Airways Obstructive Diseases and the Health and Environment Study (900 participants). As part of the parent study follow-up procedures, participants will be surveyed at periodic intervals for the incidence and recurrence of cardiovascular disease events. The study provides sufficient statistical power for assessing OSA and other SDB as risk factors for major cardiovascular events, including myocardial infarction and stroke.     

Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors

The dopamine D3 receptor is expressed primarily in regions of the brain that are thought to influence motivation and motor functions. To specify in vivo D3 receptor function, we generated mutant mice lacking this receptor. Our analysis indicates that in a novel environment, D3 mutant mice are transiently more active than wild-type mice, an effect not associated with anxiety state. Moreover, D3 mutant mice exhibit enhanced behavioral sensitivity to combined injections of D1 and D2 class receptor agonists, cocaine and amphetamine. However, the combined electrophysiological effects of the same D1 and D2 agonists on single neurons within the nucleus accumbens were not altered by the D3 receptor mutation. We conclude that one function of the D3 receptor is to modulate behaviors by inhibiting the cooperative effects of postsynaptic D1 and other D2 class receptors at systems level.     

Human cytochrome P4502B6: interindividual hepatic expression, substrate specificity, and role in procarcinogen activation

In situ hybridization was combined with serotonin (5-hydroxytryptamine, 5-HT) or tyrosine hydroxylase immunocytochemistry and with Fluoro-Gold retrograde labeling of bulbo-spinal pathways in order to investigate the expression of GAP-43 mRNA in monoamine cell groups of the adult rat brain stem. Consistent with previous reports, GAP-43 mRNA was observed in serotonin and dopamine cell groups in the pons. In addition, GAP-43 expressing cells were observed in all the major monoamine cell groups in the medulla. Thus the B1, B2 and B3 serotonin cell groups all showed high GAP-43 expression in all contained many GAP-43 expressing serotonin cells with spinal cord projections. The A1, A2, A5 and A6 noradrenaline cell groups also showed high GAP-43 expression, although cells with spinal cord projections were largely restricted to the A5 group and A6 subcoeruleus region. In all areas, GAP-43 expressing cells with spinal cord projections were also observed which were not serotonergic or noradrenergic.     

Markedly altered colchicine kinetics in a fatal intoxication: examination of contributing factors

1. Colchicine poisoning, which is relatively rare, is associated with significant morbidity and mortality. Whilst a new treatment modality, in the form of colchicine-specific Fab fragments is on the horizon, currently available therapy is largely supportive. 2. The elimination of colchicine occurs primarily by hepatic metabolism, following a first-order process, with significant enterohepatic circulation. Renal extraction is responsible for approximately 20% of colchicine elimination. 3. We report a case of colchicine intoxication, complicated by the presence of co-ingestants, in which serum colchicine concentrations remained quasi-constant over the 3 days of the patient's survival, consistent with marked alterations both in metabolism and excretion. The initial presentation was relatively benign but the subsequent course was one of severe colchicine poisoning, resulting in death. 4. Severe colchicine toxicity appears to have resulted in a vicious cycle of progressive organ dysfunction and impaired elimination. 5. Josamycin, one of the co-ingestants and an inhibitor of P-glycoprotein, the membrane pump responsible for multidrug resistance, may have played a significant role in impeding the cellular and biliary elimination of colchicine. Co-ingested opioid and anticholinergic compounds may have altered colchicine absorption and gastrointestinal transit. 6. This case serves as a reminder of the need for attention to co-ingested drugs, to early aggressive therapy, and if available, to consideration of immunotherapy.