Histamine H3 receptors contribute to drinking elicited by eating in rats

A role for endogenous histamine and its H3 receptor subtype for mediating drinking elicited by eating was examined in adult male Sprague-Dawley rats. The i.p. injection of the H3 agonist R-alpha-methylhistamine (Ramh, 2.5 mg/kg) shortened the latency to initiate drinking and increased 1-h water intake in nondeprived rats freely eating pellets and drinking water. The ICV injection (through a surgically implanted chronic cannula) of 10 micrograms Ramh increased water intake; this Ramh-induced drinking was abolished by previous ICV injection of the H3 antagonist thioperamide (Th, 60 micrograms). For rats drinking and eating after 24-h food deprivation, s.c. Th inhibited drinking behavior: for example, 10 mg/kg Th s.c. delayed the latency to initiate drinking and inhibited 1-h water intake without inhibition of food intake. In contrast, 60 micrograms Th ICV failed to inhibit food-related drinking in rats eating after food deprivation. For nondeprived rats eating a small cracker, 10 mg/kg Th s.c. delayed the latency to initiate drinking and abolished water intake without effect of eating, and 60 micrograms Th ICV had similar effects upon drinking elicited by ingestion of cracker. The IG infusion (through a surgically implanted gastric catheter) of 2 ml 600 or 900 mOsm/kg NaCl, a treatment that is subthreshold for increase in systemic plasma osmolality at the initiation of drinking, elicited drinking that was abolished by 10 mg/kg Th s.c. and attenuated by 60 micrograms Th ICV. The IG infusion of 2 ml 1800 mOsm/kg NaCl, a treatment that is above threshold for increase in systemic plasma osmolality, elicited drinking that was attenuated by 10 mg/kg s.c. or 60 micrograms Th ICV. These results demonstrate that peripheral and central H3 receptors for histamine have a role in drinking elicited by eating and the postprandial gastrointestinal osmotic consequences of eating. These findings extend the evidence demonstrating a histaminergic contribution to food-related drinking in rats.     

Induction of c-fos and c-jun proto-oncogene expression by asbestos is ameliorated by N-acetyl-L-cysteine in mesothelial cells

Asbestos fibers cause dose-dependent, persistent increases in mRNA levels of c-jun and c-fos proto-oncogenes in rat pleural mesothelial (RPM) cells, the progenitor cells of asbestos-induced mesothelioma (N. Heintz, Y. M. W. Janssen, and B. T. Mossman. Proc. Natl. Acad. Sci. USA, 90: 3299-3303, 1993). Here we report that addition of N-acetyl-L-cysteine decreases asbestos-mediated induction of c-fos and c-jun mRNA levels in a dose-dependent fashion. Exposure of RPM cells to asbestos causes depletion of total cellular glutathione, a response that can be abolished by pretreatment with N-acetyl-L-cysteine. Pretreatment of cells with buthionine sulfoximine, an agent which diminishes glutathione pools, increases the magnitude of induction of c-fos and c-jun mRNA by asbestos. To determine whether asbestos-induced effects on proto-oncogene expression could be attributed to extracellular generation of active oxygen species (AOS), RPM cells were exposed to H2O2 or xanthine and xanthine oxidase, a generating system of AOS. These oxidant stresses did not decrease cellular glutathione levels nor alter mRNA levels of c-fos or c-jun. However, increased mRNA levels of manganese-containing superoxide dismutase and heme oxygenase were observed, indicating that RPM cells respond to AOS by increased expression of genes encoding antioxidant enzymes. These data indicate that the signaling pathways leading to c-fos/c-jun proto-oncogene induction by asbestos are not triggered directly by formation of extracellular AOS. However, intracellular thiol levels appear to influence the expression of c-fos and c-jun, suggesting a redox-sensitive component in the signaling cascade which modulates gene expression of c-fos and c-jun by asbestos.     

VH gene family utilization of anti-acetylcholine receptor antibodies in experimental autoimmune myasthenia gravis

The immunoglobulin heavy chain (VH) gene family usage in experimental autoimmune myasthenia gravis (EAMG) model was investigated by RNA slot blot hybridization using VH gene family specific probes. Anti-acetylcholine receptor (AChR) monoclonal antibodies (mAbs) isolated from susceptible C57BL/6 and resistant BALB/c mice were found to be encoded by VH genes from at least six different families. The Vgam3.8 family was overrepresented in alpha-bungarotoxin blocking mAbs. Expression of cross-reactive idiotypes by anti-AChR mAbs was irrespective of the VH gene family usage. Strain dependent differences in susceptibility for EAMG were not reflected in an aberrant VH gene family usage of anti-AChR mAbs.     

Sleep in relation to age, sex, and chronotype in Japanese workers

The Morningness-Eveningness Questionnaire and Life Habits Inventory were administered to 622 Japanese workers matched for sex and age. We investigated the distributions of the scores on the Morningness-Eveningness Questionnaire and sleep-wake habits by age and sex. Subjects were classified into five age groups and three chronotypes. The distributions and mean scores on the questionnaire advanced slightly toward the Morning type from the young to the aged group. The habitual bedtimes and waking times were significantly earlier in all the chronotypes from the young to the aged group, and the preferred bedtimes and waking times were also clearly earlier from the young to the aged group. The length of sleep was shorter for the Evening than the Morning types, especially in the group below 24 yr. The differences in habitual and preferred sleep length were greater than 1 hour for all age groups, especially the two groups under 34 yr. The number of awakenings during night sleep increased from the young to the aged group for all chronotypes. The older Evening type tended more toward frequent napping and longer naptime. The variabilities of bedtime and sleep length were larger for the young and Evening type than for the old group and Morning types. Further, the mood upon waking and satisfaction with sleep length were better in the aged Evening type than the young Morning type. The women under 44 yr. woke up earlier than the men of the same age, and the women of the 35-54 yr. groups had a shorter length of sleep than others. These may be related to childcare and housework. These results indicated that the phase of circadian rhythms had moved forward from the young to the aged group, and the individual's rhythm, of those that were aged Morning types, showed better agreement with sleep-wake rhythms than did others.     

NMDA receptors mediate peripheral chemoreceptor afferent input in the conscious rat

N-methyl-D-aspartate (NMDA) glutamate receptors mediate critical components of cardiorespiratory control in anesthetized animals. The role of NMDA receptors in the ventilatory responses to peripheral and central chemoreceptor stimulation was investigated in conscious, freely behaving rats. Minute ventilation (VE) responses to 10% O2, 5% CO2, and increasing intravenous doses of sodium cyanide were measured in intact rats before and after intravenous administration of the NMDA receptor antagonist MK-801 (3 mg/kg). After MK-801, eupcapnic tidal volume (VT) decreased while frequency increased, resulting in a modest reduction in VE. Inspiratory time (TI) decreased, whereas expiratory time remained unchanged. The VE responses to hypercapnia were qualitatively similar in control and MK-801 conditions, with slight reductions in respiratory drive (VT/TI) after MK-801. In contrast, responses to hypoxia were markedly attenuated after MK-801 and were primarily due to reduced frequency changes, whereas VT was unaffected. Sodium cyanide doses associated with significant VE increases were 5 and 50 microg/kg before and after MK-801, respectively. Thus 1-log shift to the right of individual dose-response curves occurred with MK-801. Selective carotid body denervation reduced VE during hypoxia by 70%, and residual hypoxic ventilatory responses were abolished after MK-801. These findings suggest that, in conscious rats, carotid and other peripheral chemoreceptor-mediated hypoxic ventilatory responses are critically dependent on NMDA receptor activation and that NMDA receptor mechanisms are only modestly involved during hypercapnia.     

PAK-104P, a pyridine analogue, reverses paclitaxel and doxorubicin resistance in cell lines and nude mice bearing xenografts that overexpress the multidrug resistance protein

For ethical decision-making near the end of life, autonomy is the moral North Star. At the same time, for some treatments, the burdens so clearly outweigh benefits that physicians may make a judgment not to offer the treatment. This is often clearer in surgery. A person with colon cancer and metastases may not insist on resection of the metastases. For some reason, some treatments have escaped these logical constraints. Attempted resuscitation of a dying patient is a good example. The circumstances in which a physician may make choices on behalf of a competent, terminally-ill patient without consent, and even without notification, are hotly debated, but data suggest that physicians do so frequently. Patients who lack capacity present even more difficult challenges. Advance directives, when available, can be extremely helpful, but even with them difficult problems can remain. If advance directives have not been established, family and close friends are an obvious source of guidance. Their legal role varies in different jurisdictions; in practice, they are crucial in bedside decision-making. Guardianship and alternatives to it remain a poor last resort. Euthanasia is a very difficult problem. We believe it is semantically misleading to lump under the term "passive euthanasia" those circumstances where potentially life-sustaining treatment is withheld or withdrawn. The tension between patient autonomy and medical common sense remains unresolved within the "futility" controversy. The authors believe it serves no purpose to discuss carefully with dying patients propositions that are nonsense. At the same time, physicians must not confuse decisions about quality of life with judgements about treatment effectiveness. We believe that what many, although not all, dying patients want are physicians with intelligent compassion who can take care of them through the dying process.