Multiple single units and population responses during inhibitory gating of hippocampal auditory response in freely-moving rats

Paired clicks were presented to awake, freely-moving rats to examine neuronal activity associated with inhibitory gating of responses to repeated auditory stimuli. The rats had bundles of eight microwires implanted into each of four different brain areas: CA3 region of the hippocampus, medial septal nucleus, brainstem reticular nucleus, and the auditory cortex. Single-unit recordings from each wire were made while the local auditory-evoked potential was also recorded. The response to a conditioning stimulus was compared to the response to a test stimulus delivered 500 ms later: the ratio of the test response to the conditioning response provided a measure of inhibitory gating. Auditory-evoked potentials were recorded at all sites. Overall, brainstem reticular nucleus neurons showed the greatest gating of local auditory-evoked potentials, while the auditory cortex showed the least. However, except for the auditory cortex, both gating and non-gating of the evoked response were recorded at various times in all brain regions. Gating of the hippocampal response was significantly correlated with gating in the medial septal nucleus and brainstem reticular nucleus, but not the auditory cortex. Single-unit neuron firing in response to the clicks was most pronounced in the brainstem reticular nucleus and the medial septal nucleus, while relatively few neurons responded in the CA3 region of the hippocampus and the auditory cortex. Taken together, these data support the hypothesis that inhibitory gating of the auditory-evoked response originates in the non-lemniscal pathway and not in cortical areas of the rat brain.     

Breast feeding and later psychosocial adjustment

The relationship between the duration of breast feeding and psychosocial outcomes measured between the ages of 15 and 18 years was examined in a birth cohort of 999 New Zealand children. During the period from birth to 1 year, information was collected on maternal breast-feeding practices. Between the ages of 15 and 18 years, sample members were assessed using a range of psychosocial measures, including measures of the quality of parent-child relationships, juvenile delinquency, substance abuse and mental health. Children who were breast fed for a longer duration were more likely to report higher levels of parental attachment and tended to perceive their mothers as being more caring and less overprotective towards them compared with bottle-fed children. No association was found between the extent of breast feeding and subsequent rates of juvenile offending, substance use and mental health in later life. Mothers who elected to breast feed were also more likely to be older, better educated, living with a partner, less likely to smoke during pregnancy, and to come from advantaged socio-economic backgrounds characterised by better living standards and a higher family income. Rates of breast feeding were also greater among mothers who gave birth to a first-born child of higher birthweight. After adjustment for these maternal and perinatal factors, the duration of breast feeding remained significantly associated with adolescent perceptions of maternal care, with increasing duration of breast feeding being associated with higher levels of perceived maternal care during childhood. It is concluded that: (a) it is unlikely that breast feeding is associated with reduced risks of psychiatric disorder in later life; (b) breast feeding may lead to closer parent-child relationships; and (c) it is unlikely that the association between breast feeding and cognitive development is mediated by intervening processes relating to improved psychosocial adjustment in breast-fed children.     

Chronic hypoxia differentially alters the responses of pulmonary arteries and veins to endothelin-1 and other agents.

The effects of chronic hypoxia on the responses of rat large pulmonary arteries and veins to vasoactive agents have been examined. Endothelin-1-induced contractions of pulmonary arteries and pulmonary veins were reduced by chronic hypoxia. In contrast, chronic hypoxia augmented sarafotoxin 6c-induced contractile responses in pulmonary veins but not in pulmonary arteries. Chronic hypoxia augmented the constrictor effect of phenylephrine in pulmonary arteries, but not in pulmonary veins. The thromboxane receptor agonist, U46619 (9,11-dideoxy-9alpha,11alpha-epoxy-methanoprostaglandin++ + f2alpha) contracted pulmonary arteries and pulmonary veins, and although maximal responses were not altered in chronically hypoxic preparations, the EC50 value in pulmonary arteries was increased following chronic hypoxia. The relaxant effects of acetylcholine and isoprenaline on pulmonary arteries were potentiated by chronic hypoxia. In contrast, ionomycin-mediated relaxations of pulmonary arteries and pulmonary veins were reduced, while sodium nitroprusside-induced relaxation of pulmonary arteries and veins were not altered by chronic hypoxia. Previous studied have looked primarily at the effects of chronic hypoxia on pulmonary arteries. This data provides evidence that chronic hypoxia also causes selective changes in the reactivity of large pulmonary veins.     

4-Hydroxy-1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine: a novel, potent, and selective NR1/2B NMDA receptor antagonist.

A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)-4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC(50) = 0.63 microM). We report on the optimization of this lead compound in terms of potency, side effect liability, and in vivo activity. Potency was assayed by electrical recordings in Xenopus oocytes expressing cloned rat NMDA receptors. Side effect liability was assessed by measuring affinity for alpha(1)-adrenergic receptors and inhibition of neuronal K(+) channels. Central bioavailability was gauged indirectly by determining anticonvulsant activity in a mouse maximal electroshock (MES) assay. Making progressive modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a approximately 25-fold increase in NR1A/2B potency (IC(50) = 0.025 microM). p-Methyl substitution on the benzyl ring (10b) produced a approximately 3-fold increase in MES activity (ED(50) = 0.7 mg/kg iv). Introduction of a second hydroxyl group into the C-4 position on the piperidine ring (10e) resulted in a substantial decrease in affinity for alpha(1) receptors and reduction in inhibition of K(+) channels with only a modest decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperid ine, Co 101244/PD 174494) had the optimum pharmacological profile and was selected for further biological evaluation.     

The U.S. health insurance industry: an alternative view.

The health insurance industry in the U.S. can be characterized as a concentrated industry. It has evolved into its current structure as a result of certain historical conditions, particularly those following the Great Depression. The structure of the industry has had an effect on the manner in which the industry functions and the cost increases in the health care sector. Specifically, the pricing mechanism is that of a price leader setting a limit price; health premium prices are higher than would be expected under a competitive structure. Regulation has been ineffective, because it has been dominated historically by health care providers and insurers. The costs of health care in general, and hospital care in particular, have increased beyond what would be expected as a result of "cost-pass-through."     

One hospital's experience with a "Do not resuscitate" policy.

A "No not resuscitate" policy was instituted at McMaster University Medical Centre, Hamilton, in January 1979. Its objectives were to ensure that physicians decide on the appropriateness of resuscitation attempts before they might be needed; to have each physician consult his or her patients, or the families of incompetent patients, to determine their wishes concerning further treatment; and to provide legal protection of or physicians and the hospital in regard to the policy. To determine the effectiveness of the "Do not resuscitate" policy a questionnaire was sent to a sample of the professional staff of the hospital; the overall response rate was 87%. The respondents felt that a better way of informing hospital staff of the policy and its objectives was needed. However, the results of the questionnaire suggested that, on the whole, the policy was perceived as beneficial to both patients and physicians at the hospital.     

The vasa vasorum and angioplasty

Interruption of flow in the vasa vasorum may lead to medial necrosis and aneurysm formation. The purpose of this study was to determine whether angioplasty produces significant alterations in the morphology or blood flow of the vasa vasorum of the dilated artery. The morphology of the canine vasa vasorum was studied before and after angioplasty; in a separate experiment vessel wall blood flow (VWBF) in canine carotid arteries was measured after angioplasty to determine whether physiologic regulation of the blood flow was disrupted by arterial dilation. No morphologic changes could be demonstrated in the vasa vasorum of the dilated artery; however, VWBF was increased by 1194 +/- 215% (mean +/- standard error, p less than 0.01) between 90 and 120 minutes after angioplasty. VWBF in the adjacent nondilated arterial segment was also increased (720 +/- 177% between 10-30 minutes, p less than 0.01) but returned toward normal after 60 minutes. Adenosine caused a "paradoxical" decrease in VWBF (p less than 0.05) of the dilated arterial segment while causing increased VWBF (p less than 0.05) in the thoracic aorta. Angioplasty appears to produce persistent hyperemia in the dilated arterial wall. A paradoxical response to adenosine suggests that vasa vasorum in the dilated arterial segment are maximally vasodilated. This may be due to mechanical disruption of vasomotor tone or to release of vasoactive substances.     

The influence of harvesting technique on endothelial preservation in saphenous veins.

To study optimal conditions of preparation of saphenous veins as coronary artery bypass grafts, segments of saphenous veins were obtained from 29 consecutive patients undergoing coronary artery bypass grafting. The saphenous vein segments were divided into three groups. In Group I, 10 saphenous vein segments were harvested using a "no-touch" technique without any other preparation aids. In Group II, 10 saphenous vein segments were removed while distended at 70-120 mm Hg with a balanced pH electrolyte solution at 37 degrees C. In Group III, consisting of 10 saphenous vein segments, nitroglycerin (1 microgram/ml) was added to the distending solution used in Group II. Samples of saphenous vein were assessed in a blind study using light and scanning electron microscopy to estimate endothelial cell preservation by the three harvest techniques. Saphenous veins receiving only a no-touch dissection technique without distention solution (Group I) revealed significantly better endothelial preservation (P less than 0.005). The administration of distention solution alone, or with nitroglycerin, to saphenous veins in situ using our operative technique during harvest does not appear to protect endothelial-integrity and may be harmful.     

Vehicle year and the risk of car crash injury

OBJECTIVE: To quantify the association between vehicle age and risk of car crash injury. DESIGN AND SETTING: Data from a population based case-control study conducted in the Auckland region in 1998/99 was used to examine the adjusted risk of car crash injury or death due to vehicle age, after controlling for a range of known confounders. Cases were all cars involved in crashes in which at least one occupant was hospitalized or killed anywhere in the Auckland region, and controls were randomly selected cars on Auckland roads. The drivers of the 571 case vehicles and 588 control vehicles completed a structured interview. MAIN OUTCOME MEASURE: Hospitalisation or death of a vehicle occupant due to car crash injury. RESULTS: Vehicles constructed before 1984 had significantly greater chance of being involved in an injury crash than those constructed after 1994 (odds ratio 2.88, 95% confidence interval (CI) 1.20 to 6.91), after adjustment for potential confounders. There was also a trend for increasing crash risk with each one year increase in vehicle age after adjustment for potential confounders (odds ratio 1.05, 95% CI 0.99 to 1.11; p = 0.09). CONCLUSION: This study quantifies the increased risk of car crash injury associated with older vehicle year and confirms this as an important public health issue.