Recent Advances of Silver Nanoparticles in Cancer Diagnosis and Treatment.

BACKGROUND: Silver nanoparticles (AgNPs) are well-known as a promising antimicrobial material; they have been widely used in many commercial products against pathogenic agents. Despite a growing concern regarding the cytotoxicity, AgNPs still have attracted considerable interest worldwide to develop a new generation of diagnostic tool and effective treatment solution for cancer cells. OBJECTIVE: This paper aims to review the advances of AgNPs applied for cancer diagnosis and treatment. METHODS: The database has been collected, screened and analysed through up-to-date scientific articles published from 2007 to May 2019 in peer-reviewed international journals. RESULTS: The findings of the database have been analysed and divided into three parts of the text that deal with AgNPs in cancer diagnosis, their cytotoxicity, and the role as carrier systems for cancer treatment. Thanks to their optical properties, high conductivity and small size, AgNPs have been demonstrated to play an essential role in enhancing signals and sensitivity in various biosensing platforms. Furthermore, AgNPs also can be used directly or developed as a drug delivery system for cancer treatment. CONCLUSION: The review paper will help readers understand more clearly and systematically the role and advances of AgNPs in cancer diagnosis and treatment.

Microbial contributions to subterranean methane sinks.

Sources and sinks of methane (CH4 ) are critical for understanding global biogeochemical cycles and their role in climate change. A growing number of studies have reported that CH4 concentrations in cave ecosystems are depleted, leading to the notion that these subterranean environments may act as sinks for atmospheric CH4 . Recently, it was hypothesized that this CH4 depletion may be caused by radiolysis, an abiotic process whereby CH4 is oxidized via interactions with ionizing radiation derived from radioactive decay. An alternate explanation is that the depletion of CH4 concentrations in caves could be due to biological processes, specifically oxidation by methanotrophic bacteria. We theoretically explored the radiolysis hypothesis and conclude that it is a kinetically constrained process that is unlikely to lead to the rapid loss of CH4 in subterranean environments. We present results from a controlled laboratory experiment to support this claim. We then tested the microbial oxidation hypothesis with a set of mesocosm experiments that were conducted in two Vietnamese caves. Our results reveal that methanotrophic bacteria associated with cave rocks consume CH4 at a rate of 1.3-2.7 mg CH4  · m-2  · d-1 . These CH4 oxidation rates equal or exceed what has been reported in other habitats, including agricultural systems, grasslands, deciduous forests, and Arctic tundra. Together, our results suggest that depleted concentrations of CH4 in caves are most likely due to microbial activity, not radiolysis as has been recently claimed. Microbial methanotrophy has the potential to oxidize CH4 not only in caves, but also in smaller-size open subterranean spaces, such as cracks, fissures, and other pores that are connected to and rapidly exchange with the atmosphere. Future studies are needed to understand how subterranean CH4 oxidation scales up to affect local, regional, and global CH4 cycling.

Human rhinovirus infections in hospitalized children: clinical, epidemiological and virological features.

Molecular epidemiology and clinical impact of human rhinovirus (HRV) are not well documented in tropical regions. This study compared the clinical characteristics of HRV to other common viral infections and investigated the molecular epidemiology of HRV in hospitalized children with acute respiratory infections (ARIs) in Vietnam. From April 2010 to May 2011, 1082 nasopharyngeal swabs were screened for respiratory viruses by PCR. VP4/VP2 sequences of HRV were further characterized. HRV was the most commonly detected virus (30%), in which 70% were diagnosed as either pneumonia or bronchiolitis. Children with single HRV infections presented with significantly higher rate of hypoxia than those infected with respiratory syncytial virus or parainfluenza virus (PIV)-3 (12·4% vs. 3·8% and 0%, respectively, P < 0·05), higher rate of chest retraction than PIV-1 (57·3% vs. 34·5%, P = 0·028), higher rate of wheezing than influenza A (63·2% vs. 42·3%, P = 0·038). HRV-C did not differ to HRV-A clinically. The genetic diversity and changes of types over time were observed and may explain the year-round circulation of HRV. One novel HRV-A type was discovered which circulated locally for several years. In conclusion, HRV showed high genetic diversity and was associated with significant morbidity and severe ARIs in hospitalized children.

Sex hormone levels as determinants of bone mineral density and osteoporosis in Vietnamese women and men.

This study sought to investigate the prevalence of osteoporosis and the role of sex hormone levels in the determination of bone mineral density (BMD) and osteoporosis in a Vietnamese population of women and men. The cross-sectional study involved 269 women and 222 men aged 13-83 years, who were randomly selected from urban and rural areas in northern Vietnam. Serum concentrations of estradiol and testosterone were analyzed, and BMD was measured by dual X-ray absorptiometry. We found that the prevalence of osteoporosis in postmenopausal women was 18, 17, and 37 % for the femoral neck, total hip, and lumbar spine, respectively. For men aged 50 years or older, the corresponding values were 8, 7, and 12 %. In men, the most important predictors of BMD for the femoral neck and total hip were age, body mass index, and serum levels of estradiol. For the BMD of the lumbar spine, testosterone also had a significant influence. Determinants of osteoporosis in men for the total hip and lumbar spine were age, weight, and serum concentrations of estradiol and testosterone. In postmenopausal women, age, weight, and residence (urban vs rural) were the most important predictors of BMD and osteoporosis. For all women (including those of reproductive age), serum levels of estradiol were also significant. These data suggest that the prevalence of osteoporosis in the Vietnamese population is high also in men, and that estradiol levels are essential for bone mass in both men and women. The results should have clinical implications and increase awareness of an important health issue within Vietnamese society.

Vitamin D deficiency in northern Vietnam: prevalence, risk factors and associations with bone mineral density.

PURPOSE: Vitamin D deficiency has been linked to osteoporosis and also to the risk of cancer, autoimmune disorders and cardiovascular diseases. This study sought to determine the prevalence of, and risk factors for, vitamin D deficiency and its relationship with bone mineral density (BMD) in a Vietnamese population. METHODS: This cross-sectional study involved 269 women and 222 men aged 13-83 years, who were randomly selected from urban and rural areas in northern Vietnam. Serum concentrations of 25-hydroxy-vitamin D [25(OH)D] and parathyroid hormone (PTH) were measured by electrochemiluminescence immunoassay. Vitamin D deficiency was defined as serum 25(OH)D levels below 20 ng/mL. BMD was measured by dual X-ray absorptiometry. RESULTS: The prevalence of vitamin D deficiency in women was 30%, almost two-fold higher than in men (16%). Significant predictors of vitamin D deficiency in women were urban residency (p<0.01) and age less than 30 years (p<0.01), whereas use of contraceptive pills was protective (p<0.01). In men, winter season was the only significant predictor of vitamin D deficiency (p<0.01). In multiple linear regression analysis, serum levels of 25(OH)D were positively associated with BMD in both women (p<0.001) and men (p<0.001). CONCLUSIONS: These data suggest that the prevalence of vitamin D deficiency is high in the Vietnamese population, and that part of this prevalence could be explained by low exposure to sunlight (urban residency and winter season). The high prevalence of vitamin D deficiency should raise the awareness of potentially important health issues such as osteoporosis within the Vietnamese society.

Effects of radiation and lifestyle factors on risks of urothelial carcinoma in the Life Span Study of atomic bomb survivors.

Among the Life Span Study (LSS) of Atomic-bomb survivors, recent estimates showed that unspecified bladder cancer had high radiation sensitivity with a notably high female-to-male excess relative risk (ERR) per radiation dose ratio and were the only sites for which the ERR did not decrease with attained age. These findings, however, did not consider lifestyle factors, which could potentially confound or modify the risk estimates. This study estimated the radiation risks of the most prevalent subtype of urinary tract cancer, urothelial carcinoma, while accounting for smoking, consumption of fruit, vegetables, alcohol and level of education (a surrogate for socioeconomic status). Eligible study subjects included 105,402 (males = 42,890) LSS members who were cancer-free in 1958 and had estimated radiation doses. Members were censored due to loss of follow-up, incident cancer of another type, death, or the end of calendar year 2001. Surveys (by mail or clinical interview) gathered lifestyle data periodically for 1963-1991. There were 63,827 participants in one or more survey. Five hundred seventy-three incident urothelial carcinoma cases occurred, of which 364 occurred after lifestyle information was available. Analyses were performed using Poisson regression methods. The excess relative risk per weighted gray unit (the gamma component plus 10 times the neutron component, Gy(w)) was 1.00 (95% CI: 0.43-1.78) but the risks were not dependent upon age at exposure or attained age. Lifestyle factors other than smoking were not associated with urothelial carcinoma risk. Neither the magnitude of the radiation ERR estimate (1.00 compared to 0.96), nor the female-to-male (F:M) ERR/Gy(w) ratio (3.2 compared to 3.4) were greatly changed after accounting for all lifestyle factors. A multiplicative model of gender-specific radiation and smoking effects was the most revealing though there was no evidence of significant departures from either the additive or multiplicative joint effect models. Among the LSS cohort members with doses greater than 0.005 Gy(w) (average dose 0.21 Gy(w)), the attributable fraction of urothelial carcinoma due to radiation was 7.1% in males and 19.7% in females. Among current smokers, the attributable fraction of urothelial carcinoma due to smoking was 61% in males and 52% in females. Relative risk estimates of smoking risk were approximately two for smokers compared to nonsmokers. After adjustment for lifestyle factors, gender-specific radiation risks and the F:M ERR/Gy(w), the ratios of excess urothelial carcinoma risk were similar to the estimates without adjusting for lifestyle factors. Smoking was the primary factor responsible for excess urothelial carcinoma in this cohort. These findings led us to conclude that the radiation risk estimates of urothelial carcinoma do not appear to be strongly confounded or modified by smoking, consumption of alcohol, fruits, or vegetables, or level of education.

Reduced intubation rates for infants after introduction of high-flow nasal prong oxygen delivery.

PURPOSE: To describe the change in ventilatory practice in a tertiary paediatric intensive care unit (PICU) in the 5-year period after the introduction of high-flow nasal prong (HFNP) therapy in infants <24 months of age. Additionally, to identify the patient subgroups on HFNP requiring escalation of therapy to either other non-invasive or invasive ventilation, and to identify any adverse events associated with HFNP therapy. METHODS: The study was a retrospective chart review of infants <24 months of age admitted to our PICU for HFNP therapy. Data was also extracted from both the local database and the Australian New Zealand paediatric intensive care (ANZPIC) registry for all infants admitted with bronchiolitis. RESULTS: Between January 2005 and December 2009, a total of 298 infants <24 months of age received HFNP therapy. Overall, 36 infants (12%) required escalation to invasive ventilation. In the subgroup with a primary diagnosis of viral bronchiolitis (n = 167, 56%), only 6 (4%) required escalation to invasive ventilation. The rate of intubation in infants with viral bronchiolitis reduced from 37% to 7% over the observation period corresponding with an increase in the use of HFNP therapy. No adverse events were identified with the use of HFNP therapy. CONCLUSION: HFNP therapy has dramatically changed ventilatory practice in infants <24 months of age in our institution, and appears to reduce the need for intubation in infants with viral bronchiolitis.

Regional ventilation distribution in the first 6 months of life.

Electrical impedance tomography (EIT) has been used to study regional ventilation distribution in neonatal and paediatric lung disease; however, little information has been obtained in healthy newborns and infants. Data on regional ventilation distribution and regional filling characteristics were obtained using EIT in the neonatal period, at 3 and 6 months of age, in spontaneously breathing infants during non-rapid eye movement sleep. Regional ventilation distribution was described using regional end-expiratory and end-inspiratory impedance amplitudes, and geometric centre of ventilation. Regional filling characteristics were described with the phase lag or lead of the regional impedance change in comparison to global impedance change. 32 infants were measured in the supine position. Regional impedance amplitudes increased with age but regional ventilation distribution remained unchanged in all infants at any age, with the dependent (posterior) lung always better ventilated. Regional filling characteristics showed that the dependent lung filled during inspiration before the nondependent lung during all follow-up measurements. Regional ventilation distribution and regional filling characteristics remained unchanged over the first 6 months of life, and the results obtained on regional ventilation distribution are very similar to those in adult subjects.

Housing environment influences the need for pain relief during post-operative recovery in mice.

The impact of invasive experimental procedures on perceived stress and pain may be dependent on both physical and social environmental conditions. The aim of this study was to evaluate the effects of a physically and a socially enriched environment on the need for pain relief following painful experimental procedures. A non-invasive method to administer analgesics post-operatively is by means of self-administration which is a feasible objective method to measure perceived pain during the post-operative recovery period. In the present study eight groups of mice housed in different conditions underwent the surgical procedure of caecal manipulation or only exposure to anaesthesia. After surgery the mice were given the choice to self-administer an analgesic available in one of their water bottles during two post-operative weeks. It was shown that socially enriched mice drank i.e. self-administered, less from the analgesic containing water than the non-enriched and socially deprived groups. Mice that underwent operation self-administered more analgesic than mice that received only anaesthesia without operation. The findings indicate that the recovery environment can contribute positively to attenuate the need for pain relief in animals submitted to invasive procedures.

Oral symptoms predict mortality: a prospective study in Japan.

Several studies have reported positive associations between oral infections and systemic diseases. The purpose of the present study was to evaluate the effects of oral symptoms on mortality from cardiovascular disease (CVD) and pneumonia. Using data from a cohort study in Japan, we analyzed 4,139 individuals aged 40-79 years. The baseline questionnaire included the following items related to oral symptoms: 'sensitive teeth', 'difficulty in chewing tough food substances', 'bleeding gums', and 'mouth feels sticky'. We used the Cox proportional hazard model to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs) for mortality, after adjustments for lifestyle, socio-economic factors, and history of diseases. Persons complaining that their 'mouth feels sticky' had a two-fold higher risk of pneumonia (HR = 2.1; 95%CI, 1.2-3.6), while those complaining of 'sensitive teeth' had a lower risk of CVD (HR = 0.4; 95%CI, 0.2-0.9). Some oral symptoms may be predictors of mortality from pneumonia and CVD.

Neither environmental enrichment nor voluntary wheel running enhances recovery from incomplete spinal cord injury in rats.

Environmental enrichment and exercise may be neuroprotective or promote recovery after different forms of CNS injury. Here, we tested the possible effects of moderate environmental enrichment and voluntary exercise on the outcome of incomplete spinal cord injury in rats. We provided rats in standard cages with basic environmental enrichment (carton house, nesting material, tube, gnawing sticks). We also analyzed the effect of increased activity by housing spinal-cord-injured rats in cages with or without access to running wheels. In a third experiment, we looked at the possible effect of pre-injury training. In all experiments, a battery of behavior tests were used. Enriched environment provided before, after or both before and after injury did not alter the outcome on any of these tests. Similarly, despite excessive running after injury, no differences in terms of recovery and behavior were found in the running experiment. Similarly, running prior to injury did not significantly decrease the degree of functional deficit caused by the injury. Since there were no effects of further enrichment, above the possible effects of being socially housed, and since exercise did not improve the outcome, we conclude that these forms of increased activity do not render the animals significantly less sensitive to spinal cord injury and do not cause robust improvement when initiated after injury. While these results pose a limit to how helpful environmental and physical training programs may be in rodent impact injury models, they do not contradict the fact that voluntary and guided training can be effective tools in human spinal cord rehabilitation.

Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain.

A number of studies have demonstrated that both morphological and biochemical indices in the brain undergo alterations in response to environmental influences. In previous work we have shown that rats raised in an enriched environmental condition (EC) perform better on a spatial memory task than rats raised in isolated conditions (IC). We have also found that EC rats have a higher density of immunoreactivity than IC rats for both low and high affinity nerve growth factor (NGF) receptors in the basal forebrain. In order to determine if these alterations were coupled with altered levels of neurotrophins in other brain regions as well, we measured neurotrophin levels in rats that were raised in EC or IC conditions. Rats were placed in the different environments at 2 months of age and 12 months later brain regions were dissected and analyzed for NGF, brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) levels using Promega ELISA kits. We found that NGF and BDNF levels were increased in the cerebral cortex, hippocampal formation, basal forebrain, and hindbrain in EC animals compared to age-matched IC animals. NT-3 was found to be increased in the basal forebrain and cerebral cortex of EC animals as well. These findings demonstrate significant alterations in NGF, BDNF, and NT-3 protein levels in several brain regions as a result of an enriched versus an isolated environment and thus provide a possible biochemical basis for behavioral and morphological alterations that have been found to occur with a shifting environmental stimulus.

Inhalation of low concentrations of toluene induces persistent effects on a learning retention task, beam-walk performance, and cerebrocortical size in the rat.

The organic solvent toluene is widely used in industry. The threshold limit value for extended occupational exposure to toluene is presently set to 200 ppm in the United States. We have investigated the effect of an inhalation exposure of 80 ppm for 4 weeks (6 h/day, 5 days/week), followed by a postexposure period of at least 4 weeks, on behavior and brain features in the rat. Toluene exposure appeared to affect spatial memory, since toluene-exposed rats showed a longer time in the correct quadrant in a Morris swim maze. This effect may indicate that the exposed rats used their praxis strategy longer before they started to look for the platform elsewhere. Toluene-exposed rats showed trends for increases in both locomotion and rearing behaviors and a significantly reduced beam-walk performance. The area of the cerebral cortex, especially the parietal cortex, was decreased by 6-10% in toluene-exposed rats, as shown by magnetic resonance imaging of living rats and autoradiograms of frozen brain sections. The K(D) and B(max) values of the dopamine D(3) agonist [(3)H]PD 128907 were not affected by toluene, as measured in caudate-putamen and subcortical limbic area using biochemical receptor binding assays and in caudate-putamen and islands of Calleja using quantitative receptor autoradiography. Hence, previously demonstrated persistent effects by toluene on the binding characteristics of radioligands binding to both D(2) and D(3) receptors seem to indicate a persistent effect of toluene selectively on dopamine D(2) receptors. Taken together, the present results indicate that exposure to low concentrations of toluene leads to persistent effects on cognitive, neurological, and brain-structural properties in the rat.

Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year.

This study examined the effects of long-term differential rearing on levels of brain nerve growth factor, its receptors, and their relationships to cognitive function. Adult rats (two months old) were placed into either enriched or standard housing conditions where they remained for 12 months. Animals from the enriched condition group had significantly higher levels of nerve growth factor in hippocampus, visual and entorhinal cortices compared with animals housed in isolated condition. Immunohistochemical analysis of brain tissue from the medial septal area revealed higher staining intensity and fibre density with both the low-affinity and the high-affinity nerve growth factor receptors. Enriched rats performed better than isolated rats in acquisition of spatial learning and had lower locomotion scores in the open field. These results provide further evidence that experimental stimulation results in increased production of trophic factors and structural reorganization in specific brain regions known to be involved in cognitive function.

Hypertension, cardiovascular disease, and health care dilemmas in the Philadelphia Vietnamese community.

BACKGROUND AND OBJECTIVES: Prior studies have shown low awareness of hypertension and cardiovascular disease and low health care utilization in the US Vietnamese community. This study assessed awareness and understanding of these chronic conditions, health care barriers, and cultural beliefs in the Philadelphia Vietnamese community. METHODS: This qualitative study analyzed data collected from focus groups, family interviews, and individual interviews of community members and health care providers during 1996 and 1997. RESULTS: Awareness of hypertension was higher than expected but low for heart disease. Understanding of the cause and primary prevention of these illnesses was low, as was health care utilization. Major barriers to receiving health care included problems with language, medical insurance, and transportation. Desired resources were interpreter services, increased medical insurance, translated educational materials, health education classes, and community health fairs. The community widely held the belief that Western medicine is "stronger, faster, and curative" while folk medicine is "weaker, slower, but preventive." CONCLUSIONS: The Vietnamese community appreciates the importance of hypertension and cardiovascular disease and believes that traditional, Western medicine is necessary for care but perceives significant barriers. Providing needed services and specific intervention programs could improve access and understanding, as well as enable health promotion, disease prevention, and appropriate care.

Effects of environmental enrichment on cognitive function and hippocampal NGF in the non-handled rats.

In this study we examine whether exposure to differential housing after weaning would counteract the effects of postnatal handling (H) or nonhandling (NH) treatment by affecting learning and memory processes in young rats. In addition, we seek to determine if experience in enriched environment would alter hippocampal nerve growth factor (NGF) levels which is one of the factors known to be involved in the regulation of the survival and differentiation of developing basal forebrain neurones. Rats were either exposed to handling treatment, or left undisturbed starting day 1 after birth through day 21. After weaning on day 22, we exposed half of the H rats and half of the NH rats to environmental enrichment for 60 days. The other respective half of the rats was housed in isolated environmental condition (IC). Behavioural measures were taken in open field test, and spatial water maze test. Exposure to enriched environment following postnatal handling and nonhandling increased hippocampal NGF levels, and improved cognitive function in the both groups, with NH rats being more responsive to the effects of enrichment. Our results suggest that environmental enrichment has the potential to prevent or reduce the cognitive and neurochemical deficits in the adult animals associated with nonhandling.

Neonatal handling in rats induces long-term effects on dynorphin peptides.

The effects of neonatal handling on the opioid dynorphin peptides in the brain and pituitary gland of Sprague-Dawley rats were investigated. Ten weeks after the neonatal handling, handled rats had higher tissue levels of dynorphin A and B in the hypothalamus, pituitary gland and striatum and slightly higher dynorphin B levels in the hippocampus, medulla oblongata and midbrain as compared with non-handled controls. The results indicate a persistent upregulation of the dynorphin system in certain brain areas after neonatal handling, which could contribute to the behavioural changes in these rats observed later in life. Observation in the open field and the elevated plus-maze tests confirmed behavioural effects of neonatal handling, i.e. showing that handled rats exhibit attenuated fearfulness in novel environments as compared with non-handled rats.

Distinct GABAB actions via synaptic and extrasynaptic receptors in rat hippocampus in vitro.

Intracellular recordings were obtained from pyramidal cells to examine gamma-aminobutyric acid-B (GABAB)-mediated synaptic mechanisms in the CA1 region of rat hippocampal slices. To investigate if heterogeneous ionic mechanisms linked to GABAB receptors originate from distinct sets of inhibitory fibers, GABAB-mediated monosynaptic late inhibitory postsynaptic potentials (IPSPs) were elicited in the presence of antagonists of ionotropic glutamate and GABAA receptors and of an inhibitor of GABA uptake and were compared after direct stimulation of inhibitory fibers in three different CA1 layers: stratum oriens, radiatum, and lacunosum-moleculare. No significant differences were found in mean amplitude, rise time, or time to decay to half-amplitude of IPSPs evoked from the three layers. Mean equilibrium potential (Erev) of late IPSPs was similar for all groups and close to the equilibrium potential of K+. Bath application of the GABAB antagonist CGP55845A blocked all monosynaptic late IPSPs. During recordings with micropipettes containing guanosine-5'-O-(3-thiotriphosphate) (GTPgammaS), the mean amplitude of all GABAB IPSPs gradually was reduced. Bath application of Ba2+ completely eliminated monosynaptic late IPSPs evoked from any of the stimulation sites. Late IPSPs were blocked completely during Ba2+ applications that reduced the GABAB-mediated hyperpolarizations elicited by local application of exogenous GABA only by approximately 50%. These results indicate that heterogenous K+ conductances activated by GABAB receptors do not originate from separate sets of inhibitory fibers in these layers. To examine if synchronous release of GABA from a larger number of inhibitory fibers could activate heterogeneous GABAB mechanisms, giant GABAB IPSPs were induced by 4-aminopyridine (4-AP) in the presence of antagonists of ionotropic glutamate and GABAA receptors. The amplitude and time course 4-AP-induced late IPSPs were approximately double that of evoked monosynaptic late IPSPs, but their voltage sensitivity, Erev, and antagonism by the GABAB antagonist CGP55845A and intracellular GTPgammaS were similar. Ba2+ completely abolished 4-AP-induced late IPSPs, whereas responses elicited by exogenous GABA were only reduced by approximately 50% in the same cells. These results indicate that synchronous activation of large numbers of inhibitory fibers, as induced by 4-AP, may not activate heterogenous GABAB-mediated conductances. Similarly, Ba2+ almost completely blocked late inhibitory postsynaptic currents evoked by stimulus trains. Overall, our results show that exogenous GABA can activate heterogenous K+ conductances via GABAB receptors, but that GABA released synaptically, either by electrical stimulation or 4-AP application, can only activate K+ conductances homogeneously sensitive to Ba2+. Thus GABAB receptors located at synaptic and extrasynaptic sites on hippocampal pyramidal cells may be linked to distinct K+ conductances.

Effects of neonatal stimulation on later cognitive function and hippocampal nerve growth factor.

This study examined the behavioural and physiological effects of chronic mild stress on neonatally handled and non-handled rats. Neonatally handled and non-handled rats were exposed to chronic mild stress from weaning time to 6 months of age. They were behaviourally tested at 6 months of age, and sacrificed for analysis of nerve growth factor (NGF) in the hippocampus and hypothalamus. In contrast to the reported deleterious effect of acute strong stress, mild stress appeared to stimulate production of NGF in the hippocampus and improve spatial learning in both handled and nonhandled rats. Because neonatal handling produces neuroanatomical changes in the rat hippocampus and enhances cognitive function throughout the rats life span, these results implicate hippocampal NGF in the neuroprotective effects of handling.

Multiple postsynaptic actions of GABA via GABAB receptors on CA1 pyramidal cells of rat hippocampal slices.

1. The effects of gamma-aminobutyric acid (GABA) on non-GABAA receptors were investigated with intracellular recordings in CA1 pyramidal cells of rat hippocampal slices in the presence of antagonists of GABAA receptors (50 microM bicuculline and 50 microM picrotoxin), N-methyl-D-aspartate (NMDA) and non-NMDA receptors (100 microM 2-amino-5-phosphonopentanoic acid and 40 microM 6-cyano-7-nitroquinoxaline-2,3-dione, respectively), and of a blocker of GABA uptake (1 mM nipecotic acid). The effects of GABA were compared with those of the selective GABAB agonist (-)baclofen [CGP-11973A; (-)BAC]. 2. In the presence of these antagonists, micropressure application of GABA into stratum radiatum evoked hyperpolarizations with relatively fast peak latency (2 s) and decay (12 s). (-)BAC, in the absence of antagonists, hyperpolarized cells, but with a slower time course (peak latency 8 s, decay 78 s). The mean equilibrium potential (Erev) of responses to GABA (-94 mV; n = 11) was similar to that of (-)BAC (-87 mV; n = 8), suggesting that both responses were mediated by K+ conductances. 3. Bath applications of 1 mM Ba2+ partly antagonized GABA responses in a reversible manner. The mean amplitude of the Ba(2+)-resistant GABA response was 46% of control (n = 16, P < 0.05). In contrast, (-) BAC responses were completely abolished by Ba2+ (n = 15), and the effect was reversible. Thus both GABA and (-)BAC activate a common Ba(2+)-sensitive conductance, but GABA may also activate another Ba(2+)-resistant conductance. 4. The Ba(2+)-resistant GABA response had a similar time course to control GABA responses, but its Erev was more depolarized (-79 mV, n = 8, P < 0.05). 5. During recordings with electrodes containing KCl to reverse the Cl- gradient, although GABA responses were smaller in amplitude, their time course and Erev (-91 mV; n = 10) were similar to those recorded with potassium acetate electrodes. Thus Cl- conductances may not be involved in these non-GABAA responses elicited by GABA. 6. During recordings with electrodes containing CsCl to block outward K+ currents, hyperpolarizing GABA responses were not observed (n = 8). In these conditions, GABA elicited depolarizing responses with a faster time course (peak latency 1 s, decay 5 s) than the hyperpolarizing responses recorded with electrodes containing KCl. Thus GABA may produce hyperpolarizations by activating K+ conductances, but it may also produce an additional depolarzing response via other Cs(+)-insensitive conductances. 7. During recordings with electrodes containing LiCl to interfere with G protein activation, hyperpolarizing GABA responses were blocked and depolarizing responses were unmasked (n = 5). These depolarizing responses were generally similar to those recorded with electrodes containing CsCl. GABA responses were also reduced during recordings with electrodes containing the irreversible G protein activator guanosine-5'-O-(3-thiotriphosphate). Thus hyperpolarizing GABA responses may involve G protein activation, but the depolarizing responses may not. 8. Bath application of the selective GABAB antagonist CGP-35348 (1 mM) did not significantly reduce hyperpolarizing GABA responses (18% reduction in amplitude, n = 6, P > 0.05), but completely suppressed (-)BAC responses (n = 2). The more potent and selective GABAB antagonist CGP-55845A (5 microM) abolished all GABA responses (n = 7). Thus all non-GABAA responses elicited by GABA may be mediated by GABAB receptors. 9. In conclusion, GABA, in the presence of GABAA antagonists, may produce in CA1 pyramidal cells two distinct postsynaptic responses mediated via GABAB receptors and G protein activation: l) GABA [and (-)BAC] may activate a Ba(2+)-sensitive K+ conductance, and 2) GABA [but not (-)BAC] may also generate a Ba(2+)-insensitive K+ conductance. GABA may also generate other ionic changes, via GABAB receptors, resulting in depolarization of pyramidal cells.