Systems genetics uncover new loci containing functional gene candidates in Mycobacterium tuberculosis-infected Diversity Outbred mice.

Mycobacterium tuberculosis, the bacillus that causes tuberculosis (TB), infects 2 billion people across the globe, and results in 8-9 million new TB cases and 1-1.5 million deaths each year. Most patients have no known genetic basis that predisposes them to disease. We investigated the complex genetic basis of pulmonary TB by modelling human genetic diversity with the Diversity Outbred mouse population. When infected with M. tuberculosis, one-third develop early onset, rapidly progressive, necrotizing granulomas and succumb within 60 days. The remaining develop non-necrotizing granulomas and survive longer than 60 days. Genetic mapping using clinical indicators of disease, granuloma histopathological features, and immune response traits identified five new loci on mouse chromosomes 1, 2, 4, 16 and three previously identified loci on chromosomes 3 and 17. Quantitative trait loci (QTLs) on chromosomes 1, 16, and 17, associated with multiple correlated traits and had similar patterns of allele effects, suggesting these QTLs contain important genetic regulators of responses to M. tuberculosis. To narrow the list of candidate genes in QTLs, we used a machine learning strategy that integrated gene expression signatures from lungs of M. tuberculosis-infected Diversity Outbred mice with gene interaction networks, generating functional scores. The scores were then used to rank candidates for each mapped trait in each locus, resulting in 11 candidates: Ncf2, Fam20b, S100a8, S100a9, Itgb5, Fstl1, Zbtb20, Ddr1, Ier3, Vegfa, and Zfp318. Importantly, all 11 candidates have roles in infection, inflammation, cell migration, extracellular matrix remodeling, or intracellular signaling. Further, all candidates contain single nucleotide polymorphisms (SNPs), and some but not all SNPs were predicted to have deleterious consequences on protein functions. Multiple methods were used for validation including (i) a statistical method that showed Diversity Outbred mice carrying PWH/PhJ alleles on chromosome 17 QTL have shorter survival; (ii) quantification of S100A8 protein levels, confirming predicted allele effects; and (iii) infection of C57BL/6 mice deficient for the S100a8 gene. Overall, this work demonstrates that systems genetics using Diversity Outbred mice can identify new (and known) QTLs and new functionally relevant gene candidates that may be major regulators of granuloma necrosis and acute inflammation in pulmonary TB.

Cognitive impairment in temporal lobe epilepsy: role of online and offline processing of single cell information.

Cognitive impairment is a common comorbidity in temporal lobe epilepsy (TLE) and is often considered more detrimental to quality of life than seizures. While it has been previously shown that the encoding of memory during behavior is impaired in the pilocarpine model of TLE in rats, how this information is consolidated during the subsequent sleep period remains unknown. In this study, we first report marked deficits in spatial memory performance and severe cell loss in the CA1 layer of the hippocampus lower spatial coherence of firing in TLE rats. We then present the first evidence that the reactivation of behavior-driven patterns of activity of CA1 place cells in the hippocampus is intact in TLE rats. Using a template-matching method, we discovered that real-time (3-5 s) reactivation structure was intact in TLE rats. Furthermore, we estimated the entropy rate of short time scale (∼250 ms) bursting activity using block entropies and found that significant, extended temporal correlations exist in both TLE and control rats. Fitting a first-order Markov Chain model to these bursting time series, we found that long sequences derived from behavior were significantly enriched in the Markov model over corresponding models fit on randomized data confirming the presence of replay in shorter time scales. We propose that the persistent consolidation of poor spatial information in both real time and during bursting activity may contribute to memory impairments in TLE rats.

Personality correlates of alienation in a university sample.

In a study of alienation among urban university students, 85 men and 136 women completed the Gould Manifest Alienation Measure and the 44-item Big Five Inventory. Multivariate analysis of variance disclosed that the 77 college students high on Alienation, irrespective of sex, scored higher on the Neuroticism scale and lower on the Conscientiousness and Openness scales of the Big Five Inventory. None of the interactions between sex and scores on the Big Five Inventory was significant. Results suggest that college students scoring high on alienation can survive in a supportive university environment, although they appear to experience increased anxiety and tension and have a relatively constricted awareness of their environments. Students scoring high on alienation may also be more tolerant of deviant behavior given their perceived irrelevance of social norms.

The effect of waitresses' touch on alcohol consumption in dyads.

A total of 96 men and 48 women participated in a study on the effect of touch in the natural setting of public taverns in the United States. Participants in the same-gender (men-men) or mixed-gender dyads were either touched or not touched by waitress confederates. Regardless of dyad type, participants who were touched consumed more alcohol than participants who were not touched. Men in the mixed-gender dyads consumed more alcohol when the women was touched. Same-gender (men-men) dyads aggregately consumed more alcohol than mixed-gender dyads. The results are interpreted in terms of the environmental cues and the dynamics of the group.

Carbon monoxide poisoning in racing car drivers.

BACKGROUND: To determine if carbon monoxide (CO) exposure during competition racing is significant enough to cause post-racing symptoms among professional racing drivers. METHODS: Closed vehicle professional racing drivers were questioned after competition regarding symptoms consistent with heat exposure, dehydration, and carbon monoxide poisoning. All drivers, regardless of symptoms, underwent expired CO monitoring using a breath analyzer both before and after competition events. CO measurements were performed prior to any post-race interviews. Driver smoking history, laps at low speed (under caution), cockpit fire or damage to the exhaust system were also noted. An association between driver symptoms, track and vehicle condition, and increases in expired CO levels during racing was sought. RESULTS: Twenty-eight drivers completed the study. Each driver was tested both before and after each competition event, and some drivers were tested at different tracks. All of the tested drivers experienced an increase in carboxyhemoglobin concentrations during the competition event. Drivers who smoked had higher baseline levels than non-smokers, but were no more likely to have symptoms. The driver with the highest post-race CO level was exposed to a fire which completely destroyed the vehicle, but he complained of no symptoms after the race. Most drivers complained of post-race symptoms or appeared symptomatic, but no correlation could be shown between post-race CO levels and symptoms. CONCLUSIONS: There is a mild increase in driver CO levels during professional road racing competition, however, no correlation with CO level and driver symptomatology can be demonstrated. Carbon monoxide does not appear to be a significant cause of post-race driver symptoms such as fatigue, nausea, headache, and weakness.

Alienation and irrational beliefs in a nonclinical university population.

A total of 126 college students, 53 men and 73 women, completed the Manifest Alienation Scale and the Irrational Beliefs Scale to assess alienation and irrationality. A linear relationship indicated students with elevated Alienation scores showed substantially higher irrationality than did students scoring lower. Analysis suggests that a positive linear effect for measured irrationality and reported Alienation characterizes students in a nonclinical population. The relationship between normal and pathological Alienation and irrational belief are addressed, and potential interventions in clinical situations are considered.

Need for cognition and irrational beliefs.

A total of 149 college students, 48 men and 101 women, completed the Irrational Beliefs and the Need for Cognition scales to assess irrationality and the tendency to engage in effortful cognitive activity. Although substantial overlap between the constructs was found (r = -.29, p < .001), the relationship was not linear. Need for Cognition appears to be a process variable, while irrational belief appears to be a content variable. Results suggest that the Need for Cognition must achieve a minimum threshold before spontaneous critical self-examination can occur.

Factor structure of Ellis' irrational beliefs in a nonclinical college population.

In a study of irrational beliefs among nonclinical populations, 54 male and 75 female college students completed the Irrational Beliefs Survey. Analysis suggests that the survey measures a coherent construct and that a simple summary score is adequate for most uses. Factor analysis disclosed a unidimensional monotonic dimension of irrationality in beliefs among nonclinical respondents. The findings contrast with the appearance of ambiguous clusters of irrational beliefs reported with an inpatient population. The existence of a single dimension of irrational belief is substantially supported.

Pleural effusion associated with chronic dantrolene administration.

OBJECTIVE: To report a case of pleural effusion associated with chronic dantrolene administration. DESIGN: Case report. SETTING: Private, university-affiliated, teaching hospital. RESULTS: Twelve years after the initiation of low-dose dantrolene therapy for chronic spasticity, a 35-year-old man developed a pleural effusion with pleural and peripheral eosinophilia. This reaction gradually resolved over several months after discontinuation of the dantrolene therapy. CONCLUSIONS: In patients treated with chronic dantrolene therapy, the presence of pleural effusions should raise the suspicion of dantrolene-induced disease. Withdrawal of dantrolene therapy has generally been associated with an alleviation of signs and symptoms within several months.

Therapeutic frontiers in Alzheimer's disease.

Alzheimer's disease (AD), the most common type of primary degenerative dementia, is the leading cause of cognitive impairment in the geriatric population. It is a devastating illness, both to the patients and the families involved. Although much research continues to be conducted, the etiology and effective treatment for the disease remain to be found. One of the primary hypotheses of the disease is that the cognitive decline of AD involves the loss of related cholinergic neurons. Although the cholinergic theory is still valid, efforts aimed at increasing levels of acetylcholine have yielded disappointing results. Currently, in the United States, several drugs are in various stages of development for the treatment of AD. The mechanisms of these agents include cerebral protectants, enhancers of neuronal signal amplification, tonic stimulation, and nerve growth factors. Other avenues being investigated include the development of novel drug delivery systems to enhance CNS concentrations of therapeutic agents.

A device for studying the influence of declining water table on poplar growth and survival.

Riparian poplar forests are declining downstream from many dams in the western prairie regions of North America. Drought-induced seedling and sapling mortality caused by abrupt drops in water table level following river flow regulation may be contributing to this forest decline. Here we describe a device, the rhizopod, for studying the influence of a changing water table on poplar seedling survival and growth. Seeds of a natural poplar hybrid (Populus deltoides x P. balsamifera) were planted in five rhizopods and treated to water table declines of 0, 1, 2, 4, or 8 cm day(-1). Each rhizopod consisted of 15 growth tubes connected to a central water reservoir through which the water level was regulated. Seedling survival was over 90% in rhizopods in which water table declined by 0, 1 or 2 cm day(-1), but was reduced to about 40% and less than 25% in rhizopods in which the water table level declined by 4 and 8 cm day(-1), respectively. Maximum shoot height, leaf number, and leaf area were observed in the rhizopod with a constant water table and decreased progressively with increasing rates of water table decline. Maximum root mass and length were observed in plants subjected to declines in water table level of 0 and 1 cm day(-1), respectively.

Voluntary control of male sexual arousal.

Forty-eight adult male volunteers attempted to suppress sexual arousal while viewing a sexually explicit videotape and generate an arousal response while viewing a neutral videotape. Attendance to the stimuli was assured by requiring subjects to provide an ongoing verbal description of the videotape they were viewing. While significant effects in controlling arousal were obtained, the degree of subject success varied as a function of the criteria used for evaluating outcome. The most conservative analysis, a simultaneous discriminant analysis procedure comparing subjects penile plethysmographic responses across the entire 3 min of each condition, revealed that in no case was a subject able to produce a pattern of sexual response that was misclassified as the condition he was attempting to emulate. Results support the value of requiring attendance to experimental stimuli and of analyzing trends/patterns of arousal across an entire experimental period in identifying attempts to "fake" sexual preferences. Theoretical and clinical implications of these findings are discussed.

The role of anxiety in premature ejaculation: a psychophysiological model.

Despite the prevalence of premature ejaculation and the success in its treatment, researchers have yet to offer a compelling, empirically based theory regarding its nature or etiology. This study explored a model that argues that anxiety may not be necessary for the existence of this dysfunction. Fifteen premature ejaculators (PEs) and 17 nonpremature ejaculators (NPEs) engaged in self-stimulation to orgasm both in the laboratory and at home. The following specific hypotheses were tested: Compared to NPEs, PEs would demonstrate (i) shorter orgasmic latencies, both in the lab and at home, and (ii) equally accurate estimates of these latencies. Results offered strong support for both hypotheses. These findings, and those derived from a questionnaire completed by subjects, were seen as consistent with a psychophysiologic model of premature ejaculation. According to this model, the role of anxiety is seen as variable, interacting with the somatic vulnerability of the individual to determine orgasmic latency.

Stimulatory effect of enprostil, an anti-ulcer prostaglandin, on gastric mucus secretion.

Enprostil, a synthetic analogue of prostaglandin E2, is known to be a potent inhibitor of gastric acid secretion, and has marked anti-ulcer activity in rodents. Enprostil was administered in doses ranging from 15 to 250 micrograms/kg to rats prepared using the Shay procedure. Three hours later, the rats' stomachs were removed and processed either for the chemical determination of mucus, or for scanning electron microscopy. For the chemical determination, the secreted gastric juice was removed and the adherent gastric mucus was eluted with 2 M sodium chloride. The anthrone method was used to determine the mucus present. Enprostil was found to significantly increase gastric mucus at a dose of 60 micrograms/kg when measured by the anthrone test. Enprostil administered by the oral route was most effective in stimulating mucus secretion, suggesting a local or topical action of enprostil on mucus-secreting cells. Scanning electron microscopy of rat fundic mucosa after enprostil administration (50 to 100 micrograms/kg) revealed the presence of thin veil-like layers covering the epithelial surface, which was interpreted as an increase in mucus secretion. Higher magnifications (X 2,000) clearly showed the layers of mucus covering the surface epithelial cells. Enprostil's apparent increase of gastric mucus secretion may contribute to its anti-ulcer activity and may promote gastric healing.

Drug effects on the neovascularization response to silver nitrate cauterization of the rat cornea.

Neovascular growth into the cornea induced by silver nitrate cauterization is the basis of this experimental model developed to test potential anti-inflammatory drugs for ocular use. Cauterization of the rat cornea with a silver nitrate applicator stick provides the stimulus for neovascularization, which is scored by a "blinded" investigator. Burn stimulus intensity is also scored to substantiate a consistent stimulus among the groups. Compounds showing activity in this model include topical dexamethasone, prednisolone, ticabesone propionate, ketorolac, and phenidone. This model is presented as a practical method for testing anti-inflammatory drugs in the eye.

The effect of orally administered prostaglandins on gastric mucus secretion in the rat.

The secretion of gastric mucus may play a role in the protective effect of prostaglandins against gastric ulcers. To investigate the effect of prostaglandins E1, E2, F1alpha, F2alpha, A1, A2 and 15 (S) 15 methyl prostaglandin E2-methyl ester on gastric mucus secretion, these prostaglandins were given orally to rats at doses of 0.1, 1.0 and 4.0 mg/kg. The anthrone method was used to analyze the amount of mucus washed from the stomach with 2 M Nacl. Gastric secretory volume effects were also observed. All of the compounds tested increased both gastric mucus and secretory volume. The most active compound was 15(S)15 methyl PGE2 Me ester. The mucus stimulating effect of these prostaglandins, when administered locally, may be relevant to the understanding of the anti-ulcer effect of prostaglandins.