Stimulation of gastrointestinal antibody to Shiga toxin by orogastric immunization in mice

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141579/1/imcb69.pd

Sex Differences in the Activation of the Spinoparabrachial Circuit by Visceral Pain

Women are more sensitive to most noxious visceral stimuli, both in terms of intensity and frequency. The spinoparabrachial (spino-PBn) pathway is an essential neural circuit for the central relay of viscerosensitive information, but studies characterizing the anatomical and physiological characteristics of this pathway have only been conducted in males. Sex differences in the anatomical and/or physiological organization of the spino-PBn may contribute to the sexually dimorphic incidence rate for visceral pain syndromes. Retrograde labeling and colorectal distention (CRD) induced Fos expression was used to delineate the spino-PBn circuit in male and cycling female Sprague-Dawley rats. The ability of morphine to suppress CRD was also examined. Neurons retrogradely labeled from the PBn were localized primarily within the superficial dorsal horn and sacral parasympathetic nucleus of the L5-S1 spinal cord. While no sex differences were noted in either the distribution of spino-PBn neurons or in CRD-induced Fos expression, significantly greater Fos expression was noted specifically in spino-PBn neurons in males compared to females. Morphine selectively attenuated Fos expression in spino-PBn neurons in males, but not females. Subsequent anatomical studies showed significantly reduced mu opioid receptor protein levels and radioligand binding within the PBn of males in comparison to females. Together, these data indicate that there are profound sex differences in how visceral pain and opiates engage the spino-PBn pathway, which may account for the observed clinical differences in visceral pain sensitivity and morphine antinociception

Fas/CD95 Deficiency in ApcMin/+ Mice Increases Intestinal Tumor Burden

Fas, a member of the tumor necrosis family, is responsible for initiating the apoptotic pathway when bound to its ligand, Fas-L. Defects in the Fas-mediated apoptotic pathway have been reported in colorectal cancer.In the present study, a variant of the Apc(Min/+) mouse, a model for the human condition, Familial Adenomatous Polyposis (FAP), was generated with an additional deficiency of Fas (Apc(Min/+)/Fas(lpr)) by cross-breeding Apc(Min/+) mice with Fas deficient (Fas(lpr)) mice. One of the main limitations of the Apc(Min/+) mouse model is that it only develops benign polyps. However, Apc(Min/+)/Fas(lpr) mice presented with a dramatic increase in tumor burden relative to Apc(Min/+) mice and invasive lesions at advanced ages. Proliferation and apoptosis markers revealed an increase in cellular proliferation, but negligible changes in apoptosis, while p53 increased at early ages. Fas-L was lower in Apc(Min/+)/Fas(lpr) mice relative to Apc(Min/+) cohorts, which resulted in enhanced inflammation.This study demonstrated that imposition of a Fas deletion in an Apc(Min/+) background results in a more aggressive phenotype of the Apc(Min/+) mouse model, with more rapid development of invasive intestinal tumors and a decrease in Fas-L levels

Comparison of the Host Ranges and Antigenicity of Cryptosporidium parvum and Cryptosporidium wrairi from Guinea Pigs

Oocysts of a Cryptosporidium isolate from guinea pigs were not infectious for adult mice, but were infectious for two of three newborn calves and for suckling mice. However, oocysts isolated from calves or mice infected with guinea pig Cryptosporidium were not infectious for guinea pigs. Four isolates of C. parvum from calves were incapable of infecting weanling guinea pigs. Microscopic examination of tissue from the colon and cecum of suckling guinea pigs inoculated with C. parvum revealed sparse infection of some pups. These host range studies and previously described differences in 125 I-labeled oocyst surface protein profiles between Cryptosporidium sp. from guinea pigs and C. parvum suggest they are distinct species. We propose the name Cryptosporidium wrairi be retained. Studies with monoclonal antibodies indicate that C. wrairi and C. parvum are antigenically related.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75184/1/j.1550-7408.1992.tb01471.x.pd

Comparison of the talk test and percent heart rate reserve for exercise prescription

Exercise intensity is traditionally prescribed using %HRmax, %HRR, %VO2max, or %VO2R. Recently, the Talk Test (TT) has been proposed as an alternative method to guide exercise intensity. However, it is unknown if prescribing exercise intensity solely using the TT can provoke training responses that are comparable to traditional guidelines. This study compared the responses to training using either the TT or %HRR. Forty-four subjects (17 males and 27 females: age=20.4±3.02 years; body height=170.5±9.79 cm; body weight=71.9±13.63 kg) completed an incremental maximal cycle ergometer test, were stratified by VO2max and gender, and randomly assigned to training groups guided by either %HRR (n=20) or the TT (n=24). Both groups completed 40-minute training sessions three days per week for 10 weeks. In the HRR group, exercise intensity was targeted (per ACSM guidelines) at 40-59% HRR for weeks 1-4, 50-59% HRR for weeks 5-8, and 60-79% HRR for weeks 9-10. In the TT group, exercise intensity was targeted at the highest power output (PO) that still allowed for comfortable speech. Changes in VO2max, peak power output (PPO), VO2 at ventilatory threshold (VT), and PO at VT were compared between the groups using two-way ANOVA with repeated measures. There were significant (p0.05) interaction effect. Guiding exercise prescription using the TT is a simple and effective method for prescribing exercise intensity and elicits improvements in exercise performance that are comparable to the traditional %HRR guidelines

Cross-species global and subset gene expression profiling identifies genes involved in prostate cancer response to selenium

BACKGROUND: Gene expression technologies have the ability to generate vast amounts of data, yet there often resides only limited resources for subsequent validation studies. This necessitates the ability to perform sorting and prioritization of the output data. Previously described methodologies have used functional pathways or transcriptional regulatory grouping to sort genes for further study. In this paper we demonstrate a comparative genomics based method to leverage data from animal models to prioritize genes for validation. This approach allows one to develop a disease-based focus for the prioritization of gene data, a process that is essential for systems that lack significant functional pathway data yet have defined animal models. This method is made possible through the use of highly controlled spotted cDNA slide production and the use of comparative bioinformatics databases without the use of cross-species slide hybridizations. RESULTS: Using gene expression profiling we have demonstrated a similar whole transcriptome gene expression patterns in prostate cancer cells from human and rat prostate cancer cell lines both at baseline expression levels and after treatment with physiologic concentrations of the proposed chemopreventive agent Selenium. Using both the human PC3 and rat PAII prostate cancer cell lines have gone on to identify a subset of one hundred and fifty-four genes that demonstrate a similar level of differential expression to Selenium treatment in both species. Further analysis and data mining for two genes, the Insulin like Growth Factor Binding protein 3, and Retinoic X Receptor alpha, demonstrates an association with prostate cancer, functional pathway links, and protein-protein interactions that make these genes prime candidates for explaining the mechanism of Selenium's chemopreventive effect in prostate cancer. These genes are subsequently validated by western blots showing Selenium based induction and using tissue microarrays to demonstrate a significant association between downregulated protein expression and tumorigenesis, a process that is the reverse of what is seen in the presence of Selenium. CONCLUSIONS: Thus the outlined process demonstrates similar baseline and selenium induced gene expression profiles between rat and human prostate cancers, and provides a method for identifying testable functional pathways for the action of Selenium's chemopreventive properties in prostate cancer

Effect of increasing intraperitoneal infusion rates on bupropion hydrochloride-induced seizures in mice

<p>Abstract</p> <p>Background</p> <p>It is not known if there is a relationship between input rate and incidence of bupropion-induced seizures. This is important, since different controlled release formulations of bupropion release the active drug at different rates.</p> <p>Methods</p> <p>We investigated the effect of varying the intraperitoneal infusion rates of bupropion HCl 120 mg/kg, a known convulsive dose₅₀(CD₅₀), on the incidence and severity of bupropion-induced convulsions in the Swiss albino mice. A total of 69 mice, approximately 7 weeks of age, and weighing 21.0 to 29.1 g were randomly assigned to bupropion HCl 120 mg/kg treatment by intraperitoneal (IP) administration in 7 groups (9 to 10 animals per group). Bupropion HCl was infused through a surgically implanted IP dosing catheter with infusions in each group of 0 min, 15 min, 30 min, 60 min, 90 min, 120 min, and 240 min. The number, time of onset, duration and the intensity of the convulsions or absence of convulsions were recorded.</p> <p>Results</p> <p>The results showed that IP administration of bupropion HCl 120 mg/kg by bolus injection induced convulsions in 6 out of 10 mice (60% of convulsing mice) in group 1. Logistic regression analysis revealed that infusion time was significant (p = 0.0004; odds ratio = 0.974) and increasing the IP infusion time of bupropion HCl 120 mg/kg was associated with a 91% reduced odds of convulsions at infusion times of 15 to 90 min compared to bolus injection. Further increase in infusion time resulted in further reduction in the odds of convulsions to 99.8% reduction at 240 min.</p> <p>Conclusion</p> <p>In conclusion, the demonstration of an inverse relationship between infusion time of a fixed and convulsive dose of bupropion and the risk of convulsions in a prospective study is novel.</p

Convulsive liability of bupropion hydrochloride metabolites in Swiss albino mice

<p>Abstract</p> <p>Background</p> <p>It is known that following chronic dosing with bupropion HCl active metabolites are present in plasma at levels that are several times higher than that of the parent drug, but the possible convulsive effects of the major metabolites are not known.</p> <p>Methods</p> <p>We investigated the convulsive liability and dose-response of the three major bupropion metabolites following intraperitoneal administration of single doses in female Swiss albino mice, namely erythrohydrobupropion HCl, threohydrobupropion HCl, and hydroxybupropion HCl. We compared these to bupropion HCl. The actual doses of the metabolites administered to mice (n = 120; 10 per dose group) were equimolar equivalents of bupropion HCl 25, 50 and 75 mg/kg. Post treatment, all animals were observed continuously for 2 h during which the number, time of onset, duration and intensity of convulsions were recorded. The primary outcome variable was the percentage of mice in each group who had a convulsion at each dose. Other outcome measures were the time to onset of convulsions, mean convulsions per mouse, and the duration and intensity of convulsions.</p> <p>Results</p> <p>All metabolites were associated with a greater percentage of seizures compared to bupropion, but the percentage of convulsions differed between metabolites. Hydroxybupropion HCl treatment induced the largest percentage of convulsing mice (100% at both 50 and 75 mg/kg) followed by threohydrobupropion HCl (50% and 100%), and then erythrohydrobupropion HCl (10% and 90%), compared to bupropion HCl (0% and 10%). Probit analysis also revealed the dose-response curves were significantly different (p < 0.0001) with CD₅₀values of 35, 50, 61 and 82 mg/kg, respectively for the four different treatments. Cox proportional hazards model results showed that bupropion HCl, erythrohydrobupropion HCl, and threohydrobupropion HCl were significantly less likely to induce convulsions within the 2-h post treatment observation period compared to hydroxybupropion HCl. The mean convulsions per mouse also showed the same dose-dependent and metabolite-dependent trends.</p> <p>Conclusion</p> <p>The demonstration of the dose-dependent and metabolite-dependent convulsive effects of bupropion metabolites is a novelty.</p

Early Antiretroviral Therapy Reduces AIDS Progression/Death in Individuals with Acute Opportunistic Infections: A Multicenter Randomized Strategy Trial

Background: Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined. Methods and Findings: A5164 was a randomized strategy trial of ‘‘early ART’’ - given within 14 days of starting acute OI treatment versus ‘‘deferred ART’’ - given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) [greater than or equal to] 50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS. 282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively. The difference in the primary endpoint did not reach statistical significance: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27–0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30–0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events. Conclusions: Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications

Expressions 1993-1994

https://openspace.dmacc.edu/expressions/1015/thumbnail.jp