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Objectives: To examine the association between alpha-blocker use and sexual dysfunction among men participating in a population-based cohort of men residing in Olmsted County, MN. Lower urinary tract symptoms (LUTS) in men have previously been associated with sexual dysfunction. The use of alpha-adrenergic receptor blocking agents results in an improvement in LUTS for many men. If sexual dysfunction and LUTS share a common etiology, alpha-blocker use might also be associated with a decreased risk of sexual dysfunction.Methods: White men, aged 40-79 years, were randomly selected in 1990 and assessed for alpha-blocker use and LUTS severity. Sexual function was assessed using the Brief Male Sexual Function Inventory. Men who used alpha-blockers before any sexual dysfunction were considered "exposed." Hazard ratios and 95% confidence intervals were estimated separately for each sexual function domain using Cox proportional hazard models.Results: Of the 1724 men with a regular sexual partner included in the present study (mean age 57.74 years), 263 (15.3%) reported alpha-blocker use. alpha-Blocker use was associated with a decreased risk of sexual dysfunction across all domains for men > or =50 years old (age-adjusted hazard ratio 0.53-0.69). A decreased risk of erectile dysfunction and low libido remained significant only among those using alpha-blockers who also experienced an improvement in LUTS (P = .01).Conclusions: The use of alpha-blockers for LUTS was associated with a decreased risk of sexual dysfunction. Improvement in sexual function correlated with the improvement in LUTS more strongly among those using alpha-blockers. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease of age with no effective preventative or treatment approaches. Deeper understanding of the mechanisms underlying the accumulation of toxic β-amyloid oligopeptides and the formation of amyloid plaque in AD has the potential to identify new therapeutic targets. Prior research links the insulin-like growth factor (IGF) system to pathologic mechanisms underlying AD. Suppression of local IGF-I receptor (IGFIR) signaling in AD mice has been shown to reduce plaque formation in the brain and delay neurodegeneration and behavioral changes. However, direct inhibitors of IGFIR signaling are not a viable treatment option for AD due to the essentiality of the IGFIR in physiological growth and metabolism. We have previously demonstrated a more selective means to reduce local IGFIR signaling through inhibition of PAPP-A, a novel zinc metalloprotease that regulates local IGF-I bioavailability through cleavage of inhibitory IGF binding proteins. Here we tested if deletion of PAPP-A in a mouse model of AD provides protection against pathology and behavioral changes. We show that compared to AD mice, AD/PAPP-A KO mice had significantly less plaque burden, reduced astrocytic activation, decreased IGF-IR activity, and improved cognition. Human senile AD plaques showed specific immunostaining for PAPP-A. Thus, inhibition of PAPP-A expression or activity may represent a novel treatment strategy for AD., Competing Interests: Declaration of competing interest DJB has a potential conflict related to his research. He is co-inventor on patents held by Mayo Clinic, patent applications licensed or to be filed by Unity Biotechnology and is a Unity Biotechnology shareholder. Research in the Baker laboratory has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo conflict of interest policies. The other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute pancreatitis (AP) is a common disease with no targeted therapy and has varied outcomes ranging from spontaneous resolution to being lethal. Although typically painful, AP can also be painless. Various agents, including opioids, are used for pain control in AP; the risks and benefits of which are often debated. As experimental AP in mice is used to study the efficacy of potential therapies, we studied the effect of a commonly used opioid, buprenorphine, on the initiation and progression of AP. For this, we administered extended-release buprenorphine subcutaneously before inducing the previously established severe AP model that uses interleukins 12 and 18 (IL12,18) in genetically obese (ob/ob) mice and compared this to mice with AP but without the drug. Mice were monitored over 3 days, and parameters of AP induction and progression were compared. Buprenorphine significantly reduced serum amylase, lipase, pancreatic necrosis, and AP-associated fat necrosis, which is ubiquitous in obese mice and humans. Buprenorphine delayed the AP-associated reduction of carotid artery pulse distention and the development of hypothermia, hastened renal injury, and muted the early increase in respiratory rate versus IL12,18 alone. The site of buprenorphine injection appeared erythematous, inflamed, and microscopically showed thinning, loss of epidermal layers that had increased apoptosis. In summary, subcutaneous extended-release buprenorphine interfered with the induction of AP by reducing serum amylase, lipase, pancreatic and fat necrosis, the worsening of AP by delaying hypotension, hypothermia, while hastening renal injury, respiratory depression, and causing cutaneous injury at the site of injection. NEW & NOTEWORTHY Extended-release buprenorphine interferes with the initiation and progression of acute pancreatitis at multiple levels.

Background & Aims: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis., Methods: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4 + T-cell-induced murine colitis models., Results: Mitochondria-endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria-endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 β, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 β pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r -/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs., Conclusions: IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4 + T-cell-driven chronic intestinal inflammation., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Sepsis is a life-threatening state that arises due to a hyperactive inflammatory response stimulated by infection and rarely other insults (e.g., non-infections tissue injury). Although changes in several proinflammatory cytokines and signals are documented in humans and small animal models, far less is known about responses within affected tissues of large animal models. We sought to understand the changes that occur during the initial stages of inflammation by administering intravenous lipopolysaccharide (LPS) to Yorkshire pigs and assessing transcriptomic alterations in the brain, kidney, and whole blood. Robust transcriptional alterations were found in the brain, with upregulated responses enriched in inflammatory pathways and downregulated responses enriched in tight junction and blood vessel functions. Comparison of the inflammatory response in the pig brain to a similar mouse model demonstrated some overlapping changes but also numerous differences, including oppositely dysregulated genes between species. Substantial changes also occurred in the kidneys following LPS with several enriched upregulated pathways (cytokines, lipids, unfolded protein response, etc.) and downregulated gene sets (tube morphogenesis, glomerulus development, GTPase signal transduction, etc.). We also found significant dysregulation of genes in whole blood that fell into several gene ontology categories (cytokines, cell cycle, neutrophil degranulation, etc.). We observed a strong correlation between the brain and kidney responses, with significantly shared upregulated pathways (cytokine signaling, cell death, VEGFA pathways) and downregulated pathways (vasculature and RAC1 GTPases). In summary, we have identified a core set of shared genes and pathways in a pig model of systemic inflammation., (© 2023. The Author(s).)

As experienced authors, statisticians, editors, and scientists, we present the following comments to highlight some usages or omissions that are common in research manuscripts. Consideration of these comments will improve practices of data analysis and reporting.

Aims: As has been shown in larger animal models, knee immobilization can lead to arthrofibrotic phenotypes. Our study included 168 C57BL/6J female mice, with 24 serving as controls, and 144 undergoing a knee procedure to induce a contracture without osteoarthritis (OA)., Methods: Experimental knees were immobilized for either four weeks (72 mice) or eight weeks (72 mice), followed by a remobilization period of zero weeks (24 mice), two weeks (24 mice), or four weeks (24 mice) after suture removal. Half of the experimental knees also received an intra-articular injury. Biomechanical data were collected to measure passive extension angle (PEA). Histological data measuring area and thickness of posterior and anterior knee capsules were collected from knee sections., Results: Experimental knees immobilized for four weeks demonstrated mean PEAs of 141°, 72°, and 79° after zero, two, and four weeks of remobilization (n = 6 per group), respectively. Experimental knees demonstrated reduced PEAs after two weeks (p < 0.001) and four weeks (p < 0.0001) of remobilization compared to controls. Following eight weeks of immobilization, experimental knees exhibited mean PEAs of 82°, 73°, and 72° after zero, two, and four weeks of remobilization, respectively. Histological analysis demonstrated no cartilage degeneration. Similar trends in biomechanical and histological properties were observed when intra-articular violation was introduced., Conclusion: This study established a novel mouse model of robust knee contracture without evidence of OA. This was appreciated consistently after eight weeks of immobilization and was irrespective of length of remobilization. As such, this arthrofibrotic model provides opportunities to investigate molecular pathways and therapeutic strategies.Cite this article: Bone Joint Res  2023;12(1):58-71.

The therapeutic value of phage as an alternative to antibiotics for the treatment of bacterial infections is being considered in the wake of mounting antibiotic resistance. In this study, the pharmacokinetic properties of Staphylococcus aureus phage K following intravenous and intra-articular administration were investigated in a rabbit model. Using a traditional plaque assay and a novel quantitative PCR assay to measure phage levels in specimens over time, it was found that intra-articularly administered phage enters the systemic circulation; that phage may be detected in synovial fluid up to 24 h following the intra-articular, but not intravenous, administration; and that qPCR-based enumeration is generally more sensitive than plaque enumeration, with fair to moderate correlation between the two methods. Findings presented should inform the design of phage therapy experiments and therapeutic drug monitoring in preclinical and human phage studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Totten, Cunningham, Gades, Etzioni and Patel.)

Percutaneous transendocardial injections of therapeutic agents into the myocardium may not always be effective. We used an animal model for assessing the efficacy of the injections using linoleic acid as a testing agent. Efficacious delivery into the myocardium of a beating heart was indicated by rapidly developed local myocardial necrosis and wall motion abnormalities using echocardiography. We employed this experimental model to test our innovative technology, an acoustically active injection catheter. The Doppler ultrasound-guided acoustically active injection catheter effectively delivers the substance to the myocardium but needs further technical improvements to minimize an unwanted systemic distribution of the agent., (© 2021 American Institute of Ultrasound in Medicine.)

In collaboration with the American College of Veterinary Pathologists.

Background and aims  Endoscopic resections are associated with bleeding and perforation and may be managed with through-the-scope (TTS) clips, over-the-scope clips and endoscopic suturing. The aim of this preclinical study was to compare technical success of closure using a novel TTS tissue helix tack and suture device (X-Tack) to TTS clips in a porcine model. Materials and methods  Four subjects underwent 40 mucosal resections, diameter range 25-50 mm, in the stomach (n = 24) and colon (n = 16). Closures were randomized to X-Tack (n = 24) or clip (n = 16). Animals underwent weekly endoscopic follow-up for 4 weeks. Results  Technical closure with X-Tack was successful in 24 of 24 (100 %) cases and with clips in 13 of 16 cases (81.3 %) ( P  = 0.0001). One colonic perforation occurred and was successfully managed using X-Tack. The rate of healing was not statistically different between the groups, and all sites healed at 4 weeks including the perforation and were confirmed by histology. Conclusions  Compared to TTS clip, X-Tack is superior for effecting large mucosal defect closure, including durable sealing of full-thickness perforation. There was no difference in rate of healing between devices., Competing Interests: Competing interests This study was funded by a research grant from Apollo Endosurgery. Dr. Abu Dayyeh has received a research grant from Apollo Endosurgery. Dr. Storm has received a research grant and consulting fees from Apollo Endosurgery and consulting fees from ERBE., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Female athymic nude rats ( Rattus norvegicus ; n = 45; age, 6 wk) were used in an IACUC-approved protocol to investigate mechanisms and potential treatments associated with brain, spine, and spinal cord metastases from triple negative breast cancer. The analgesic plan included the use of buprenorphine SR LAB (0.6 mg/kg; 0.11 mL/rat) subcutaneously and an oral NSAID delivered via the water. Thirty-seven rats reached the experimental end point at 3 mo after xenotransplantation and were euthanized for tissue harvest. Grossly, all 37 rats had nodules in the subcutis over the shoulders; these were identified as small, cystic structures (diameter, approximately 0.25 cm). The cysts and haired skin were submitted for LC-MS/MS (liquid chromatography-tandem mass spectrometry) and histopathology. Histologically, the cysts were lined by fibrous connective tissue mildly infiltrated by macrophages, lymphocytes, and plasma cells. Adjacent blood vessels were rimmed by a mild infiltrate of lymphocytes and plasma cells. The cysts contained variable accumulations of a light pink, proteinaceous fluid. The cause for the cysts could not be determined histologically; there was no evidence of neoplasia. LC-MS/MS analysis revealed that the cysts contained buprenorphine. We hypothesize that the lack of T cells and a cell-mediated immune response in these rats prevented the dissolution of the vehicle and absorption of the buprenorphine. The manufacturer provides a cautionary statement regarding the use of this formulation in nude mice due to skin reactions, but to our knowledge, this report is the first description of an apparent lack of absorption of the drug in immunodeficient animals.

Pharmacokinetics of drugs may differ between small and large mammals (including humans); therefore, drug testing in animal models must be carefully designed. Sprague-Dawley rats were used in cardiac experiments, during which the lopinavir concentration in serum had to match human therapeutic levels (4-10 μg/mL). Lopinavir was administered as a co-formulated drug of lopinavir and ritonavir. It was found that after a single administration of a standard human peroral dose (lopinavir 13.3 mg/kg of body weight), the serum concentration of lopinavir was only one-tenth of the target level. It remained below the minimum target level even after 10-fold the standard dose was administered. After initial pilot tests, a dose escalation study was conducted with oral doses 10- and 15-fold the standard clinical dose of lopinavir (i.e. 133 and 200 mg/kg, respectively). A second administration 2 h later effectively increased and maintained higher concentrations during the experimental ischaemia and reperfusion periods. A dose-dependent increase in serum concentration of the drug was observed. Thus, the target therapeutic serum level of lopinavir in the rats was achieved by administrating 10- to 15-fold the standard human dose twice, separated by a 2 h interval.

The purpose of this study was to ascertain if prophylactic ingestion of a diet rich in vitamin E would prevent or impede the development of ulcerative dermatitis in mice on a C57BL/6 background. Mice were fed either a standard mouse diet, vitamin E (99 IU/kg), or a mouse diet fortified with vitamin E (3000 IU/kg) after weaning. Cases of ulcerative dermatitis were recorded by individuals unmasked to the diet assignment. The incidence of ulcerative dermatitis in a retrospective cohort of mice on standard diet was compared with the group on the diet fortified with vitamin E. Age was associated with ulcerative dermatitis in standard diet and vitamin E fortified diet groups, r = 0.43, p-value < 0.0001 and r = 0.18, p-value < 0.02, respectively. The average age of incidence for ulcerative dermatitis in the mice fed the standard diet was 89 weeks and for the mice fed the vitamin E diet it was 41 weeks. The unadjusted odds ratio comparing the incidence of ulcerative dermatitis between the two diet groups was 4.6 with a 95% confidence interval of (2.44, 8.58), χ(2) p-value < 0.0001. Therefore, there was an association between the diets and ulcerative dermatitis, with the mice on the vitamin E fortified diet having almost five times the odds of having ulcerative dermatitis compared with mice on the standard diet. Incidence of ulcerative dermatitis was not influenced by sex or genotype. Our study results show that a diet fortified in vitamin E initiated at weaning does not prevent or impede the development of ulcerative dermatitis in mice on a C57BL/6 background and may accelerate development when administered to young mice.

Introduction: The presence of erectile or ejaculatory dysfunction may indicate physical problems; however, individual perceptions (e.g., sexual satisfaction) may reflect the degree of concern about these changes. Long-term data showing how changes in multiple sexual function domains track together may be useful in understanding the importance of physical declines vs. sexual satisfaction., Aim: The aim of this study was to describe changes in sexual function among a population-based sample of aging men., Methods: A population-based cohort study using data from the Olmsted County Study of Urinary Symptoms and Health Status among Men. Sexual function was assessed biennially from 1996 to 2004 using a previously validated questionnaire in a random sample of 2,213 men., Main Outcome Measures: Changes in erectile function, libido, ejaculatory function, sexual problems, and sexual satisfaction., Results: Overall, we observed declines in all of the sexual function domains, ranging from an annual decrease of 0.03 point per year for sexual satisfaction to an annual decrease of 0.23 point per year in erectile function. Moderate correlations were observed among all longitudinal changes in sexual function (range in age-adjusted r(s) = 0.14-0.43); however, significantly smaller correlations between changes in the functional domains and changes in sexual satisfaction and problem assessment were observed among older men (range in age-adjusted r(s) = 0.03-0.29)., Conclusion: Overall, these results demonstrate that longitudinal changes in five sexual function domains change together over time in our community-based cohort. Erectile function, ejaculatory function, and sexual drive decrease over time with greater rates of decline for older men. However, older men may be less likely to perceive these declines as a problem and be dissatisfied. These data may prove helpful to patients and clinicians in understanding and discussing changes in multiple aspects of sexual function.

Introduction: Testosterone replacement therapy has been used in the treatment of sexual dysfunction; however, its use remains controversial, and the effectiveness and long-term health implications are unknown., Aim: To evaluate the association between sex hormone serum levels, erectile function, and sexual drive in a population-based sample of men., Methods: A stratified random sample of men residing in Olmsted County, Minnesota, completed a questionnaire containing questions from the Brief Male Sexual Function Inventory (BMSFI), and participated in a clinical exam, which included serum hormone measurements., Main Outcome Measures: Levels of sexual drive (libido) and erectile function as assessed by the BMSFI and serum testosterone, bioavailable testosterone, and estradiol measurements., Results: Out of 414 men, 294 had a regular sexual partner and androgen measurements at the 14th year of follow-up. Total testosterone and erectile function were significantly correlated even after adjustment for age (r = 0.12, P = 0.04). Conversely, total testosterone was not significantly correlated with sex drive (r = 0.08, P = 0.17). Bioavailable testosterone was significantly correlated with both erectile function and sex drive (r = 0.16, P = 0.01 and r = 0.20, P = 0.001, respectively). However, these associations disappeared after age adjustment (r = 0.04 and r = 0.09)., Conclusions: These cross-sectional results suggest the relationship between sex hormones and sexual function is complex, and that the age-related decline in sexual function may be due to age-related declines in levels of bioavailable testosterone rather than total testosterone levels.

Mice in a colony used for pancreatic cancer research and maintained in a barrier animal facility presented with vulvar masses. A census and examination of all colony animals was conducted on 17 February 2006; line, gender, and mass location were recorded; a slide caliper was used to measure the width, length, and height of each mass; and the volume of each mass was calculated. Progeny female mice from crossbreeding of the B6.FVB-Tg(Ipf1-cre)1Tuv and B6;129-Kras2tm4Tyj (KRAS(G12D/+)) strains presented with external vulvar and periauricular papillomas. The papillomas were present in 41.2% of all female crossbred mice and ranged in size from 8 to 36 mm3. Age of mice and tumor size were not correlated. Compared with the B6.FVB-Tg(Ipf1-cre)1Tuv line, the crossbred female mice were more likely to have a vulvar mass, with an odds ratio of 29.3, 95% confidence interval (1.5, 563.9) and a positive predictive value of 42.9%. Diagnostic evaluation, including electron microscopy, light microscopy, serology, and bacteriology, did not reveal a viral or other infectious etiology. Therefore, we speculate that interaction between the genetic background of the mice and the introduced Kras oncogene may be responsible for these papillomas.

Introduction: Severe obstructive sleep apnea has been associated with sexual dysfunction; however, it is unclear whether milder forms of sleep disturbances might also be associated with sexual problems., Aim: To evaluate the association between snoring and five measures of sexual dysfunction in a population-based sample of men., Methods: A stratified random sample of men residing in Olmsted County, Minnesota completed a questionnaire containing questions from the Brief Male Sexual Function Inventory (BMSFI) and a sleep questionnaire., Main Outcome Measures: Levels of sexual drive (libido), erectile function, ejaculatory function, sexual problem assessment, and sexual satisfaction as assessed by the BMSFI., Results: Of 827 men with a regular sexual partner, subjects were divided into categories of heavy (N = 95), moderate (N = 573), and none/mild (N = 159) snoring. Their median age was 64 years (range 51-90). The sexual satisfaction domain score was significantly lower in the heavy snoring group (P value = 0.01). The odds of low sexual satisfaction was 2.3 (95% CI 1.2, 4.1) among the heavy snorers compared with the none/mild snoring group. This association remained statistically significant after adjustment for smoking, medical comorbidities, and mental health status. However, there was no significant difference in ejaculatory function, erectile function, sexual drive, and sexual problem assessment across snoring categories., Conclusions: These data provide evidence of an association between snoring severity and reduced sexual satisfaction in a population of elderly community males. Snoring was not associated with biologic measures of sexual dysfunction.

Objectives: Tacrolimus is an effective immunosuppressant, safely administered in clinical practice by monitoring blood levels. In experimental transplants, many dosage regimens have been reported, often without such determinations. Anorexia and organ toxicity commonly occur. We report the toxic effects of tacrolimus in rabbits receiving intramuscular injections (1 mg/kg/d) and the subsequent dosage modifications that resulted in improved animal survival without toxic effects., Materials and Methods: To obtain nontoxic drug concentrations in the blood, 3 dosage regimens were required. Drug concentrations were targeted using therapeutic human values as a guide (range, 5-20 ng/mL). First, a group of 12 Dutch-Belted rabbits received vascularized femoral allografts and were treated with intramuscular dosages of tacrolimus (1 mg/kg/d) for 14 days. Subsequently, dosage reductions in 10 more rabbits, to 0.2 mg/kg/d for 14 days, were necessary. Finally, another group of 20 rabbits was treated with 0.08 mg/kg for 3 days, and then every other day thereafter. Weight loss > 30%, cardiopulmonary failure, and/or creatinine levels > 221 micromol/L were the criteria approved by our local Institutional Animal Care and Use Committee for euthanizing the animals. Treated animals were compared with 20 nonimmunosuppressed controls that underwent the same operation., Results: At an intramuscular dosage of 1 mg/kg/d, the mean tacrolimus blood level was 90.7 ng/mL. Ten of the 12 animals in the original group died or required euthanasia. At necropsy, renal failure, cardiac abnormalities, and pulmonary edema were found. The tacrolimus dosage of 0.2 mg/kg/d produced a mean tacrolimus blood level of 17.6 ng/mL; however, 8 of the subsequent 10 rabbits died when given this dosage. Ultimately, the 0.08 mg/kg regimen in 20 rabbits permitted survival of 18 animals with a mean tacrolimus blood level of 6.8 ng/mL. None of 20 nonimmunosuppressed controls died after surgery., Conclusions: For successful immunosuppression, Dutch-Belted rabbits require intramuscular tacrolimus dosages lower those required in other rabbit breeds. This has not been reported previously. The 0.08 mg/kg/d dosage combined with intermittent drug level monitoring permits survival without significant complications.

Background: Reasons for attrition in studies vary, but may be a major concern in long-term studies if those who drop out differ systematically from those who continue to participate. Factors associated with dropout were evaluated in a twelve-year community-based, prospective cohort study of urologic disease in men., Methods: During 1989-1991, 2,115 randomly selected Caucasian men, ages 40-79 years from Olmsted County, Minnesota were enrolled and followed with questionnaires biennially; 332 men were added in follow-up. A random subset (approximately 25%) received a urologic examination. Baseline characteristics including age, benign prostatic hyperplasia (BPH) symptoms, comorbidities, and socioeconomic factors were compared between subjects who did and did not participate after the twelfth year of follow-up., Results: Of the 2,447 men, 195 died and were excluded; 682 did not participate in 2002. Compared with men in the 40-49 year age group, men > or = 70 years of age at baseline had a greater relative odds of dropout, 2.65 (95% CI: 1.93, 3.63). In age-adjusted analyses, relative to men without stroke, men who had suffered a stroke had a higher odds of dropout, age-adjusted OR 3.07 (95% CI: 1.49, 6.33). Presence of at least one BPH symptom was not associated with dropout, (age-adjusted OR 1.12 (95% CI: 0.93, 1.36))., Conclusion: These results provide assurance that dropout was not related to primary study outcomes. However, factors associated with dropout should be taken into account in analyses where they may be potential confounders.

Objective: To estimate the frequency of conditions associated with lower urinary tract symptoms (LUTS, typically included when assessing benign prostatic hyperplasia, BPH), as other causes of LUTS should be excluded when diagnosing BPH, using data from the Olmsted County Study of Urinary Symptoms and Health Status among Men., Subjects and Methods: During 1989-91, Caucasian men aged 40-79 years were randomly selected from the Olmsted County population. Before contact, eligibility was determined by reviewing the community medical records. Baseline exclusion criteria included comorbid pre-existing conditions or treatments, e.g. prostate, bladder or lower back surgery, bladder neck contracture or cancer, diabetes with lower extremity amputation, and neurological diseases, including Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, tabes dorsalis and stroke. Men with these conditions were excluded from the Olmsted County Study at baseline, because these conditions are potentially associated with LUTS., Results: Of the 5100 randomly sampled men, 13.4% met at least one of the pre-existing exclusion criteria. Individually, the frequency of exclusions was 7.8% for prostate cancer or surgery, 4.8% for back surgery, 1.3% for bladder surgery and 1.4% for neurological conditions. All other conditions represented <1.0% of the study exclusions. Older men were more likely to meet at least one of the exclusion criteria, with men in their fifth to eighth decade having a total exclusion frequency of 1.4%, 5.4%, 8.5% and 32.8%, respectively. The most common reason for men in their fifth decade to be excluded was lower back surgery (0.9%), whereas the most common reason in the eighth was prostate surgery (21.8%)., Conclusions: In men, conditions that may contribute to LUTS, other than BPH, are prevalent in the community and increase in frequency with age. It is important that other conditions associated with LUTS be excluded before a definitive diagnosis of BPH. Any oversight in this initial evaluation can potentially result in misclassification bias, misdiagnosis and incorrect treatment of patients.

The association between smoking and erectile dysfunction was evaluated in a cohort of 2,115 Caucasian men, aged 40-79 years, randomly selected from Olmsted County, Minnesota. Smoking status was assessed by questionnaire; during the fourth biennial examination, erectile dysfunction was assessed with the Brief Male Sexual Function Inventory. Of the 1,329 men with a regular sexual partner, 173 were current smokers, 836 had previously smoked, and 203 reported erectile dysfunction. Compared with former and never smokers, current smokers in their forties had the greatest relative odds of erectile dysfunction, 2.74 (95% confidence interval (CI): 0.44, 16.89), compared with 1.38 (95% CI: 0.51, 3.74), 1.70 (95% CI: 0.82, 3.51), and 0.77 (95% CI: 0.27, 2.21) for men in their fifties, sixties, and seventies, respectively. Compared with men who never smoked, men who smoked at some time had a greater likelihood of erectile dysfunction (age-adjusted odds ratio = 1.42, 95% CI: 1.00, 2.02), and there was a dose response. Although the causal pathway underlying this association is not clear, this study contributes to the growing literature describing an association between smoking and erectile dysfunction.

The treatment of iron poisoning has typically not included the administration of activated charcoal due to the lack of evidence supporting its efficacy. Several in vitro studies have demonstrated good adsorption of iron in a variety of pH ranges that were comparable to those found with other drugs for which activated charcoal is clinically used. This study was designed to determine whether activated charcoal altered the gastrointestinal absorption of toxic doses of iron as ferrous sulfate in an in vivo model. Seventy-five male Sprague-Dawley rats were randomly assigned into 5 groups: control given only distilled water; 100 mg elemental Iron and water; 1:1 charcoal to iron; 2:1 charcoal to iron; and 4:1 charcoal to iron. All treatments were administered consecutively by gavage within 5 min. Physiological measurements and blood samples were taken at 0, 1, 4 and 8 h after treatment. There were no consistent differences in physiological measurements among the 5 groups. Mean serum iron concentrations did not differ among Groups 2, 3, 4 and 5 at the 4 sampling times except at I h between Groups 4 and 5. The area under the curve for serum iron concentrations did not differ among the treatment groups. Activated charcoal did not alter the extent of iron absorption in the experimental model.

Carboxylesterases are important in the metabolism of cocaine, catalyzing the hydrolysis of cocaine to its two major metabolites, benzoylecgonine and ecgonine methyl ester. In the presence of ethanol, some cocaine undergoes transesterification with ethanol instead of hydrolysis with water producing the active metabolite, cocaethylene. The metabolic fate of cocaethylene is unknown, but given its structural similarity to cocaine, it was hypothesized that cocaethylene would also be metabolized by carboxylesterases and its elimination decreased in the presence of ethanol, as is cocaine's. Dogs were given cocaine alone, cocaethylene alone, cocaine and ethanol, cocaethylene and ethanol, and cocaine and cocaethylene on separate study days and sequential blood samples drawn. Plasma concentrations of cocaine, benzoylecgonine, and cocaethylene were determined by high-performance liquid chromatography. The pharmacokinetic dispositions of cocaine and cocaethylene were similar with clearance values of 0.91 +/- 0.22 and 0.79 +/- 0.16 l/min, and volumes of distribution of 2.6 +/- 0.82 and 2.7 +/- 0.47 l/kg, respectively. Both cocaine and cocaethylene clearances were decreased about 20% when given with ethanol. Following administration of cocaethylene alone, benzoylecgonine achieved similar plasma concentrations as those attained following cocaine alone, which indicates that benzoylecgonine is a major metabolite of cocaethylene. Carboxylesterases play an important role in the elimination of both cocaine and cocaethylene.

Finite element modelling of the heart for the purpose of studying the electric fields of defibrillation shocks requires knowledge of the geometry of the heart during fibrillation. However, the standard method of measuring this geometry, MRI. cannot be used during fibrillation because the heart geometry changes rapidly and perhaps unpredictably. We present a new ultrasound approach to measuring the right ventricular geometry during fibrillation and preliminary data using this technique. In six anaesthetized pigs, we find that a short axis cross-sectional area of the right ventricle increases by 38% during a 30 s episode of ventricular fibrillation. A long axis cross-sectional area increases by 19% during this same time. By fitting parameters of a simple geometric model to the experimental data, we estimate that the volume of blood in the right ventricular cavity increases by approximately 30% during the episode of ventricular fibrillation. We present the first study of the RV area during-fibrillation with the estimated volume. Our data suggest changes in defibrillation threshold may be linked to current shunting through the increased blood volume.

Chronic venous cannulation in mice is an acceptable and useful technique for repeated blood sampling or continuous intravenous administration of substances, for which mild restraint of the animal may be necessary. Because chronic restraint has drawn considerable attention in the animal welfare community, the purpose of this study was to evaluate physiologic indices of stress in mice restrained by using an established tail restraint method. Serum corticosterone levels and body, thymus, adrenal, and spleen weights on days 2, 5, 8, and 12 were compared between tail-restrained and unrestrained mice. There were no significant differences between the two groups at the time points evaluated. Corticosterone levels were highest on day 8 for both groups and were significantly different from those on days 2 (P<0.009) and 5 (P<0.04) for restrained mice and on day 2 (P<0.02) for unrestrained mice. Levels in both groups declined by day 12, suggesting habitation. Weight loss was observed in all mice whether restrained or unrestrained. Significant differences in body, thymus, adrenal, and spleen weights were not evident between restrained and unrestrained mice. This study provides important information for balancing issues of prolonged restraint, animal well-being, and research goals.

Swine have supplanted dogs and other large animal species in many biomedical applications and have become the model of choice for numerous areas of research. Anatomic, behavioral, and handling concerns often require pigs to be surgically instrumented for many procedures. Oral dosing in pigs can be accomplished by feeding substances in a palatable substrate, temporarily placing an oral or nasal gastric tube, or permanent surgical placement of an esophagostomy or gastrostomy tube. Oral and nasal gastric tube placement is difficult in conscious, unrestrained animals and is suitable only for short-term enteral access. Placing esophagostomy and gastrostomy tubes is suitable for long-term enteral access and allows easy and rapid administration of substances directly into the stomach. However, these methods frequently require major surgical manipulation for placement. Nonendoscopic percutaneous gastrostomy tube placement is used in companion animals to establish permanent or temporary enteral access. We successfully have adapted this procedure in swine as a method for short-term enteral access. This technique has several advantages over the traditional surgical method for gastrostomy tube placement. It is minimally invasive, results in less animal pain and distress, requires less procedural and recovery time, and is inexpensive. Disadvantages include the potential for splenic entrapment, splenic penetration, perforation of the esophagus, and other complications related to misplacement of the tube or applicator. This paper describes the equipment, technique, and potential complications for placing a nonendoscopic percutaneous gastrostomy tube in swine.

This study was designed to evaluate the efficacy of several analgesic regimens for use after intraperitoneal implantation of telemetry transmitters in mice. The lengths of time required for postoperative recovery of food and water intake, locomotor activity, and core temperature of mice that did not receive postsurgical analgesic medication were compared to those of mice that were given either an analgesic in the drinking water or buprenorphine injections. Many measured variables were not substantially altered by analgesic medications. However, ibuprofen-treated mice demonstrated significantly greater locomotor activity on days 2 through 5 after surgery and a more rapid return to stable postsurgical levels of activity and water intake as compared to those in untreated mice. These changes are consistent with potential analgesic efficacy of the ibuprofen treatment regimen. Buprenorphine injections elicited hyperactivity, hyperthermia, and reduced food and water intake during both the immediate postsurgical recovery period and after apparent recuperation from surgery, as compared to effects observed in saline-treated mice. Evaluating the effect of analgesic regimens on postsurgical changes in physiologic and behavioral variables can be useful in assessing the efficacy of analgesic treatments, but some changes may indicate pharmacologic effects that do not reflect pain relief.

This study was designed to determine the magnitude and duration of the analgesic effect of three commonly used opioids: buprenorphine (0.5 mg/kg for rats; 2.0 mg/kg for mice), butorphanol (2.0 mg/kg for rats; 5.0 mg/kg for mice), and morphine (10 mg/kg for rats and mice). We used two standard tests, the hot plate and tail flick assays, to measure opioid analgesia in 62 male, 200 to 300 g Sprague-Dawley rats and 61 male, 25 to 35 g ICR mice. We obtained five baseline measurements then administered the drugs subcutaneously. Morphine gave the highest analgesic effect and was intermediate in duration (2 to 3 h in rats and mice) of analgesia. Butorphanol provided the lowest level of and shortest (1 to 2 h in rats and mice) analgesia. Buprenorphine had an intermediate analgesic effect and the longest duration (6 to 8 h in rats and 3 to 5 h in mice). In light of our results, we recommend the use of morphine (with frequent redosing) for severe pain, butorphanol for mild pain of short duration, and buprenorphine for mild to moderate pain of increased duration. The dosing intervals suggested by our study are 2 to 3 h for morphine in both rats and mice, 1 to 2 h for butorphanol in both rats and mice; and 6 to 8 h in rats and 3 to 5 h in mice for buprenorphine.

A litter of eight 10- to 12-day-old SPF Sprague-Dawley rat pups (Rattus norvegicus) was observed as runted, with rough, yellow-discolored hair coats and perineal scalding and soiling. The dam also had soft stool and perineal soiling. Both the dam and pups were active despite their unthrifty appearance. The clinical signs were consistent with diarrhea. Differential diagnoses for diarrhea in neonatal rats were considered, including bacterial, viral, and parasitic etiologies. The dam and pups were sacrificed, and the following diagnostic tests were performed: complete blood count, serology, necropsy, bacterial culture, and histopathology. Histopathology and culture results were consistent with a diagnosis of streptococcal enteropathy.