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Introduction: Infection remains a prominent concern following penile implantation. Recognition of the risk factors for infection may help to guide surgeons toward reducing the risk of prosthetic contamination., Aim: To gain a further understanding of infectious adverse events following penile prosthesis, we performed a systematic literature review., Methods: As part of the 2018 American Urological Association Erectile Dysfunction Clinical Guidelines and with the support of the American Urological Association, we performed a comprehensive review of the PubMed, Embase, and Cochrane databases to search for eligible articles published between January 1, 1965, and July 20, 2016, to identify articles reporting infectious adverse events following prosthesis placement., Main Outcome Measure: The main outcome measure was infectious adverse events following penile prosthesis placement., Results: Ninety-one articles reporting infectious adverse events representing 97 study arms were identified. Prosthetic infection rates ranged from 0% to 24.6% across all series. Inflatable penile prostheses displayed a wider range (0-24.6%) than malleable devices (0-9.1%); the most frequently reported infection rate for inflatable devices was 5% or less. With the advent of device coatings and improved surgical techniques, infectious adverse events have decreased. Infections among diabetic patients also decreased throughout the reviewed body of literature, with the most recent series reporting rates consistent with those of non-diabetic patients. Furthermore, no glycosylated hemoglobin cutoff was found to infer increased or decreased risk of prosthesis infection., Conclusion: Overall penile prosthetic infectious adverse events have decreased as surgical techniques have improved and the use of antimicrobial coating has gained in popularity. These advances have demonstrated significant benefits for all patients, particularly diabetic patients who experience infection rates similar to those of non-diabetic patients in recent reports. Further technological advancements for the prevention of biofilm formation is warranted. Mahon J, Dornbier R, Wegrzyn G, et al. Infectious Adverse Events Following the Placement of a Penile Prosthesis: A Systematic Review. Sex Med Rev 2020;8:348-354., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this guideline is to provide a clinical strategy for the diagnosis and treatment of erectile dysfunction., Materials and Methods: A systematic review of the literature using the Pubmed, Embase, and Cochrane databases (search dates 1/1/1965 to 7/29/17) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of erectile dysfunction. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions., Results: The American Urological Association has developed an evidence-based guideline on the management of erectile dysfunction. This document is designed to be used in conjunction with the associated treatment algorithm., Conclusions: Using the shared decision-making process as a cornerstone for care, all patients should be informed of all treatment modalities that are not contraindicated, regardless of invasiveness or irreversibility, as potential first-line treatments. For each treatment, the clinician should ensure that the man and his partner have a full understanding of the benefits and risk/burdens associated with that choice., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

In August 2015, an expert colloquium commissioned by the Sexual Medicine Society of North America (SMSNA) convened in Washington, DC, to discuss the common clinical scenario of men who present with low testosterone (T) and associated signs and symptoms accompanied by low or normal gonadotropin levels. This syndrome is not classical primary (testicular failure) or secondary (pituitary or hypothalamic failure) hypogonadism because it may have elements of both presentations. The panel designated this syndrome adult-onset hypogonadism (AOH) because it occurs commonly in middle-age and older men. The SMSNA is a not-for-profit society established in 1994 to promote, encourage, and support the highest standards of practice, research, education, and ethics in the study of human sexual function and dysfunction. The panel consisted of 17 experts in men's health, sexual medicine, urology, endocrinology, and methodology. Participants declared potential conflicts of interest and were SMSNA members and nonmembers. The panel deliberated regarding a diagnostic process to document signs and symptoms of AOH, the rationale for T therapy, and a monitoring protocol for T-treated patients. The evaluation and management of hypogonadal syndromes have been addressed in recent publications (ie, the Endocrine Society, the American Urological Association, and the International Society for Sexual Medicine). The primary purpose of this document was to support health care professionals in the development of a deeper understanding of AOH, particularly in how it differs from classical primary and secondary hypogonadism, and to provide a conceptual framework to guide its diagnosis, treatment, and follow-up., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of Peyronie's disease., Materials and Methods: A systematic review of the literature using the PubMed®, EMBASE® and Cochrane databases (search dates 1/1/1965 to 1/26/15) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of PD. The review yielded an evidence base of 303 articles after application of inclusion/exclusion criteria., Results: The systematic review was used to create guideline statements regarding treatment of PD. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high quality evidence; high certainty), B (moderate quality evidence; moderate certainty), or C (low quality evidence; low certainty). Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional consensus statements related to the diagnosis of PD are provided as Clinical Principles and Expert Opinions due to insufficient published evidence., Conclusions: There is a continually expanding literature on PD; the Panel notes that this document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient in the context of that patient's history, values, and goals for treatment. As the science relevant to PD evolves and improves, the strategies presented here will be amended to remain consistent with the highest standards of clinical care., Competing Interests: DISCLOSURES All panel members completed COI disclosures. Relationships that have expired (more than one year old) since the panel’s initial meeting, are listed. Those marked with (C) indicate that compensation was received; relationships designated by (U) indicate no compensation was received. Consultant/Advisor: Ralph Alterowitz, MEA, The Center for Intimacy After Cancer Therapy Inc. (U); Mohit Khera, MD, Coloplast (C); American Medical Systems (C); Endo Pharmaceuticals (C); Kevin T. McVary, MD, Watson Pharmaceuticals (C), Lilly/ICOS (C), Health Publishing: Arthur L. Burnett II, MD, Urology Times Editorial Council (C); VIVUS (C); Alan W. Shindel, M.D., Endotext.com (C), International Society for Sexual Medicine (C) Leadership Position: Ralph Alterowitz, MEA, The Center for Intimacy After Cancer Therapy Inc. (U); Alan W. Shindel, M.D., Sexual Medicine Society of North America (C) Meeting Participant or Lecturer: Ralph Alterowitz, MEA, The Center for Intimacy After Cancer Therapy Inc. (U); Kevin T. McVary, MD, Watson Pharmaceuticals (C), Lilly/ICOS (C), Lawrence S. Hakim, MD, ENDO Urology (C), Slate/Auxilium (C) Scientific Study or Trial: Arthur L. Burnett II, MD, Acorda Therapeutics (C); Endo Pharmaceuticals (C); Pfizer (C); Auxilium Inc. (C); American Medical Systems (C); Coloplast (C); Astellas (C); Reflexonic LLC (C); VIVUS (C); Kevin T. McVary, MD, Astellas (C), Lilly/ICOS (C), NxThera (U), American Medical Systems (C), Sophris (C); Hossein Sadeghi-Nejad, MD, Endo Pharmaceuticals/Auxilium (C) Other: Kevin T. McVary, MD, Lilly/ICOS, Principal Investigator (C), NIDDK, Principal Investigator (C), Christian J. Nelson, PhD, American Medical Systems (U)., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this amendment is to provide an updated clinical framework for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome based upon data received since the publication of original guideline in 2011., Materials and Methods: A systematic literature review using the MEDLINE(®) database (search dates 1/1/83-7/22/09) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of IC/BPS. This initial review yielded an evidence base of 86 treatment articles after application of inclusion/exclusion criteria. The AUA update literature review process, in which an additional systematic review is conducted periodically to maintain guideline currency with newly published relevant literature, was conducted in July 2013. This review identified an additional 31 articles, which were added to the evidence base of this Guideline., Results: Newly incorporated literature describing the treatment of IC/BPS was integrated into the Guideline with additional treatment information provided as Clinical Principles and Expert Opinions when insufficient evidence existed. The diagnostic portion of the Guideline remains unchanged from the original publication and is still based on Expert Opinions and Clinical Principles., Conclusions: The management of IC/BPS continues to evolve as can be seen by an expanding literature on the topic. This document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient. As the science relevant to IC/BPS evolves and improves, the strategies presented will require amendment to remain consistent with the highest standards of care., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this guideline is to provide a clinical framework for the use of radiotherapy after radical prostatectomy as adjuvant or salvage therapy., Materials and Methods: A systematic literature review using the PubMed®, Embase, and Cochrane databases was conducted to identify peer-reviewed publications relevant to the use of radiotherapy after prostatectomy. The review yielded 294 articles; these publications were used to create the evidence-based guideline statements. Additional guidance is provided as Clinical Principles when insufficient evidence existed., Results: Guideline statements are provided for patient counseling, the use of radiotherapy in the adjuvant and salvage contexts, defining biochemical recurrence, and conducting a re-staging evaluation., Conclusions: Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy (i.e., seminal vesicle invasion, positive surgical margins, extraprostatic extension) and should offer salvage radiotherapy to patients with prostatic specific antigen or local recurrence after prostatectomy in whom there is no evidence of distant metastatic disease. The offer of radiotherapy should be made in the context of a thoughtful discussion of possible short- and long-term side effects of radiotherapy as well as the potential benefits of preventing recurrence. The decision to administer radiotherapy should be made by the patient and the multi-disciplinary treatment team with full consideration of the patient's history, values, preferences, quality of life, and functional status. Please visit the ASTRO and AUA websites (http://www.redjournal.org/webfiles/images/journals/rob/RAP%20Guideline.pdf and http://www.auanet.org/education/guidelines/radiation-after-prostatectomy.cfm) to view this guideline in its entirety, including the full literature review., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this guideline was to provide a clinical framework for the use of radiation therapy after radical prostatectomy as adjuvant or salvage therapy., Methods and Materials: A systematic literature review using PubMed, Embase, and Cochrane database was conducted to identify peer-reviewed publications relevant to the use of radiation therapy after prostatectomy. The review yielded 294 articles; these publications were used to create the evidence-based guideline statements. Additional guidance is provided as Clinical Principles when insufficient evidence existed., Results: Guideline statements are provided for patient counseling, use of radiation therapy in the adjuvant and salvage contexts, defining biochemical recurrence, and conducting a restaging evaluation., Conclusions: Physicians should offer adjuvant radiation therapy to patients with adverse pathologic findings at prostatectomy (ie, seminal vesicle invastion, positive surgical margins, extraprostatic extension) and salvage radiation therapy to patients with prostate-specific antigen (PSA) or local recurrence after prostatectomy in whom there is no evidence of distant metastatic disease. The offer of radiation therapy should be made in the context of a thoughtful discussion of possible short- and long-term side effects of radiation therapy as well as the potential benefits of preventing recurrence. The decision to administer radiation therapy should be made by the patient and the multidisciplinary treatment team with full consideration of the patient's history, values, preferences, quality of life, and functional status. The American Society for Radiation Oncology and American Urological Association websites show this guideline in its entirety, including the full literature review., (Copyright © 2013. Published by Elsevier Inc.)

Background and Purpose: With the increased incidence of low-stage renal cancers, thermal ablation technology has emerged as a viable treatment option for extirpation in selected persons and is supported by the current American Urological Association guidelines. We present a 9-year, single institution experience with radiofrequency ablation (RFA) using real-time peripheral temperature monitoring of small renal masses focusing on oncologic outcomes., Patients and Methods: We reviewed our prospectively collected database of patients with renal masses who were treated between November 2001 and January 2011 with laparoscopic (LRFA) or CT-guided percutaneous RFA (CTRFA) with simultaneous real-time peripheral fiberoptic thermometry. Patients were followed radiographically at 1 month, 6 months, 1 year, and then annually. Clinicopathologic outcomes were collected and analyzed., Results: A total of 274 patients (211 male) aged 18 to 88 years (mean 67 years) with 292 renal tumors underwent LRFA (112) or CTRFA (180). Mean tumor size was 2.5 cm (0.7-5.3 cm). An intraoperative preablation biopsy showed 197 (67.4%) renal-cell carcinomas (RCC), and 77 (26.4%) benign tumors. Mean follow-up was 26 months (1-98 mos). The single ablation treatment radiographic success rate was 96% for all tumors and 94% for RCC. Metastatic RCC developed in one patient, who died. The Kaplan-Meier (KM) 3-year and 5-year cancer-specific survival was 100% and 98.6%, respectively. The KM 3-year and 5-year overall survival was 90.4% and 74.2%, respectively., Conclusion: RFA is a clinically effective and safe nephron-sparing treatment of patients with small renal masses. Our large cohort and intermediate-term experience adds to the building evidence for the efficacy of RFA for small renal cancers.

Purpose: To provide a clinical framework for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome., Materials and Methods: A systematic review of the literature using the MEDLINE® database (search dates 1/1/83-7/22/09) was conducted to identify peer reviewed publications relevant to the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. Insufficient evidence-based data were retrieved regarding diagnosis and, therefore, this portion of the Guideline is based on Clinical Principles and Expert Opinion statements. The review yielded an evidence base of 86 treatment articles after application of inclusion/exclusion criteria. These publications were used to create the majority of the treatment portion of the Guideline. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate) or C (low). Additional treatment information is provided as Clinical Principles and Expert Opinion when insufficient evidence existed. See text and algorithm for definitions, and detailed diagnostic management, and treatment frameworks., Results: The evidence-based guideline statements are provided for diagnosis and overall management of interstitial cystitis/bladder pain syndrome as well as for various treatments. The panel identified first through sixth line treatments as well as developed guideline statements on treatments that should not be offered., Conclusions: Interstitial cystitis/bladder pain syndrome is best identified and managed through use of a logical algorithm such as is presented in this Guideline. In the algorithm the panel identifies an overall management strategy for the interstitial cystitis/bladder pain syndrome patient. Diagnosis and treatment methodologies can be expected to change as the evidence base grows in the future., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: With the volume of medical research currently published, any one practitioner cannot independently review the literature to determine best evidence-based medical care. Additionally, non-specialists usually do not have the experience to know best practice for all of the frequent clinical circumstances for which there is no good evidence. Clinical practice guidelines (CPGs) help clinicians to address these problems because they are systematically created documents that summarize knowledge and provide guidance to assist in delivering high-quality medicine. They aim to improve health care by identifying evidence that supports the best clinical care and making clear which practices appear to be ineffective., Methods: Non-structured literature review., Results: CPGs combine evidence-based medicine (on topics for which evidence exists) with expert opinion (on topics for which there is no evidence). The optimal CPG applies structured and transparent judgments, from an unbiased and diverse panel which includes both clinical experts and non-physicians, to a systematic evidence review. It includes decisions in areas in which clinical data are both available and unavailable. The resulting guideline statements should be clearly linked to the quality of the available evidence and the target patient(s) should be clearly defined, so that the reader can assess strength and applicability of the statements to an individual patient., Conclusions: The application of high-quality CPGs improves patient care, but all too often CPGs are not used to the greatest advantage because of inadequate dissemination and incorporation into practice. This article provides an overview of CPGs, focusing on their justification, creation, improvement, and use.

Oleamide (cis-9-octadecenamide) is a member of an emerging class of lipid-signaling molecules, the primary fatty acid amides. A growing body of evidence indicates that oleamide mediates fundamental neurochemical processes including sleep, thermoregulation, and nociception. Nevertheless, the mechanism for oleamide biosynthesis remains unknown. The leading hypothesis holds that oleamide is synthesized from oleoylglycine via the actions of the peptide amidating enzyme, peptidylglycine alpha-amidating monooxygenase (PAM). The present study investigated this hypothesis using pharmacologic treatments, physiologic assessments, and measurements of serum oleamide levels using a newly developed enzyme-linked immunosorbant assay (ELISA). Oleamide and oleoylglycine both induced profound hypothermia and decreased locomotion, over equivalent dose ranges and time courses, whereas, closely related compounds, stearamide and oleic acid, were essentially without effect. While the biologic actions of oleamide and oleoylglycine were equivalent, the two compounds differed dramatically with respect to their effects on serum levels of oleamide. Oleamide administration (80mg/kg) elevated blood-borne oleamide by eight-fold, whereas, the same dose of oleoylglycine had no effect on circulating oleamide levels. In addition, pretreatment with the established PAM inhibitor, disulfiram, produced modest reductions in the hypothermic responses to both oleoylglycine and oleamide, suggesting that the effects of disulfiram were not mediated through inhibition of PAM and a resulting decrease in the formation of oleamide from oleoylglycine. Collectively, these findings raise the possibilities that: (1) oleoylglycine possesses biologic activity that is independent of its conversion to oleamide and (2) the increased availability of oleoylglycine as a potential substrate does not drive the biosynthesis of oleamide.

To assess the potential of Drosophila to analyze clinically graded aspects of human disease, we developed a transgenic fly model to characterize Presenilin (PS) gene mutations that cause early-onset familial Alzheimer's disease (FAD). FAD exhibits a wide range in severity defined by ages of onset from 24 to 65 years . PS FAD mutants have been analyzed in mammalian cell culture, but conflicting data emerged concerning correlations between age of onset and PS biochemical activity . Choosing from over 130 FAD mutations in Presenilin-1, we introduced 14 corresponding mutations at conserved residues in Drosophila Presenilin (Psn) and assessed their biological activity in transgenic flies by using genetic, molecular, and statistical methods. Psn FAD mutant activities were tightly linked to their age-of-onset values, providing evidence that disease severity in humans primarily reflects differences in PS mutant lesions rather than contributions from unlinked genetic or environmental modifiers. Our study establishes a precedent for using transgenic Drosophila to study clinical heterogeneity in human disease.

Context: The hypothalamic-pituitary-adrenal axis (HPA) is restrained by activation of gamma-amino-butyric acid receptors. Alprazolam (APZ) and dehydroepiandrosterone (DHEA) are purported to be gamma-amino-butyric acid agonists and antagonists, respectively., Objective: Our objective was to examine the effects of APZ and DHEA alone and in combination on HPA axis activity., Design: This was a double-blind, crossover, placebo-controlled study., Setting: The study setting was the general community., Participants: Subjects consisted of 15 men (age, 20-45 yr) with a body mass index of 20-25 kg/m2., Interventions: DHEA (100 mg/d) or placebo was given for 4 wk, followed by a 2-wk washout; participants ingested 0.5 mg APZ or placebo 10 and 2 h before high-intensity exercise., Outcome Measures: We measured basal and exercise-induced ACTH, arginine vasopressin (AVP), cortisol, DHEA, and GH responses. It was hypothesized that DHEA would enhance and APZ would blunt exercise-induced ACTH and cortisol release., Results: DHEA significantly increased the AVP response to exercise (P < 0.01). APZ treatment significantly increased basal GH and blunted plasma cortisol, ACTH, AVP, and DHEA responses to exercise (P < 0.05). DHEA and APZ in combination significantly increased the GH response to exercise (P < 0.01)., Conclusions: DHEA may alter a subset of receptors involved in AVP release. Together DHEA and APZ may up-regulate GH during exercise by blunting a suppressive (HPA axis) and potentiating an excitatory (glutamate receptor) system.

More than 90% of cigarette smokers begin smoking during adolescence. This between-subjects repeated-measures experiment examined: (1) nicotine's acute effects on activity in adolescent and adult female Sprague-Dawley rats (Drug Phase I); (2) the effects of age of initial nicotine exposure on activity when nicotine was not administered (Interim Phase); and (3) the effects of age of initial nicotine exposure on later responses to nicotine (Drug Phase II). The experiment consisted of three separate phases. In Drug Phase I, animals were administered either 0 (saline), 0.01, 0.10, 0.50, or 1.0 mg/kg nicotine via subcutaneous injections for 12 days and horizontal activity was measured daily. During the Interim Phase (no drug phase), activity was measured but nicotine was not administered. During Drug Phase II, the same animals were administered the same nicotine dosages as in Drug Phase I for 12 days and activity was measured daily. Drug Phase I revealed dose-response differences between adolescent and adult female rats. In addition, animals initially exposed to nicotine in adolescence exhibited greater sensitivity to nicotine's activity-increasing effects than did females initially exposed to nicotine in adulthood (i.e., Drug Phase II).

Gender and genotype result in differential sensitivity to stress and to nicotine. Male and female Sprague-Dawley and Long-Evans rats exhibit different behavioral responses to immobilization stress and to chronically-administered nicotine, suggesting that these animals may be useful to model human variability in stress and nicotine sensitivity. It is possible that differences in sensitivity of the hypothalamo-pituitary-adrenocortical (HPA) axis might account for these sex and strain differences. This experiment examined corticosterone (CORT) and adrenocorticotropin hormone (ACTH) responses of male and female Sprague-Dawley (n=117) and Long-Evans (n=120) rats administered 0, 6, or 12 mg/kg/day nicotine for 14 days; half of each treatment group was exposed to immobilization stress (20 min/day). Feeding and body weight also were measured. Nicotine increased CORT and ACTH levels of Sprague-Dawley females only. Stress increased CORT and ACTH levels of all groups except for Long-Evans females. Nicotine and stress decreased feeding and body weight with greatest effects in Long-Evans females. CORT, feeding, and body weight were positively correlated among stressed females. These findings suggest that strain differences in HPA axis, body weight, and feeding responses to nicotine and to stress are robust among females but not among males. CORT reactivity and female sex hormones may explain these differences.

The Reactive Irritability Scale (RIS) uses magnitude estimation to measure reactive irritability. Respondents rate target sounds in comparison to a neutral reference sound. The RIS proved more sensitive than self-report measures to detect irritability associated with withdrawal from cigarette smoking and with exposure to a stressful environment, but was too long (30 min) for routine use. We report here on a shortened version (13 min)--RIS-II. The RIS-II exhibited robust test-retest reliability and correlated strongly with the original RIS (Study 1). In Study 2, the RIS-II was administered to subjects who experienced psychological stress and then were exposed to progressive relaxation, music, cognitive tasks, or silence; the Progressive Relaxation group was the most irritable. In Study 3, the RIS-II was administered to chronic pain patients. Pain patients found the sounds less irritating than did controls with the exception of the reference sound; repeated presentation of the reference sound increased irritability. These studies indicate that the RIS-II is a reliable instrument that may have utility for the measurement of irritability in laboratory and clinical settings. In addition, these studies indicate that the RIS-II is understandable by individuals of different ages who are from educationally- and culturally-diverse backgrounds and individuals who are healthy as well as individuals suffering from chronic medical conditions who are on multiple medications.

Over 4500 adolescents start smoking every day in the United States. Of these, one-third will die prematurely from smoking-related diseases. The current experiment examined the effects of repeated-acute nicotine administration (saline, 0.1, 0.5, or 1.0 mg/kg daily) on elevated plus maze (EPM) and locomotor behaviors of 160 adolescent and adult male and female Sprague-Dawley rats. Nicotine's effects depended on age and sex of animal. On the EPM, nicotine exerted anxiolytic effects (increased percentage of time in the open arms) in adolescent males, but exerted anxiogenic effects (decreased percentage of time in the open arms) in adolescent females and in adult males and females. For adults, peak locomotor activity occurred at the 0.5-mg/kg dosage, and the 1.0-mg/kg dosage reduced activity below the saline level on Day 1 and below the 0.5-mg/kg level on Days 1, 3, and 5. For adolescents, peak locomotor activity occurred at the 1.0-mg/kg dosage and there were no activity-depressant effects. These findings suggest there are age differences in sensitivity to nicotine that may affect vulnerability to long-term tobacco use.

The adverse effects of tobacco smoking on the cardiovascular system are well established. Effects of nicotine on the heart, in contrast, are not well characterized. Understanding specific effects of nicotine on the heart and on blood volume is relevant to (a) elucidating the mechanisms by which nicotine may contribute to heart disease and (b) determining potential risks associated with nicotine products used in smoking cessation or to treat various medical conditions. The present experiment investigated effects of continuous nicotine administration for 14 days (0, 6, or 12 mg/kg/day) on heart histopathology and blood volume (a measure of hemoconcentration) in 59 male and 59 female rats of two strains (Sprague-Dawley and Long-Evans). Following nicotine administration, animals were sacrificed and blood volume was measured. Heart length; heart weight; left ventricle, right ventricle, lateral wall, anterior wall, and posterior wall thicknesses; and intraventricular width (i.e., septum) were measured. Nicotine reduced heart weight, heart length, and overall blood volume. Females were more sensitive than males to the effects of nicotine on heart weight. In contrast, males were more sensitive than females to the effects of nicotine on heart length. Together, these findings suggest that males and females differ in their sensitivity to nicotine's cardiac effects.

Stress exerts deleterious effects on the cardiovascular system. Left ventricular hypertrophy has been identified as a risk factor for heart disease. The effects of stress on other heart parameters, including heart size and heart shape, are not well-characterized. In addition, the extent to which males and females differ in stress effects on these measures has not been examined, but may help to further explain gender differences in heart disease morbidity and mortality. The present experiment examined effects of mild daily stress on heart morphology and blood volume (obtained by ex-sanguination at decapitation) in 39 male and 40 female rats of two strains. Following 14 days of stress exposure, rats were killed and blood volume was measured. Heart length, heart weight, left ventricle cavity width, right ventricle width, lateral wall thickness, anterior wall thickness, posterior wall thickness, and septal wall thickness were measured. In males, after controlling for body weight, stress decreased heart length and left ventricle cavity width and increased septal wall thickness. In females, after controlling for body weight, stress reduced total blood volume, but did not significantly affect other heart parameters. These findings suggest that stress exposure can alter heart morphology and blood volume and that there are sex differences in these effects.

More than 90% of cigarette smokers begin smoking during adolescence, suggesting that adolescents may be particularly vulnerable to nicotine's effects. This experiment examined: (1) nicotine's acute effects on locomotion in adolescent and adult male Sprague-Dawley rats (Drug Phase I); (2) the effects of age of initial nicotine exposure on locomotion when nicotine was not administered (Interim Phase); and (3) the effects of age of initial nicotine exposure on later responses to nicotine (Drug Phase II). In Drug Phase I, animals were administered 0, 0.01, 0.10, 0.50, or 1.0 mg/kg nicotine sc for 12 days and horizontal activity was measured daily. During the Interim Phase, activity was measured but nicotine was not administered. During Drug Phase II, animals were administered the same nicotine dosages as in Drug Phase I for 12 days, and activity was measured daily. Drug Phase I revealed dose-response differences between adolescents and adults such that adolescents exhibited peak activity at both the 0.50- and 1.0-mg/kg dosages, but adults exhibited peak activity at the 0.50-mg/kg dosage. Initial nicotine exposure in adolescence (0.50 and 1.0 mg/kg), but not in adulthood, resulted in hyperactivity in adulthood in the absence of nicotine (Interim Phase). Reexposure to nicotine when all animals were adults (Drug Phase II) revealed that initial nicotine exposure in adolescence compared to adulthood resulted in dose-response differences in adulthood similar to those in Drug Phase I. In addition, animals initially exposed in adolescence exhibited sensitization to nicotine's activity-increasing effects in adulthood. These findings suggest that there are age differences in nicotine sensitivity that could predispose individuals initially exposed to nicotine in adolescence to long-term smoking.

Locomotor activity is widely used to study nicotine effects, including genotypic differences, in rodents. In rats, chronic nicotine's (administered via osmotic minipump) effects on locomotion may differ based on animal strain, with Long-Evans rats more sensitive than Sprague-Dawley rats. Males and females also may differ in sensitivity. No studies, however, have compared males and females of the two strains. In addition, stress relief is a frequently cited reason for smoking, but the behavioral consequences of nicotine-stress interactions have rarely been examined. This experiment evaluated locomotor responses of male and female Sprague-Dawley and Long-Evans rats to 0, 6, or 12 mg/kg/day nicotine administered by minipump. Half of the animals in each drug condition were exposed to 20 min/day of immobilization stress to examine nicotine-stress interactions. Horizontal and vertical activities were measured on Drug Days 4 and 10. Stress effects were minimal and stress did not alter effects of nicotine. Nicotine (6 mg/kg/day) increased horizontal activity among Long-Evans but not among Sprague-Dawleys, with greater effects in Long-Evans females. Nicotine (6 mg/kg/day) increased vertical activity of all groups and 12 mg/kg/day decreased vertical activity of all groups except for Sprague-Dawley males. Results indicate that genotype and sex are relevant to understand nicotine's behavioral actions.

Sensitivity to stress has been linked to the development of a variety of physical and psychological disorders. Studies to-date have focused on extreme stress phenotypes, have studied mostly male responses, have used limited dependent variables, and have included a limited number of measurement time points. The present experiment was designed to address these limitations. Feeding, body weight, open-field activity, acoustic startle reflex (ASR), and prepulse inhibition (PPI) responses of adult male and female Sprague-Dawley and Long-Evans rats to daily immobilization stress (20 min/day) were evaluated for 3 weeks. Stress significantly decreased feeding and body weight of males but generally not of females. Effects were greatest in Long-Evans males. Stress decreased 15-min activity levels for males on Stress Day 1, but not on other days. Stress did not affect 15-min activity levels of Long-Evans females but decreased 15-min activity levels of Sprague-Dawley females on every measurement day. ASR responses to stress differed based on rat strain; percent PPI responses differed based on rat strain and sex. Stress increased startle responses of Sprague-Dawley males and females but not of Long-Evans males and females. Stress reduced PPI of Long-Evans females on every measurement day but not of other groups. These findings indicate that strain and sex of rat is important to consider in evaluating behavioral and physiological responses to stress.

More than 90% of smokers begin smoking during adolescence, suggesting that nicotine's actions may differ in adults vs. adolescents in ways that render adolescents vulnerable to smoking initiation. This experiment tested the hypothesis that nicotine's biobehavioral actions differ in adult and adolescent rats. Forty-two male (21 adolescents, 21 adults) and 41 female (21 adolescents, 20 adults) Sprague-Dawley rats were administered saline or 12 mg/kg/day nicotine via osmotic minipump for 21 days. Body weight, feeding, and locomotion (horizontal activity, vertical activity, center time) were measured before, during, and after saline or nicotine administration. Nicotine's effects depended on age and sex. Nicotine reduced body weight and feeding of adult males and females, and of adolescent males, but not of adolescent females. In addition, adolescent males were more sensitive than adults or adolescent females to nicotine's activity-enhancing effects. In cessation, nicotine-exposed adolescent males continued to exhibit greater activity than saline-exposed animals. Results indicate that nicotine's biobehavioral actions differ depending on age and sex.

The acoustic startle reflex (ASR) and pre-pulse inhibition (PPI) of the ASR are used extensively to index drug effects in rodents. Important methodological issues exist, however, with regard to the specific procedures and equipment used. In particular, the effects of acclimation to the startle procedure on response stability and the effects of testing animals in groups vs. individually have not been examined but are relevant to data interpretation. The present experiment measured acoustic startle responses with and without a pre-pulse of 25 adult Sprague-Dawley rats (12 male, 13 female) tested individually and in same-sex groups at four time points. Individual testing increased startle responses and PPI of males at time 1 and altered PPI of females at times 1, 2, and 3 compared with group testing. Responses were indistinguishable in the two testing environments at time 4. Results indicate that testing environment may affect responses when subjects have not been acclimated to the testing situation and that there are sex differences in these effects. Because responses stabilized by the fourth testing point, repeated testing of subjects particularly females, may be an important methodological inclusion when evaluating effects of drugs and other manipulations on ASR and PPI.

Despite the fact that the anxiety-relieving effects of smoking are widely reported by smokers, human laboratory studies have not found consistent evidence for this effect. In animals, contrasting results also have been reported, with Sprague-Dawley rats unaffected by nicotine in behavioral tests of anxiety but with other rat strains (e.g., Wistar, Fischer-344) displaying behaviors indicative of anxiolysis. The present experiment used the social interaction test to evaluate effects of nicotine (12 mg/kg/day) chronically administered via minipump on social and non-social behaviors in 48 male and 48 female Long-Evans rats--a strain that has not previously been evaluated and that is known to differ from Sprague-Dawleys in other behavioral responses to nicotine. Because environmental conditions can alter behavioral effects of drugs, animals lived in either individual or same-sex group housing. Social interactions were measured on day 10 of drug administration and social behaviors (touch, follow, sniff-other, wrestle) as well as non-social behaviors (anxiety-related behaviors: freezing, grooming-self; exploratory behavior: moving) were scored. Group housing decreased social behaviors and increased anxiety-related behaviors. Nicotine's effects depended upon housing condition, such that nicotine further decreased social behaviors and increased anxiety-related behaviors of group-housed animals, with weaker effects in single-housed animals. Overall, the results suggest that nicotine's effects are modified by environmental conditions, and that nicotine administration at this dosage and in this particular rat strain results in anxiogenic effects.

Nicotine's behavioral actions in the human smoker by self-report depend, in part, on the individual's gender and environment. The purpose of the present experiment was to determine whether effects of nicotine on unconditioned behaviors of rats also depend on sex and environmental conditions. Long-Evans rats (96 males and 96 females) living in individual or grouped housing were administered saline or 12 mg/kg/day nicotine via osmotic minipump for 14 days. Horizontal activity (a measure of overall activity and arousal), vertical activity (a measure of exploratory behavior), and center time (a possible index of anxiety) were measured on Day 10 of drug administration and on Day 2 of nicotine cessation. Group housing decreased horizontal and vertical activity and center time, with effects occurring sooner in females. Nicotine's effects depended on housing and sex. For males, nicotine altered indices of arousal and exploration, increasing these variables for group-housed males but decreasing them for individually housed males. For females, nicotine altered possible indices of anxiety, reducing anxiety for group-housed females. In cessation, housing effects continued in females and appeared more robustly in males. Results indicate that nicotine's chronic effects depend on subjects' sex and living environment.

We recently reported that 14 days of nicotine administration (12 mg/kg/day) reduced acoustic startle reflex amplitude and impaired prepulse inhibition (PPI) of startle in male and female Long-Evans rats. These findings contrasted with reports of nicotine-induced enhancement of startle and PPI in Sprague-Dawley (a different strain) male rats. The present experiment administered 0, 6, or 12 mg/kg/day nicotine via osmotic minipump for 14 days to 120 Sprague-Dawley rats (male and female) and to 120 Long-Evans rats (male and female) and examined ASR and PPI. Half of the subjects also were stressed by immobilization once each day to examine nicotine-stress interactions. Nicotine enhanced ASR and PPI responses of Sprague-Dawley rats but impaired these responses in Long-Evans rats, regardless of sex. Effects of stress were complex and depended on strain, sex, and drug dose. These findings indicate that effects of nicotine on measures of reactivity (ASR) and sensory gating (PPI) depend on genotype and that nicotine stress interactions depend on genotype, sex, and nicotine dosage.

In rats, effects of nicotine administration on sensory gating as indexed by prepulse inhibition (PPI) of the acoustic startle reflex (ASR) are unclear. We have found that nicotine administration enhances ASR and PPI in Sprague-Dawley rats, but other investigators, using Long-Evans rats, have reported no effects or enhancement of PPI only. Numerous methodological differences exist among studies in addition to subject strain, however, making it unclear whether inconsistent behavioral responses are the result of different experimental procedures or indicate a true strain difference. To investigate the role of strain in nicotine's effects on ASR and PPI, 192 male and female Long-Evans rats were administered 12 mg/kg/day nicotine via osmotic minipump for 14 days using identical methodologies employed in studies with Sprague-Dawley subjects. Effects of grouped vs. individual housing on these responses also were examined. Nicotine administration impaired ASR and PPI in Long-Evans subjects. These effects occurred in female rats regardless of housing condition, and interacted with housing in male rats. Results indicate that sex and housing are important variables in nicotine's effects. Results suggest that subject strain may be an important variable in nicotine's effects on sensory gating, and that responses of Sprague-Dawley vs. Long-Evans rats may represent a true strain difference.