Long interspersed nuclear elements safeguard neural progenitors from precocious differentiation.

Long interspersed nuclear element-1 (L1 or LINE-1) is a highly abundant mobile genetic element in both humans and mice, comprising almost 20% of each genome. L1s are silenced by several mechanisms, as their uncontrolled expression has the potential to induce genomic instability. However, L1s are paradoxically expressed at high levels in differentiating neural progenitor cells. Using in vitro and in vivo techniques to modulate L1 expression, we report that L1s play a critical role in both human and mouse brain development by regulating the rate of neural differentiation in a reverse-transcription-independent manner.

Attitudes to ageing amongst health care professionals: a qualitative systematic review.

OBJECTIVES: Older adults utilising healthcare may be vulnerable to systemic bias regarding ageing potentially affecting care. Primary aim is to systematically review the qualitative literature examining attitudes to ageing amongst health care professionals (HCPs). Secondary aim is to describe and compare attitudes to ageing between different professional groups. METHODS: Studies examining attitudes to ageing of HCPs were identified using four databases. Original qualitative research with HCPs was included, excluding studies examining students alone, reviews, and grey literature. Three authors undertook standardised data extraction and quality rating for each study and thematic synthesis, with a fourth senior author reviewing. Quality appraisal followed the Attree and Milton guidelines (2006), including studies rated A-C. RESULTS: Of 5869 citations, 13 met initial inclusion criteria. Synthesis of the 12 studies graded A-C followed (excluding one study rated-D). Nurses, doctors, and social workers were most frequently investigated. Identified themes included Attitudes towards older persons, The role of the older persons' family, Behaviour of HCPs towards older persons, Behaviour of older persons towards HCPs, and Definitions of an older person. An overarching theme emerged of the systemic context of attitudes to ageing. Common attitudes were found across disciplines, with doctors emphasising complexity and dependency and nurses the burden of care. CONCLUSIONS: HCP's attitudes to ageing vary and are shaped by professional experiences and systemic factors. HCP attitudes may affect responses to and care of the older person. Therefore, interprofessional research, and systemic and service changes across disciplines are required to foster real and sustainable attitudinal change to support older peoples' care.

A grassroots antiracist program: The motivation and perceived growth of participants in a community-based, intergroup dialogue program.

In the United States, racial segregation still organizes the social lives of most people. This segregation of social life continues reinforcing attitudes and behaviors that sustain racial injustice in the United States. Given the longstanding structural forces sustaining the segregated status quo, why do certain individuals seek out opportunities for 'intentional integration'? And what happens when they do? This qualitative study interviewed racially diverse participants in a community-developed, sustained, and strategic intergroup dialogue program called Touchy Topics Tuesday (TTT), located in St. Louis, Missouri. Overall, participants (N = 30) described three interwoven motivations for involvement in the program-a catalytic moment, a long-term commitment mindset, and/or the influence of their social network. Of all these, participants' social network was the predominant motivating force for individuals across racial lines. Participants also reported three main categories of outcomes: intellectual growth, emotional growth, and relational growth. Each of these categories encompass both attitudinal and behavioral changes. The article interrogates these major findings in the context of the intergroup dialogue literature and studies of attitude change and psychotherapy.

Cardiovascular Safety of Testosterone-Replacement Therapy.

BACKGROUND: The cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism has not been determined. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial, we enrolled 5246 men 45 to 80 years of age who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng per deciliter. Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng per deciliter) or placebo gel. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis. A secondary cardiovascular end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, assessed in a time-to-event analysis. Noninferiority required an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo. RESULTS: The mean (±SD) duration of treatment was 21.7±14.1 months, and the mean follow-up was 33.0±12.1 months. A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). Similar findings were observed in sensitivity analyses in which data on events were censored at various times after discontinuation of testosterone or placebo. The incidence of secondary end-point events or of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups. A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group. CONCLUSIONS: In men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.).

An in vivo neuroimmune organoid model to study human microglia phenotypes.

Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly.

Risk Stratification to Support Antibiotic Stewardship and Breastfeeding Exclusivity in a Military Treatment Facility.

OBJECTIVE: To safely reduce unnecessary antibiotic exposure in neonates exposed to chorioamnionitis and inadequately treated Group B Streptococcus (GBS) using the early-onset sepsis (EOS) calculator for risk stratification and a 36-hour antibiotic duration. DESIGN: Evidence-based quality improvement initiative. SETTING/LOCAL PROBLEM: Obstetric service at a midsized military treatment facility with approximately 2,000 births annually and no standard process for neonatal EOS risk assessment. PARTICIPANTS: Clinical nurse specialist, physicians, nursing leadership, unit-level nursing champions, and nurses assigned to the mother-baby and labor and delivery units. INTERVENTION/MEASUREMENTS: An interdisciplinary working group created a protocol to institute an EOS risk assessment calculator, a note for the electronic heath record, and interdisciplinary education for all staff providing care to neonates in our facility. RESULTS: Before implementation of the EOS calculator, 97.6% of neonates exposed to chorioamnionitis or inadequate maternal GBS treatment received antibiotics; after implementation, the mean rate dropped to 32%. Exclusive breastfeeding rates before discharge in neonates exposed to chorioamnionitis or inadequate maternal GBS treatment also increased during this time, from 40% to a mean of 89%. After implementation, there were no readmissions to our institution for culture-proven sepsis within 14 days of discharge. CONCLUSION: Multidisciplinary team-led implementation of the EOS calculator and of shortened antibiotic duration were associated with safely reduced antibiotic exposure in well-appearing neonates exposed to chorioamnionitis and GBS. In addition, dramatically improved rates of exclusive breastfeeding at discharge were observed in this population.

Basal body organization and cell geometry during the cell cycle in Tetrahymena thermophila.

Tetrahymena thermophila possesses arrays of motile cilia that promote fluid flow for cell motility. These consist of intricately organized basal bodies (BBs) that nucleate and position cilia at the cell cortex. Tetrahymena cell geometry and spatial organization of BBs play important roles in cell size, swimming, feeding, and division. How cell geometry and BB organization are established and maintained remains poorly understood, and prior studies have been limited due to difficulties in accurate BB identification and small sample size. We therefore developed an automated image processing pipeline that segments single cells, distinguishes unique BB populations, assigns BBs into distinct ciliary rows, and distinguishes new from mature BBs. We identified unique features to describe the variation of cell shape and BB spatial organization in unsynchronized single-cell images. The results reveal asymmetries in BB distribution and ingression of the cytokinetic furrow within the cell. Moreover, we establish novel spatial and temporal waves in new BB assembly through the cell cycle. Finally, we used measurements from single cells across the cell cycle to construct a generative model that allows synthesis of movies depicting single cells progressing through the cell cycle. Our approach is expected to be of particular value for characterizing Tetrahymena mutants.

Apnea of prematurity and sudden infant death syndrome.

Apnea is a frequent occurrence in prematurity and its prevalence in the most severely preterm population is indicative of an immature respiratory neural control system. Preterm infants are also at increased risk of Sudden Infant Death Syndrome (SIDS), which has been associated with similar respiratory neural control dysfunction seen in prematurity. Generally, abnormalities in both central and peripheral mechanisms of respiratory control are thought to be key underlying features of abnormal respiratory system development. Numerous factors contribute to the etiology of apnea and respiratory control dysfunction including the environment (e.g., substance use/misuse), sex, genetics, a vulnerable neonate, and various underlying comorbidities. However, there are major gaps in our understanding of both normal and abnormal respiratory control system development, which highlights the need for continued research using novel and innovative methods.

Comparison of psychedelic and near-death or other non-ordinary experiences in changing attitudes about death and dying.

Both psychedelic drug experiences and near-death experiences can occasion changes in perspectives on death and dying, but there have been few direct comparisons of these phenomena. This study directly compared psychedelic occasioned and non-drug experiences which altered individuals' beliefs about death. Individuals who reported an experience that altered their beliefs about death occasioned by either a psychedelic drug or a near-death or other non-ordinary experience completed an online survey. Circumstances of the experience, mystical and near-death subjective features, changes in attitudes about death, and other persisting effects were evaluated. The study sample (n = 3192) included five groups: non-drug near-death or other non-ordinary experiences (n = 933), and drug experiences occasioned by lysergic acid diethylamide (LSD) (n = 904), psilocybin (n = 766), ayahuasca (n = 282), or N,N-dimethyltryptamine (DMT) (n = 307). Analyses of differences in experiences were adjusted statistically for demographic differences between groups. Compared to the psychedelic groups, the non-drug group was more likely to report being unconscious, clinically dead, and that their life was in imminent danger. The groups were remarkably similar in the reported changes in death attitudes attributed to the experience, including a reduced fear of death and high ratings of positive persisting effects and personal meaning, spiritual significance, and psychological insight. Although both psychedelic and non-drug participants showed robust increases on standardized measures of mystical and near-death experiences, these measures were significantly greater in the psychedelic participants. Non-drug participants were more likely to rate their experiences as the single most meaningful of their lives. Comparing across psychedelic substances, ayahuasca and DMT groups tended report stronger and more positive enduring consequences of the experience than the psilocybin and LSD groups, which were largely indistinguishable. These data provide a detailed characterization and comparison of psychedelic occasioned and non-drug experiences that changed attitudes about death and suggest the importance of future prospective psychedelic administration studies.

Effects of long-term testosterone treatment on cardiovascular outcomes in men with hypogonadism: Rationale and design of the TRAVERSE study.

BACKGROUND: Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an adequately-powered randomized trial. METHODS: The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study is a randomized, double-blind, placebo-controlled, parallel group, non-inferiority, multicenter study. Eligible participants are men, 45 to 80 years, with serum testosterone concentration <300 ng/dL and hypogonadal symptoms, who have evidence pre-existing CV disease or increased risk of CV disease. Approximately 6,000 subjects will be randomized to either 1.62% transdermal testosterone gel or a matching placebo gel daily for an anticipated duration of up to 5 years. The primary outcome is CV safety defined by the major adverse CV event composite of nonfatal myocardial infarction, nonfatal stroke, or death due to CV causes. The trial will continue until at least 256 adjudicated major adverse CV event endpoints have occurred to assess whether the 95% (2-sided) upper confidence limit for a hazard ratio of 1.5 can be ruled out. Secondary endpoints include prostate safety defined as the incidence of adjudicated high grade prostate cancer and efficacy in domains of sexual function, bone fractures, depression, anemia, and diabetes. RESULTS: As of July 1, 2021, 5,076 subjects had been randomized. CONCLUSIONS: The TRAVERSE study will determine the CV safety and long-term efficacy of testosterone treatment in middle-aged and older men with hypogonadism with or at increased risk of CV disease.

An Exploratory Study into the Implantation of Arytenoid Cartilage Scaffold in the Horse.

Respiratory function in the horse can be severely compromised by arytenoid chondritis, or arytenoid chondropathy, a pathologic condition leading to deformity and dysfunction of the affected cartilage. Current treatment in cases unresponsive to medical management is removal of the cartilage, which can improve the airway obstruction, but predisposes the patient to other complications like tracheal penetration of oropharyngeal content and dynamic collapse of the now unsupported soft tissue lateral to the cartilage. A tissue engineering approach to reconstructing the arytenoid cartilage would represent a significant advantage in the management of arytenoid chondritis. In this study, we explored if decellularized matrix could potentially be incorporated into the high motion environment of the arytenoid cartilages of horses. Equine arytenoid cartilages were decellularized and a portion of the resultant acellular scaffolds was implanted in a full-thickness defect created in the arytenoids of eight horses. The implantation was performed bilaterally in each horse, with one side randomly selected to receive an implant seeded with autologous bone marrow-derived nucleated cells (BMNCs). Arytenoids structure and function were monitored up to 4 months. In vivo assessments included laryngeal ultrasound, and laryngeal endoscopy at rest and during exercise on a high-speed treadmill. Histologic evaluation of the arytenoids was performed postmortem. Implantation of the cartilaginous graft had no adverse effect on laryngeal respiratory function or swallowing, despite induction of a transient granuloma on the medial aspect of the arytenoids. Ultrasonographic monitoring detected a postoperative increase in the thickness and cross-sectional area of the arytenoid body that receded faster in the arytenoids not seeded with BMNCs. The explanted tissue showed epithelialization of the mucosal surface, integration of the implant into the native arytenoid, with minimal adverse cellular reaction. Remodeling of the scaffold material was evident by 2 months after implantation. Preseeding the scaffold with BMNCs increased the rate of scaffold degradation and incorporation. Replacement of arytenoid portion with a tissue-engineered cartilaginous graft preseeded with BMNCs is surgically feasible in the horse, is well tolerated, and results in appropriate integration within the native tissue, also preventing laryngeal tissue collapse during exercise.

Mechanistic actions of oxygen and methylxanthines on respiratory neural control and for the treatment of neonatal apnea.

Apnea remains one of the most concerning and prevalent respiratory disorders spanning all ages from infants (particularly those born preterm) to adults. Although the pathophysiological consequences of apnea are fairly well described, the neural mechanisms underlying the etiology of the different types of apnea (central, obstructive, and mixed) still remain incompletely understood. From a developmental perspective, however, research into the respiratory neural control system of immature animals has shed light on both central and peripheral neural pathways underlying apnea of prematurity (AOP), a highly prevalent respiratory disorder of preterm infants. Animal studies have also been fundamental in furthering our understanding of how clinical interventions (e.g. pharmacological and mechanical) exert their beneficial effects in the clinical treatment of apnea. Although current clinical interventions such as supplemental O2 and positive pressure respiratory support are critically important for the infant in respiratory distress, they are not fully effective and can also come with unfortunate, unintended (and long-term) side-effects. In this review, we have chosen AOP as one of the most common clinical scenarios involving apnea to highlight the mechanistic basis behind how some of the interventions could be both beneficial and also deleterious to the respiratory neural control system. We have included a section on infants with critical congenital heart diseases (CCHD), in whom apnea can be a clinical concern due to treatment with prostaglandin, and who may benefit from some of the treatments used for AOP.

Investigation into pathophysiology of naturally occurring palatal instability and intermittent dorsal displacement of the soft palate (DDSP) in racehorses: Thyro-hyoid muscles fatigue during exercise.

Exercise induced intermittent dorsal displacement of the soft palate (DDSP) is a common cause of airway obstruction and poor performance in racehorses. The definite etiology is still unclear, but through an experimental model, a role in the development of this condition was identified in the dysfunction of the thyro-hyoid muscles. The present study aimed to elucidate the nature of this dysfunction by investigating the spontaneous response to exercise of the thyro-hyoid muscles in racehorses with naturally occurring DDSP. Intramuscular electrodes were implanted in the thyro-hyoid muscles of nine racehorses, and connected to a telemetric unit for electromyographic monitoring implanted subcutaneously. The horses were recruited based on upper airway function evaluated through wireless endoscopy during exercise. Five horses, with normal function, were used as control; four horses were diagnosed as DDSP-affected horses based on repeated episodes of intermittent dorsal displacement of the soft palate. The electromyographic activity of the thyro-hyoid muscles recorded during incremental exercise tests on a high-speed treadmill was analyzed to measure the mean electrical activity and the median frequency of the power spectrum, thereafter subjected to wavelet decomposition. The affected horses had palatal instability with displacement on repeated exams prior to surgical implantation. Although palatal instability persisted after surgery, only two of these horses displaced the palate after instrumentation. The electromyographic traces from this group of four horses showed, at highest exercise intensity, a decrease in mean electrical activity and median power frequency, with progressive decrease in the contribution of the high frequency wavelets, consistent with development of thyro-hyoid muscle fatigue. The results of this study identified fatigue as the main factor leading to exercise induced palatal instability and DDSP in a group of racehorses. Further studies are required to evaluate the fiber type composition and metabolic characteristics of the thyro-hyoid muscles that could predispose to fatigue.

Functional electrical stimulation following nerve injury in a large animal model.

INTRODUCTION: Controversy exists over the effects of functional electrical stimulation (FES) on reinnervation. We hypothesized that intramuscular FES would not delay reinnervation after recurrent laryngeal nerve (RLn) axonotmesis. METHODS: RLn cryo-injury and electrode implantation in ipsilateral posterior cricoarytenoid muscle (PCA) were performed in horses. PCA was stimulated for 20 weeks in eight animals; seven served as controls. Reinnervation was monitored through muscle response to hypercapnia, electrical stimulation and exercise. Ultimately, muscle fiber type proportions and minimum fiber diameters, and RLn axon number and degree of myelination were determined. RESULTS: Laryngeal function returned to normal in both groups within 22 weeks. FES improved muscle strength and geometry, and induced increased type I:II fiber proportion (p = 0.038) in the stimulated PCA. FES showed no deleterious effects on reinnervation. DISCUSSION: Intramuscular electrical stimulation did not delay PCA reinnervation after axonotmesis. FES can represent a supportive treatment to promote laryngeal functional recovery after RLn injury. Muscle Nerve 59:717-725, 2019.

Asymmetric recurrent laryngeal nerve conduction velocities and dorsal cricoarytenoid muscle electromyographic characteristics in clinically normal horses.

The dorsal cricoarytenoid (DCA) muscles, are a fundamental component of the athletic horse's respiratory system: as the sole abductors of the airways, they maintain the size of the rima glottis which is essential for enabling maximal air intake during intense exercise. Dysfunction of the DCA muscle leads to arytenoid collapse during exercise, resulting in poor performance. An electrodiagnostic study including electromyography of the dorsal cricoarytenoid muscles and conduction velocity testing of the innervating recurrent laryngeal nerves (RLn) was conducted in horses with normal laryngeal function. We detected reduced nerve conduction velocity of the left RLn, compared to the right, and pathologic spontaneous activity (PSA) of myoelectrical activity within the left DCA muscle in half of this horse population and the horses with the slowest nerve conduction velocities. The findings in this group of horses are consistent with left sided demyelination and axonal loss, consistent with Recurrent Laryngeal Neuropathy (RLN), a highly prevalent degenerative disorder of the RLn in horses that predominantly affects the left side. The detection of electromyographic changes compatible with RLN in clinically unaffected horses is consistent with previous studies that identified "subclinical" subjects, presenting normal laryngeal function despite neuropathologic changes within nerve and muscle confirmed histologically.

Genomic integrity in the male germ line: evidence in support of the disposable soma hypothesis.

The Big Blue λSelect-cII selection system has been employed along with whole-exome sequencing to examine the susceptibility of the male germ line to mutation in two challenging situations (i) exposure to a chemotherapeutic regime including bleomycin, etoposide and cis-platinum (BEP) and (ii) the ageing process. A 3-week exposure to BEP induced complete azoospermia associated with a loss of developing germ cells and extensive vacuolization of Sertoli cell cytoplasm. Following cessation of treatment, spermatozoa first appeared in the caput epididymis after 6 weeks and by 12 weeks motile spermatozoa could be recovered from the cauda, although the count (P < 0.001) and motility (P < 0.01) of these cells were significantly reduced and superoxide generation was significantly elevated (P < 0.001). Despite this increase in free radical generation, no evidence of chromatin instability was detected in these spermatozoa. Furthermore, embryos obtained from females mated at this 12-week time point showed no evidence of an increased mutational load. Similarly, progressive ageing of Big Blue mice had no impact on the quality of the spermatozoa, fertility or mutation frequency in the offspring despite a significant increase in the mutational load carried by somatic tissues such as the liver (P < 0.05). We conclude that the male germ line is highly resistant to mutation in keeping with the disposable soma hypothesis, which posits that genetic integrity in the germ cells will be maintained at the expense of the soma, in light of the former's sentinel position in safeguarding the stability of the genome.

Locating advance care planning facilitators in general practice increases consumer participation.

BACKGROUND: Advance care planning (ACP) can positively affect end-of-life care experiences. However, uptake of ACP completion is low. The aim of this study was to investigate whether co-locating ACP facilitators in general practice increased participation METHODS: Barwon Health commenced promoting its ACP program in 2008. Trained ACP facilitators assisted consumers, which usually occurred in the program's community-based consulting rooms. From 2012 onwards, ACP facilitators were co-located with 18 general practices, where they assisted consumers at the point of care. RESULTS: Referrals to the program increased from 2008-11 (n = 2520) to 2012-15 (n = 6847). Between 2012 and 2015, 48% of referrals to the program were from the 18 general practices with co-located ACP facilitators, and 93% of these referrals resulted in ACPs completed, compared with 74% from practices without co-located facilitators and 55% from all other sources (P DISCUSSION: Co-locating ACP facilitators in general practice increased the number of referrals to the program and produced higher plan completion rates.

Epididymal CYP2E1 plays a critical role in acrylamide-induced DNA damage in spermatozoa and paternally mediated embryonic resorptions†.

Acrylamide is a ubiquitous toxicant in human lives, due to its formation in many food products. Acrylamide induces dominant lethal mutations with administration of 25 mg/kg bw/day for 5 days in male mice. Cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1) is responsible for this dominant lethality. CYP2E1 is the only enzyme responsible for the conversion of acrylamide to the highly reactive metabolite glycidamide, which forms adducts with DNA. CYP2E1 is present predominantly in the liver, as well as the brain, kidney, intestines, and spleen. Within the male mouse reproductive tract, CYP2E1 localizes to spermatocytes. However, embryo resorptions have been demonstrated to occur only with exposure of the late stages of spermatogenesis and spermatozoa. It was determined that CYP2E1 is additionally expressed within the mouse epididymal epithelium, and this localization is responsible for acrylamide-induced dominant lethality. Further, an equivalent profile of CYP2E1 expression was identified in the human reproductive tract. While spermatozoa of both species were also established to possess CYP2E1, this did not contribute to acrylamide-induced DNA damage. In vitro studies strengthened these findings further, revealing that acrylamide exposure only induces DNA damage in human and mouse spermatozoa following metabolism by the mouse epididymal epithelial cell line (mECap18) to glycidamide. These findings emphasize, for the first time, the vital role of the epididymis in the reproductive toxicity associated with acute acrylamide exposure.

Effects of Buprenorphine, Methylnaltrexone, and Their Combination on Gastrointestinal Transit in Healthy New Zealand White Rabbits.

Among the many analgesic agents available, buprenorphine appears to be the analgesic used most often in rabbits. Unfortunately, deleterious side effects of opioids, such as gastrointestinal stasis and anorexia, may discourage the use of these agents. Methylnaltrexone is a peripheral opioid antagonist that ameliorates opioid-induced gastrointestinal stasis in others species yet preserves the analgesic effects of buprenorphine. We evaluated whether methylnaltrexone reversed buprenorphine-induced gastrointestinal stasis in 8 healthy male New Zealand White rabbits. To measure gastrointestinal transit time, each rabbit received 20 barium-filled spheres through an orogastric tube. Rabbits then received 4 treatments in random order: buprenorphine (0.05 mg/kg SC), methylnaltrexone (1 mg/kg SC), both agents combined (B+M), or normal saline (control) every 12 h for 2 d. Fecal production was measured every 6 h, and water and food consumption, and body weight, were measured daily, for 5 d after each treatment. The time to appearance of the first sphere was significantly longer for buprenorphine group than for control and methylnaltrexone groups. Daily fecal output was lowest for buprenorphine and B+M, intermediate for control, and highest for methylnaltrexone. Water and food consumption were lower for groups buprenorphine and B+M than for control and methylnaltrexone. Body weight was not affected. In conclusion, treatment with buprenorphine 0.05 mg/kg BID for 2 d in healthy rabbits decreased food and water consumption, prolonged gastrointestinal transit time and decreased the fecal output. Coadministration of methylnaltrexone at 1 mg/kg did not alleviate these negative side effects.