Co-Administration of Low-Dose Naltrexone and Bupropion Reduces Alcohol Drinking in Alcohol-Preferring (P) Rats

Background This study examined whether combining naltrexone (NTX) with bupropion (BUP) is more effective in reducing alcohol drinking in alcohol-preferring (P) rats with a genetic predisposition toward high voluntary alcohol intake than either drug alone. Methods Alcohol-experienced, adult, male, P rats were fed NTX alone in a dose of 10.0 mg/kg BW, BUP alone in a dose of 10.0 mg/kg BW, BUP alone in a dose of 20.0 mg/kg BW, NTX (10.0 mg/kg BW) + BUP (10.0 mg/kg BW), or vehicle (VEH) at 1 hour prior to onset of a daily 2-hour alcohol access period for 5 consecutive days. Results When administered alone, neither NTX (10.0 mg/kg BW) nor BUP, in either of 2 doses (10.0 mg/kg BW or 20.0 mg/kg BW), reduced voluntary alcohol intake in P rats. However, NTX combined with BUP (10.0 mg/kg NTX + 10.0 mg/kg BUP) and given as a single medication significantly reduced alcohol consumption throughout prolonged treatment. Conclusions Combining low doses of NTX and BUP, each of which is ineffective when given alone, increases the efficacy of the medication. Low drug doses circumvent the problem of negative side effects that can occur with higher doses of either drug. A reduction in side effects can facilitate patient compliance and improve clinical outcomes for alcoholics and heavy drinkers who want to reduce their alcohol intake. The results, together with those from our prior studies, demonstrate the strength of a combinatorial pharmacotherapeutic approach to the treatment of alcohol use disorder

Alcohol Drinking and Blood Alcohol Concentration Revisited

Background It is widely assumed that the amount of alcohol in the blood reflects the amount of alcohol consumed. However, several factors in addition to amount of alcohol consumed can influence blood alcohol concentration (BAC). This study examines the effect of alcohol dose, concentration, and volume on BAC in rats with a high-alcohol-drinking (HAD) phenotype. Methods Study 1 examined the relationship between the amount of alcohol consumed and BAC. Alcohol-naïve, male, HAD rats (N = 7) were given access to alcohol for 2 h/d for 9 consecutive days with food and water ad libitum. Alcohol intake and BAC were measured at 30, 60, and 90 minutes after onset of access. Study 2 examined the effects of altering alcohol dose, concentration, and volume on BAC (as measured by area under the curve). Alcohol-naïve, male, HAD rats (N = 39) were infused, via an intragastric cannulus, with 1.16, 2.44, or 3.38 g alcohol/kg body weight (BW), produced by varying alcohol volume while holding concentration constant or by holding volume constant while varying concentration. Other rats were infused with 10, 15, or 20% v/v alcohol solutions while holding dose constant. Results BAC was more strongly correlated with the ratio of alcohol intake (g/kg BW) to total fluid intake (mls) (R = 0.85 to 0.97, p < 0.05 to p < 0.001) than it was with the amount of alcohol consumed (g/kg BW) (R = 0.70 to 0.81, p < 0.05). No effect of alcohol dose was seen during the first hour following the onset of an alcohol infusion regardless of whether dose was achieved by altering alcohol volume or concentration. After 1 hour, higher alcohol doses were predictive of greater BACs. Conclusions The fact that a 3-fold difference in alcohol dose did not result in significant differences in BACs during the first 30 minutes after ingestion of alcohol has potentially important implications for interpretation of studies that measure alcohol-sensitive end points during this time

Combining Varenicline (Chantix) with Naltrexone Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone in a Rodent Model of Alcoholism

Background This study examined whether varenicline (VAR), or naltrexone (NTX), alone or in combination, reduces alcohol drinking in alcohol-preferring (P) rats with a genetic predisposition toward high voluntary alcohol intake. Methods Alcohol-experienced P rats that had been drinking alcohol (15% v/v) for 2 h/d for 4 weeks were fed either vehicle (VEH), VAR alone (0.5, 1.0, or 2.0 mg/kg body weight [BW]), NTX alone (10.0, 15.0, or 20.0 mg/kg BW), or VAR + NTX in 1 of 4 dose combinations (0.5 VAR + 10.0 NTX, 0.5 VAR + 15.0 NTX, 1.0 VAR + 10.0 NTX, or 1.0 VAR + 15.0 NTX) at 1 hour prior to alcohol access for 10 consecutive days, and the effects on alcohol intake were assessed. Results When administered alone, VAR in doses of 0.5 or 1.0 mg/kg BW did not alter alcohol intake but a dose of 2.0 mg/kg BW decreased alcohol intake. This effect disappeared when drug treatment was terminated. NTX in doses of 10.0 and 15.0 mg/kg BW did not alter alcohol intake but a dose of 20.0 mg/kg BW decreased alcohol intake. Combining low doses of VAR and NTX into a single medication reduced alcohol intake as well as did high doses of each drug alone. Reduced alcohol intake occurred immediately after onset of treatment with the combined medication and continued throughout prolonged treatment. Conclusions Low doses of VAR and NTX, when combined in a single medication, reduce alcohol intake in a rodent model of alcoholism. This approach has the advantage of reducing potential side effects associated with each drug. Lowering the dose of NTX and VAR in a combined treatment approach that maintains efficacy while reducing the incidence of negative side effects may increase patient compliance and improve clinical outcomes for alcoholics and heavy drinkers who want to reduce their alcohol intake

Closing the Feedback Loop: Collaborative Design of a Musculoskeletal Revision Course

Clinical Teaching Fellows (CTFs) at Leicester Medical School decided to supplement the learning needs of first year students on the musculoskeletal (MSK) module. Mid-unit evaluation had demonstrated that students had remarked positively on CTF teaching and many requested further anatomy teaching and demonstrations using prosections. It is increasingly important to provide students with evidence that their feedback is being acted upon, therefore CTFs collaborated in providing additional learning resources in the form of CTF-led revision courses while the MSK module was still ongoing. A survey was designed which aimed to engage students and to further explore their learning needs when developing the course. Based on these responses, two half-day CTF-led revision courses were designed, which included educational methods and topics the students themselves had suggested. CTFs collaboratively developed eight different stations, with one CTF designing and delivering the teaching material. Attendance was high and feedback indicated this was a valuable learning experience for students, with particularly positive responses about the interactive nature and high quality of the teaching. This experience demonstrates the benefits of working in partnership with students when developing learning activities, closing the feedback loop to improve student satisfaction, and collaborative planning when designing revision resources

Varenicline Reduces Alcohol Intake During Repeated Cycles of Alcohol Reaccess Following Deprivation in Alcohol-Preferring (P) Rats

Background Most alcoholics experience periods of voluntary alcohol abstinence or imposed alcohol deprivation followed by a return to alcohol drinking. This study examined whether varenicline (VAR) reduces alcohol intake during a return to drinking after periods of alcohol deprivation in rats selectively bred for high alcohol drinking (the alcohol preferring or “P” rats). Methods Alcohol-experienced P rats were given 24-hour access to food and water and scheduled access to alcohol (15% and 30% v/v) for 2 h/d. After 4 weeks, rats were deprived of alcohol for 2 weeks, followed by reaccess to alcohol for 2 weeks, and this pattern was repeated for a total of 3 cycles. Rats were fed either vehicle (VEH) or VAR, in doses of 0.5, 1.0, or 2.0 mg/kg BW, at 1 hour prior to onset of the daily alcohol reaccess period for the first 5 days of each of the 3 alcohol reaccess cycles. Results Low-dose VAR (0.5 mg/kg BW) reduced alcohol intake during the 5 days of drug treatment in alcohol reaccess cycles 1 and 2. Higher doses of VAR (1.0 mg/kg BW and 2.0 mg/kg BW) reduced alcohol intake during the 5 days of treatment in all 3 alcohol reaccess cycles. The decrease in alcohol intake disappeared with termination of VAR treatment in all alcohol reaccess cycles. Conclusions The results demonstrate that VAR decreases alcohol intake during multiple cycles of alcohol reaccess following alcohol deprivation in rats and suggests that it may prevent a return to heavy alcohol drinking during a lapse from alcohol abstinence in humans with alcohol use disorder

Reversal of loss of bone mass in old mice treated with mefloquine

Aging is accompanied by imbalanced bone remodeling, elevated osteocyte apoptosis, and decreased bone mass and mechanical properties; and improved pharmacologic approaches to counteract bone deterioration with aging are needed. We examined herein the effect of mefloquine, a drug used to treat malaria and systemic lupus erythematosus and shown to ameliorate bone loss in glucocorticoid-treated patients, on bone mass and mechanical properties in young and old mice. Young 3.5-month-old and old 21-month-old female C57BL/6 mice received daily injections of 5 mg/kg/day mefloquine for 14 days. Aging resulted in the expected changes in bone volume and mechanical properties. In old mice mefloquine administration reversed the lower vertebral cancellous bone volume and bone formation; and had modest effects on cortical bone volume, thickness, and moment of inertia. Mefloquine administration did not change the levels of the circulating bone formation markers P1NP or alkaline phosphatase, whereas levels of the resorption marker CTX showed trends towards increase with mefloquine treatment. In addition, and as expected, aging bones exhibited an accumulation of active caspase3-expressing osteocytes and higher expression of apoptosis-related genes compared to young mice, which were not altered by mefloquine administration at either age. In young animals, mefloquine induced higher periosteal bone formation, but lower endocortical bone formation. Further, osteoclast numbers were higher on the endocortical bone surface and circulating CTX levels were increased, in mefloquine- compared to vehicle-treated young mice. Consistent with this, addition of mefloquine to bone marrow cells isolated from young mice led to increased osteoclastic gene expression and a tendency towards increased osteoclast numbers in vitro. Taken together our findings identify the age and bone-site specific skeletal effects of mefloquine. Further, our results highlight a beneficial effect of mefloquine administration on vertebral cancellous bone mass in old animals, raising the possibility of using this pharmacologic inhibitor to preserve skeletal health with aging

Age- and sex-dependent role of osteocytic pannexin1 on bone and muscle mass and strength

Pannexins (Panxs), glycoproteins that oligomerize to form hemichannels on the cell membrane, are topologically similar to connexins, but do not form cell-to-cell gap junction channels. There are 3 members of the family, 1-3, with Panx1 being the most abundant. All Panxs are expressed in bone, but their role in bone cell biology is not completely understood. We now report that osteocytic Panx1 deletion (Panx1Δot) alters bone mass and strength in female mice. Bone mineral density after reaching skeletal maturity is higher in female Panx1Δot mice than in control Panx1fl/fl mice. Further, osteocytic Panx1 deletion partially prevented aging effects on cortical bone structure and mechanical properties. Young 4-month-old female Panx1Δot mice exhibited increased lean body mass, even though pannexin levels in skeletal muscle were not affected; whereas no difference in lean body mass was detected in male mice. Furthermore, female Panx1-deficient mice exhibited increased muscle mass without changes in strength, whereas Panx1Δot males showed unchanged muscle mass and decreased in vivo maximum plantarflexion torque, indicating reduced muscle strength. Our results suggest that osteocytic Panx1 deletion increases bone mass in young and old female mice and muscle mass in young female mice, but has deleterious effects on muscle strength only in males

Osteocytic miR21 deficiency improves bone strength independent of sex despite having sex divergent effects on osteocyte viability and bone turnover

Osteocytes play a critical role in mediating cell–cell communication and regulating bone homeostasis, and osteocyte apoptosis is associated with increased bone resorption. miR21, an oncogenic microRNA, regulates bone metabolism by acting directly on osteoblasts and osteoclasts, but its role in osteocytes is not clear. Here, we show that osteocytic miR21 deletion has sex‐divergent effects in bone. In females, miR21 deletion reduces osteocyte viability, but suppresses bone turnover. Conversely, in males, miR21 deletion increases osteocyte viability, but stimulates bone turnover and enhances bone structure. Further, miR21 deletion differentially alters osteocyte cytokine production in the two sexes. Interestingly, despite these changes, miR21 deletion increases bone mechanical properties in both sexes, albeit to a greater extent in males. Collectively, our findings suggest that miR21 exerts both sex‐divergent and sex‐equivalent roles in osteocytes, regulating osteocyte viability and altering bone metabolism through paracrine actions on osteoblasts and osteoclasts differentially in males vs females, whereas, influencing bone mechanical properties independent of sex

'A good fit?' Bringing the Sociology of Footwear to the Clinical Encounter in Podiatry Services : A Narrative Review

Background: This narrative review explores the ways in which drawing on theories and methods used in sociological work on footwear and identity can contribute to healthcare research with podiatrists and their patients, highlighting recent research in this field, implications for practice and potential areas for future development. Traditionally, research within Podiatry Services has tended to adopt a quantitative, positivist focus, developing separately from a growing body of sociological work exploring the importance of shoes in constructing identity and self-image. Bringing qualitative research drawing on sociological theory and methods to the clinical encounter has real potential to increase our understanding of patient values, motivations and – crucially – any barriers to adopting ‘healthier’ footwear that they may encounter. Such work can help practitioners to understand why patients may resist making changes to their footwear practices, and help us to devise new ways for practitioners to explore and ultimately break down individual barriers to change (including their own preconceptions as practitioners). This, in turn, may lead to long-term, sustainable changes to footwear practices and improvements in foot health for those with complex health conditions and the wider population. Conclusion: A recognition of the complex links between shoes and identity is opening up space for discussion of patient resistance to footwear changes, and paving the way for future research in this field beyond the temporary ‘moment’ of the clinical encounter

Speech Communication

Contains table of contents for Part V, table of contents for Section 1, reports on six research projects and a list of publications.C.J. Lebel FellowshipDennis Klatt Memorial FundNational Institutes of Health Grant R01-DC00075National Institutes of Health Grant R01-DC01291National Institutes of Health Grant R01-DC01925National Institutes of Health Grant R01-DC02125National Institutes of Health Grant R01-DC02978National Institutes of Health Grant R01-DC03007National Institutes of Health Grant R29-DC02525National Institutes of Health Grant F32-DC00194National Institutes of Health Grant F32-DC00205National Institutes of Health Grant T32-DC00038National Science Foundation Grant IRI 89-05249National Science Foundation Grant IRI 93-14967National Science Foundation Grant INT 94-2114