Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performing the delayed response task

With advancing age, monkeys become impaired on a test of spatial working memory, the delayed response task, and show increased susceptibility to interference from irrelevant stimuli (Bartus and Dean 1979). Alpha-2 adrenergic agonists such as clonidine and guanfacine have been shown to improve the delayed response performance of aged monkeys under standard testing conditions (e.g. Arnsten et al. 1988). The current study examined whether these drugs could protect the delayed response performance of aged monkeys when irrelevant stimuli were presented during the delay intervals. Aged monkeys were tested on the variable delayed response task with short delays to minimize memory demands and optimize performance on control (no interference) sessions. During interference sessions, distractors were presented during the delays on 9 of the 30 trials (distractor trials). If the aged monkeys had been pretreated with saline, performance was significantly disrupted by the irrelevant stimuli compared to matched saline control sessions. This impairment was not only evident on the 9 distractor trials, but on the 21 remaining non-distractor trials as well. However, if the aged monkeys had been pretreated with clonidine or guanfacine, performance was not impaired on the interference sessions. This beneficial effect of the alpha-2 agonists was most apparent on the nondistractor trials. Guanfacine was able to decrease the harmful effects of distraction without any apparent sedative side effects. Co-administration of the alpha-2 antagonists idazoxan or SKF104078 with clonidine blocked the protective effects of the agonist on delayed response performance, consistent with actions at alpha-2 adrenergic receptors. These findings suggest that alpha-2 agonists improve delayed response performance, at least in part, by helping to protect memory from irrelevant stimulation. Clonidine is already used in the treatment of Attention Deficit Disorder, and the current data suggest that guanfacine may also be useful in this regard.     

Gastrointestinal haemorrhage due to erosion of the duodenal wall by a biliary stent

Complications from improperly placed biliary stents are not uncommon. Free loose wires from the ends of an uncovered stent can irritate and damage adjacent mucosal surfaces. Effective management can be achieved via percutaneous placement of a second stent to alter the orientation of the original stent.     

Informant ratings of cognitive decline of elderly people: relationship to longitudinal change on cognitive tests

Formal assessment of cognitive decline with cognitive tests can be difficult, requiring either two measurement points or a comparison of 'hold' with 'don't hold' tests. Informant-based assessment provides an alternative approach because informants can adopt a longitudinal perspective and directly rate cognitive change. A study was carried out to assess the validity of informant ratings collected by means of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). A community sample of 500 subjects aged 74 or over underwent four cognitive tests on two occasions 3½ years apart. On the second occasion, informants filled out the IQCODE. Subjects rated as having moderate or severe decline were found to have greater change on the cognitive tests. These findings support the validity of informant ratings of cognitive decline.     

Association between alcohol consumption and both osteoporotic fracture and bone density

Objective

Alcoholism is a risk factor for osteoporotic fractures and low bone density, but the effects of moderate alcohol consumption on bone are unknown. We performed a systematic review and meta-analysis to assess the associations between alcohol consumption and osteoporotic fractures, bone density and bone density loss over time, bone response to estrogen replacement, and bone remodeling.

Methods

MEDLINE, Current Contents, PsychINFO, and Cochrane Libraries were searched for studies published before May 14, 2007. We assessed quality using the internal validity criteria of the US Preventive Services Task Force.

Results

We pooled effect sizes for 2 specific outcomes (hip fracture and bone density) and synthesized data qualitatively for 4 outcomes (non-hip fracture, bone density loss over time, bone response to estrogen replacement, and bone remodeling). Compared with abstainers, persons consuming from more than 0.5 to 1.0 drinks per day had lower hip fracture risk (relative risk = 0.80 [95% confidence interval, 0.71-0.91]), and persons consuming more than 2 drinks per day had higher risk (relative risk = 1.39 [95% confidence interval, 1.08-1.79]). A linear relationship existed between femoral neck bone density and alcohol consumption. Because studies often combined moderate and heavier drinkers in a single category, we could not assess relative associations between alcohol consumption and bone density in moderate compared with heavy drinkers.

Conclusion

Compared with abstainers and heavier drinkers, persons who consume 0.5 to 1.0 drink per day have a lower risk of hip fracture. Although available evidence suggests a favorable effect of alcohol consumption on bone density, a precise range of beneficial alcohol consumption cannot be determined.     

Effects of pegylated interferon alfa-2b on the pharmacokinetic and pharmacodynamic properties of methadone: a prospective, nonrandomized, crossover study in patients coinfected with hepatitis C and HIV receiving methadone maintenance treatment

BACKGROUND: Hepatitis C virus (HCV) infection is common among methadone-maintained HIV-positive individuals. Pegylated interferon (pegIFN) used in combination with ribavirin is conventional treatment for HCV. However, pegIFN has been associated with adverse effects (AEs) that may simulate opioid withdrawal and be confused with insufficient methadone dosage. OBJECTIVE: The aim of this study was to determine, using methadone pharmacokinetic properties, whether methadone dosage adjustments are needed on initiation of treatment with pegIFN alfa-2b for HCV in methadone-maintained HIV-positive patients. METHODS: This prospective, nonrandomized, crossover study was conducted at the Albert Einstein College of Medicine and Montefiore Medical Center (Bronx, New York). Patients who were aged > or =18 years, coinfected with chronic HCV and HIV, and had been receiving methadone maintenance treatment (dosage, 40-200 mg/d PO) for at least 8 weeks prior to enrollment were eligible. We determined mean methadone C(max), T(max), Cn,in, AUC, and oral clearance (CL/F) values over a 24-hour period before (baseline) and after the administration of pegIFN alfa-2b 1.5 microg/kg SC (2 doses given 1 week apart). To determine differences in opiate withdrawal symptoms, one of the primary investigators administered the Subjective Opiate Withdrawal Scale (SOWS) and Objective Opiate Withdrawal Scale (OOWS) at baseline and 7, 14, and 21 days after the administration of the first dose. Study participants underwent weekly clinical evaluation for signs and symptoms of methadone withdrawal and for AEs of pegIFN. RESULTS: Nine patients were included in the study (7 men, 2 women; 7 Hispanic, 2 black; mean [SD] age, 41 [8.3] years; mean [SD] weight, 75.0 [12.3] kg). We did not observe any significant changes from baseline in mean C(max), T(max), C(min), AUC, and CL/F values despite 80% power to detect a 30% change in either direction. Changes from baseline in SOWS and OOWS scores were not statistically significant. The only AEs reported were mild and consistent with those expected after pegIFN alfa-2b administration, such as inflammation at the injection site and mild, brief, flu-like symptoms. CONCLUSION: Based on the results of this small, prospective, nonrandomized study, pegIFN alfa-2b did not appear to precipitate opioid withdrawal in this sample of methadone-maintained persons with HIV and chronic HCV coinfection; methadone dosage adjustments were unlikely to be needed.     

Effects of Odanacatib on Bone Structure and Quality in Postmenopausal Women With Osteoporosis: 5-Year Data From the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT) and its Extension

Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double-blind, placebo-controlled, event-driven, Phase 3, Long-term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double-blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), month 24 (ODN n = 112, placebo n = 104), month 36 (ODN n = 42, placebo n = 41), and month 60 (ODN n = 27, placebo n = 20) were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN-treated versus placebo-treated patients after 2 years of treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN-treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. © 2020 American Society for Bone and Mineral Research.     

Feasibility and Preliminary Effectiveness of Varenicline for Treating Co-Occurring Cannabis and Tobacco Use

Few studies have evaluated treatment for co-occurring cannabis and tobacco use. The objective of this pilot study was to evaluate the feasibility and preliminary effectiveness of varenicline for co-occurring cannabis and tobacco use. Participants who reported cannabis use on ≥5 days per week were recruited from an urban, outpatient opioid treatment program (OTP). Participants were randomized to either four weeks of standard OTP clinical care (SCC; medication-assisted treatment for opioid use disorder and individual behavioral counseling), followed by four weeks of SCC plus varenicline (SCC+VT), or to four weeks of SCC+VT followed by four weeks of SCC. All participants contributed feasibility and outcome data during both study phases. Of 193 persons screened, seven were enrolled. Retention at eight weeks was 100%. No adverse effects prompted varenicline discontinuation. Participants reported lower cannabis craving during the SCC+VT phase compared to baseline, and lower frequencies and quantities of cannabis use compared to both baseline and the SCC alone phase. In the SCC+VT phase, participants also reported fewer cigarettes per day. Among persons with co-occurring cannabis and tobacco use, varenicline is well-tolerated and may reduce cannabis craving, cannabis use, and tobacco use.     

Percutaneous radiofrequency ablation for early hepatocellular carcinoma: Risk factors for survival

AIM: To evaluate outcomes of radiofrequency ablation(RFA) therapy for early hepatocellular carcinoma(HCC) and identify survival- and recurrence-related factors. METHODS: Consecutive patients diagnosed with early HCC by computed tomography(CT) or magnetic resonance imaging(MRI)(single nodule of ≤ 5 cm, or multi-(up to 3) nodules of ≤ 3 cm each) and who underwent RFA treatment with curative intent between January 2010 and August 2011 at the Instituto do Cancer do Estado de S o Paulo, Brazil were enrolled in the study. RFA of the liver tumors(with 1.0 cm ablative margin) was carried out under CT-fluoro scan and ultrasonic image guidance of the percutaneous ablation probes. Procedure-related complications were recorded. At 1-mo post-RFA and 3-mo intervals thereafter, CT and MRI were performed to assess outcomes of complete response(absence of enhancing tissue at the tumor site) or incomplete response(enhancing tissue remaining at the tumor site). Overall survival and diseasefree survival rates were estimated by the Kaplan-Meier method and compared by the log rank test or simple Cox regression. The effect of risk factors on survival was assessed by the Cox proportional hazard model. RESULTS: A total of 38 RFA sessions were performed during the study period on 34 patients(age in years: mean, 63 and range, 49-84). The mean follow-up time was 22 mo(range, 1-33). The study population showed predominance of male sex(76%), less severe liver disease(Child-Pugh A, n = 26; Child-Pugh B, n = 8), and single tumor(65%). The maximum tumor diameters ranged from 10 to 50 mm(median, 26 mm). The initial(immediately post-procedure) rate of RFAinduced complete tumor necrosis was 90%. The probability of achieving complete response was significantly greater in patients with a single nodule(vs patients with multi-nodules, P = 0.04). Two patients experienced major complications, including acute pulmonary edema(resolved with intervention) and intestinal perforation(led to death). The 1- and 2-year overall survival rates were 82% and 71%, respectively. Sex, tumor size, initial response, and recurrence status influenced survival, but did not reach the threshold of statistical significance. Child-Pugh class and the model for end-stage liver disease score were identified as predictors of survival by simple Cox regression, but only Child-Pugh class showed a statistically significant association to survival in multiple Cox regression analysis(HR = 15; 95%CI: 3-76 mo; P = 0.001). The 1-and 2-year cumulative disease-free survival rates were 65% and 36%, respectively. CONCLUSION: RFA is an effective therapy for local tumor control of early HCC, and patients with preserved liver function are the best candidates.