74 research outputs found
Poloxomer 188 Has a Deleterious Effect on Dystrophic Skeletal Muscle Function
Duchenne muscular dystrophy (DMD) is an X-linked, fatal muscle wasting disease for which there is currently no cure and limited palliative treatments. Poloxomer 188 (P188) is a tri-block copolymer that has been proposed as a potential treatment for cardiomyopathy in DMD patients. Despite the reported beneficial effects of P188 on dystrophic cardiac muscle function, the effects of P188 on dystrophic skeletal muscle function are relatively unknown. Mdx mice were injected intraperitoneally with 460 mg/kg or 30 mg/kg P188 dissolved in saline, or saline alone (control). The effect of single-dose and 2-week daily treatment was assessed using a muscle function test on the Tibialis Anterior (TA) muscle in situ in anaesthetised mice. The test comprises a warm up, measurement of the force-frequency relationship and a series of eccentric contractions with a 10% stretch that have previously been shown to cause a drop in maximum force in mdx mice. After 2 weeks of P188 treatment at either 30 or 460 mg/kg/day the drop in maximum force produced following eccentric contractions was significantly greater than that seen in saline treated control mice (P = 0.0001). Two week P188 treatment at either dose did not significantly change the force-frequency relationship or maximum isometric specific force produced by the TA muscle. In conclusion P188 treatment increases susceptibility to contraction-induced injury following eccentric contractions in dystrophic skeletal muscle and hence its suitability as a potential therapeutic for DMD should be reconsidered
Current Status of Pharmaceutical and Genetic Therapeutic Approaches to Treat DMD
Duchenne muscular dystrophy (DMD) is a genetic disease affecting about one in every 3,500 boys. This X-linked pathology is due to the absence of dystrophin in muscle fibers. This lack of dystrophin leads to the progressive muscle degeneration that is often responsible for the death of the DMD patients during the third decade of their life. There are currently no curative treatments for this disease but different therapeutic approaches are being studied. Gene therapy consists of introducing a transgene coding for full-length or a truncated version of dystrophin complementary DNA (cDNA) in muscles, whereas pharmaceutical therapy includes the use of chemical/biochemical substances to restore dystrophin expression or alleviate the DMD phenotype. Over the past years, many potential drugs were explored. This led to several clinical trials for gentamicin and ataluren (PTC124) allowing stop codon read-through. An alternative approach is to induce the expression of an internally deleted, partially functional dystrophin protein through exon skipping. The vectors and the methods used in gene therapy have been continually improving in order to obtain greater encapsidation capacity and better transduction efficiency. The most promising experimental approaches using pharmaceutical and gene therapies are reviewed in this article
Matrilineal behavioral and physiological changes following the death of a non-alpha matriarch in rhesus macaque
In many species, the loss of alpha matriarchs is associated with a number of negative outcomes such as troop fission, eviction, wounding, and reduced vitality. However, whether
the dramatic consequences of their loss are due to their role as an old experienced figure or
to their alpha status remains unclear. In a retrospective study, we tested that in a semi-free
ranging colony of rhesus macaques (Macaca mulatta), the removal of a non-alpha matriarch, who had a large set of kin, led to changes in behavior and physiological stress within
her matriline. Following her removal, her matriline increased in aggression, vigilance, and
social grooming. Additionally, hierarchical stability, measured by levels of rank changes,
decreased within her matriline, and levels of intense aggression by high-ranking animals
were more frequent, as well as matrilineal wounding. Although ordinal rank was positively
associated with higher chronic hair cortisol concentrations (HCCs) in the months before the
matriarch’s removal, following her removal, only those who experienced large increases in
rank within her matriline displayed higher HCCs. Changes in matrilineal stability, aggression, behavior, and HCCs within the other two matrilines in the troop were not evident,
although caution is needed due to the small sample sizes. We conclude that the removal of
the non-alpha matriarch led to matrilineal instability, characterized by higher levels of
aggression and subsequent vigilance, rank changes, physiological stress, and grooming.
We suggest that non-alpha matriarchs with a large number of kin and social support can be
integral to the stability of matrilines.Division of Intramural Research, National Institute of Child Health and Human Development, 1ZIAHD001107- 3
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Potential antidepressant overtreatment associated with office use of brief depression symptom measures.
BackgroundUse of brief depression symptom measures for identifying or screening cases may help to address depression undertreatment, but whether it also leads to diagnosis and treatment of patients with few or no symptoms-a group unlikely to have major depression or benefit from antidepressants-is unknown. We examined the associations of use of a brief depression symptom measure with depression diagnosis and antidepressant recommendation and prescription among patients with few or no depression symptoms.MethodsWe conducted exploratory observational analyses of data from a randomized trial of depression engagement interventions conducted in primary care offices in California. Analyses focused on participants scoring <10 on a study-administered 9-item Patient Health Questionnaire (PHQ-9) (completed immediately before an office visit and not disclosed to the provider) with complete chart review data (n = 595). We reviewed visit notes for evidence of practice administration of a brief symptom measure (independent of the trial) and whether the provider (1) diagnosed depression or (2) recommended and/or prescribed an antidepressant.ResultsAmong the 545 patients without a practice-administered measure, 57 (10.5%) had a visit diagnosis of depression; 9 (1.6%) were recommended and another 21 (3.8%) prescribed an antidepressant. Among the 50 patients (8.4% of total sample) with a practice-administered measure, 10 (20%) had a visit diagnosis of depression; 6 (12%) were recommended and another 6 (12%) prescribed an antidepressant. Adjusting for nesting within providers, trial intervention, stratification variables, and sample weighting, use of a brief symptom measure was associated with depression diagnosis (adjusted odds ratio, 3.2; 95% confidence interval, 1.1-9.2) and antidepressant recommendation and/or prescription (adjusted odds ratio, 3.80; 95% confidence interval, 1.0-13.9). Analyses using progressively lower PHQ-9 thresholds (<9 to <5) and examining antidepressant prescription alone yielded consistent findings. Analyses by practice-administered measure (PHQ-9 vs PHQ-2) indicated the study findings were largely associated with PHQ-9 use.ConclusionsThese exploratory findings suggest administration of brief depression symptom measures, particularly the PHQ-9, may be associated with depression diagnosis and antidepressant recommendation and prescription among patients unlikely to have major depression. If these findings are confirmed, researchers should investigate the balance of benefits and risks (eg, overdiagnosis of depression and overtreatment with antidepressants) associated with use of a brief symptom measure
Recommended from our members
Potential antidepressant overtreatment associated with office use of brief depression symptom measures.
BackgroundUse of brief depression symptom measures for identifying or screening cases may help to address depression undertreatment, but whether it also leads to diagnosis and treatment of patients with few or no symptoms-a group unlikely to have major depression or benefit from antidepressants-is unknown. We examined the associations of use of a brief depression symptom measure with depression diagnosis and antidepressant recommendation and prescription among patients with few or no depression symptoms.MethodsWe conducted exploratory observational analyses of data from a randomized trial of depression engagement interventions conducted in primary care offices in California. Analyses focused on participants scoring <10 on a study-administered 9-item Patient Health Questionnaire (PHQ-9) (completed immediately before an office visit and not disclosed to the provider) with complete chart review data (n = 595). We reviewed visit notes for evidence of practice administration of a brief symptom measure (independent of the trial) and whether the provider (1) diagnosed depression or (2) recommended and/or prescribed an antidepressant.ResultsAmong the 545 patients without a practice-administered measure, 57 (10.5%) had a visit diagnosis of depression; 9 (1.6%) were recommended and another 21 (3.8%) prescribed an antidepressant. Among the 50 patients (8.4% of total sample) with a practice-administered measure, 10 (20%) had a visit diagnosis of depression; 6 (12%) were recommended and another 6 (12%) prescribed an antidepressant. Adjusting for nesting within providers, trial intervention, stratification variables, and sample weighting, use of a brief symptom measure was associated with depression diagnosis (adjusted odds ratio, 3.2; 95% confidence interval, 1.1-9.2) and antidepressant recommendation and/or prescription (adjusted odds ratio, 3.80; 95% confidence interval, 1.0-13.9). Analyses using progressively lower PHQ-9 thresholds (<9 to <5) and examining antidepressant prescription alone yielded consistent findings. Analyses by practice-administered measure (PHQ-9 vs PHQ-2) indicated the study findings were largely associated with PHQ-9 use.ConclusionsThese exploratory findings suggest administration of brief depression symptom measures, particularly the PHQ-9, may be associated with depression diagnosis and antidepressant recommendation and prescription among patients unlikely to have major depression. If these findings are confirmed, researchers should investigate the balance of benefits and risks (eg, overdiagnosis of depression and overtreatment with antidepressants) associated with use of a brief symptom measure
Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment
Objective: We examined the serological, virological (in serum and liver) and histological profiles in chronic hepatitis B virus (HBV) patients during and after completion of multiple dose (MD) ARC-520. Design: The present phase 1b study was a multidose, open-label extension cohort of patients that had received single dose ARC-520 in our previous study. Eight patients received 4-9 4 weekly doses of MD ARC-520 and entecavir. Liver biopsies were performed in six patients. Intrahepatic and serum HBV DNA, HBV RNA and viral antigens were measured. Results: All patients had 28.9-30.4 months of follow-up after the last MD. All three hepatitis B e antigen (HBeAg)-positive patients had profound reductions in hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen and HBV RNA with two undergoing HBeAg seroconversion. One further achieved HBsAg seroconversion (anti-HBs level of 25.1 IU/L) and the remaining two had HBsAg reductions of -1.7 and -3.5 log IU/mL >30 months after MD. Among the five HBeAg-negative patients, four had modest HBsAg reduction >29 months after completion of MD and one achieved HBsAg seroconversion (anti-HBs level of 152.5 IU/L) and was negative for liver HBsAg staining. Entecavir was successfully stopped in this patient 12 months after HBsAg seroconversion. Temporally related alanine aminotransferase elevations preceded by HBsAg reductions were observed in three patients suggesting immune activation. HBcAg staining was negative in all six biopsied patients. Two patients with <10% HBsAg positive staining of hepatocytes had correspondingly low serum HBsAg levels of 1.5 and 11.5 IU/mL. Conclusions: MD ARC-520 therapy achieved sustained and profound reductions of viral antigens and HBV RNA. HBsAg seroclearance was achievable. Trial registration number: NCT02065336
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