AAV2-mediated delivery of human neurturin to the rat nigrostriatal system: long-term efficacy and tolerability of CERE-120 for Parkinson's disease

Neurturin (NTN) is a neurotrophic factor with known potential to protect and restore the function of dopaminergic substantia nigra neurons whose degeneration has been most closely linked to the major motor deficits in Parkinson's disease (PD). CERE-120, an adeno-associated virus serotype 2 (AAV2)-based gene delivery vector encoding human NTN, is being developed as a potential therapeutic for PD. In a series of preclinical studies reported herein, CERE-120 delivery to the striatum produced a dose-related neuroprotection of nigrostriatal neurons in the rat 6-hydroxydopamine (6-OHDA) lesion model. Long-lasting efficacy of CERE-120 was evidenced by substantia nigra cell protection, preserved fiber innervation of the striatum, and behavioral recovery for at least 6 months. In addition, striatal infusion of CERE-120 was found to have a safety and tolerability profile devoid of side effects or toxicological responses, for at least 12 months post-treatment, even at dose multiples 125 times that of the lowest efficacious dose tested. These results support the ongoing CERE-120 clinical program in PD patients.     

Binge eating disorder: a stable syndrome

OBJECTIVE: This study assessed the stability of binge eating disorder in a community sample. METHOD: The authors interviewed 888 first-degree relatives of 300 overweight or obese probands (150 with binge eating disorder and 150 with no lifetime eating disorder) who were recruited during a family study. They compared the total duration of illness among relatives with lifetime diagnoses of binge eating disorder (N=131), bulimia nervosa (N=17), and anorexia nervosa (N=18). RESULTS: The mean lifetime duration of binge eating disorder was 14.4 years (SD=13.9), significantly longer than for either bulimia nervosa (mean=5.8 years, SD=9.1) or anorexia nervosa (mean=5.9 years, SD=7.4). These differences changed little when analysis was restricted to female relatives or to relatives of the probands with no lifetime eating disorder. CONCLUSIONS: These findings suggest that binge eating disorder is at least as chronic as the well-validated disorders anorexia nervosa and bulimia nervosa and likely represents a stable syndrome.     

Emphysematous pyelonephritis successfully treated with laparoscopic nephrectomy

Emphysematous pyelonephritis is a severe life-threatening infection which continues to carry significant morbidity and mortality. We present a case recently managed at our institution by laparoscopic nephrectomy. The patient survived, and in comparison to some of the more conventionally managed patients in the literature, made an extremely speedy recovery. We would advocate this option to be seriously considered when patients are suitable and appropriately trained surgeons are available.     

Risk and resilience: Genetic and environmental influences on development of the stress response

Exposure to stressful events during development has consistently been shown to produce long‐lasting alterations in the hypothalamic‐pituitary‐adrenal (HPA) axis, which may increase vulnerability to disease, including posttraumatic stress disorder and other mood and anxiety disorders. Recently reported genetic association studies indicate that these effects may be mediated, in part, by gene×environment interactions involving polymorphisms within two key genes, CRHR1 and FKBP5. Data suggest that these genes regulate HPA axis function in conjunction with exposure to child maltreatment or abuse. In addition, a large and growing body of preclinical research suggests that increased activity of the amygdala‐HPA axis induced by experimental manipulation of the amygdala mimics several of the physiological and behavioral symptoms of stress‐related psychiatric illness in humans. Notably, interactions between the developing amygdala and HPA axis underlie critical periods for emotional learning, which are modulated by developmental support and maternal care. These translational findings lead to an integrated hypothesis: high levels of early life trauma lead to disease through the developmental interaction of genetic variants with neural circuits that regulate emotion, together mediating risk and resilience in adults. Depression and Anxiety Depression and Anxiety 26:984–992, 2009. Published 2009 Wiley‐Liss, Inc.     

Long-term Vaginal Sequelae Secondary to Pediatric Pelvic Fracture

BackgroundPediatric pelvic fractures often appear radiographically benign despite significant injury to viscera. Vaginal injuries are rare, and therefore require a high index of suspicion.CaseA 26-year-old female patient who sustained a pelvic fracture in a motorcycle accident at the age of 10 presented with vaginal stenosis precluding sexual intercourse. Patient menstruated through a fistula in the distal vaginal vault. Radiographic and dye studies showed almost complete vaginal obstruction with heterotopic ossification. An extensive 30-year review of the literature was conducted looking for documented cases of vaginal injuries secondary to pelvic injury.Summary and ConclusionThis is the only recorded case of a long-term vaginal complication with subsequent heterotopic ossification secondary to pelvic fracture. Preventing debilitating long-term sequelae from vaginal injuries requires close patient follow-up and age-appropriate assessments.     

Open-label study of s-citalopram therapy of chronic fatigue syndrome and co-morbid major depressive disorder

OBJECTIVE: Chronic fatigue syndrome (CFS) is a debilitating disorder with prominent symptoms of malaise, fatigue, myalgia, arthralgia, and impaired concentration. The symptoms of CFS may often overlap those of Major Depressive Disorder (MDD). Treatment of CFS has generally been disappointing. We hypothesized that s-citalopram therapy may improve the symptoms of both disorders in CFS patients with co-morbid depression. METHODS: 16 patients received s-citalopram 10 mg to 20 mg daily for up to 12 weeks. Outcome measures of CFS included the Chalder Fatigue Questionnaire (CFQ), the multi-dimensional Fatigue Impact Scale (FIS), the CFS symptom rating (CFS-SR) 100 mm visual analogue scale, and the clinical global impressions severity (CGI/S) and change (CGI/C) ratings. Secondary outcomes of MDD included the Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and the CGI/S and CGI/C ratings of MDD. RESULTS: We observed reductions in the mean CFQ score (p<0.0005), FIS score (p<0.0005), and CGI/S (p<0.0005) and CGI/C (p<0.0005) ratings over time. There was a significant improvement in 5 of the 8 CFS-SR symptoms: post-exertion malaise (p=0.001), headaches (p<0.0005), un-refreshing sleep (p<0.0005), and impaired memory and concentration (p<0.0005). There was also a reduction in mean HAM-D (p<0.0005), BDI (p<0.0005), CGI/S (p=0.001) and CGI/C (p<0.0005) ratings of MDD. LIMITATIONS: The sample size was limited and the study design was not double-blind or placebo controlled. CONCLUSION: We observed a significant reduction in both CFS and co-morbid MDD symptom severity ratings, and improvement in 5 of 8 core somatic symptoms of CFS during s-citalopram therapy.     

The integrate model of emotion, thinking and self regulation: an application to the "paradox of aging"

This study was undertaken using the INTEGRATE Model of brain organization, which is based on a temporal continuum of emotion, thinking and self regulation. In this model, the key organizing principle of self adaption is the motivation to minimize danger and maximize reward. This principle drives brain organization across a temporal continuum spanning milliseconds to seconds, minutes and hours. The INTEGRATE Model comprises three distinct processes across this continuum. Emotion is defined by automatic action tendencies triggered by signals that are significant due to their relevance to minimizing danger-maximizing reward (such as abrupt, high contrast stimuli). Thinking represents cognitive functions and feelings that rely on brain and body feedback emerging from around 200 ms post-stimulus onwards. Self regulation is the modulation of emotion, thinking and feeling over time, according to more abstract adaptions to minimize danger-maximize reward. Here, we examined the impact of dispositional factors, age and genetic variation, on this temporal continuum. Brain Resource methodology provided a standardized platform for acquiring genetic, brain and behavioral data in the same 1000 healthy subjects. Results showed a "paradox" of declining function in the "thinking" time scale over the lifespan (6 to 80+ years), but a corresponding preservation or even increase in automatic functions of "emotion" and "self regulation". This paradox was paralleled by a greater loss of grey matter in cortical association areas (assessed using MRI) over age, but a relative preservation of subcortical grey matter. Genetic polymorphisms associated with both healthy function and susceptibility to disorder (including the BDNFVal(66)Met, COMTVal(158/108)Met, MAOA and DRD4 tandem repeat and 5HTT-LPR polymorphisms) made specific contributions to emotion, thinking and self regulatory functions, which also varied according to age.