Occupational exposures and movement abnormalities among Japanese-American men: the Honolulu-Asia Aging Study

OBJECTIVE: The authors analyzed data on 1,049 men aged 71-93 years (excluding those with prevalent Parkinson's disease and stroke) from the Honolulu Heart Program (1965-1968) and the Honolulu-Asia Aging Study (1991-1999) to determine whether occupational exposures to pesticides, solvents, metals, manganese, and mercury during middle age were associated with 14 movement abnormalities 25 years later. METHODS: Analyses of variance and multivariate logistic regression were used to assess associations of interest. RESULTS: After adjustment for age, BMI, cognitive functioning, smoking, alcohol drinking, education, and physical activity, there was a positive association between abnormal 'facial expression' and the highest exposure to metals [odds ratio (OR) = 2.62; 95% confidence interval (CI) = 1.35-5.11; trend, p = 0.02], and the highest exposure to mercury (OR = 1.91; 95% CI = 1.04-3.49; trend, p = 0.03). Age was positively associated with all movement abnormalities, and cognitive function, body mass index and physical activity were inversely associated with most movement abnormalities. CONCLUSION: Higher exposure to any metal, and specifically mercury, was associated with abnormal facial expression.     

RETURN OF NORMAL GAIT AS AN OUTCOME MEASUREMENT IN ACL RECONSTRUCTED PATIENTS. A SYSTEMATIC REVIEW

Background:

Current clinical outcome measurements may overestimate the long term success of anterior cruciate ligament reconstruction (ACLR). There is a need to understand biomechanics of the knee joint during daily activities. This systematic review provides a comprehensive overview of the literature related to gait in patients following ACLR. The purpose of this systematic review was to investigate the available literature and provide a comprehensive overview of kinematic and kinetic variables that present during gait in patients after ACLR.

Methods:

A literature search was performed in AMED, CINAHL, EMBASE, Medline and Scopus between January 2000 and October 2012. Inclusion criteria included articles written in English, German or Dutch, and those reporting on gait analysis in patients after ACLR. Kinematic and/or kinetic data of the uninjured and ACLR knee and healthy controls (CTRL) were outcome measurements of interest. Each study''s methodological quality was assessed using the Critical Appraisal Skills Programme critical appraisal tool.

Results:

Twenty two studies fulfilled the inclusion criteria. A total of 479 patients with a mean age of 27.3 were examined. Time between the injury and surgery and ranged from 3 weeks to 5.7 years. Gait analysis was done at a mean of 29.3 months after surgery. Gait was found to be altered in the sagittal, frontal and transverse planes after ACLR and may take months or years to normalize, if normalization occurs at all.

Conclusion:

Patients after ACLR have altered gait patterns that can persist for up to five years after surgery. It is imperative that rehabilitation techniques are examined in order to minimize changes in knee biomechanics during gait, as they have the potential to impact on the development of osteoarthritis.

Level of evidence:

3a     

Comparative effects of sodium channel blockers in short term rat whole embryo culture

This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the l-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the l-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3 h.     

Treatment Motivation and Therapeutic Engagement in Prison-Based Substance Use Treatment

Abstract

Studies of community-based substance use treatment show that motivation for treatment is critical for clients becoming therapeutically engaged. Little research, however, has been conducted on therapeutic engagement in corrections-based substance use treatment. The current study examines the association between internal treatment motivation and therapeutic engagement for a sample of 220 male substance-using offenders enrolled in a corrections-based treatment program. Findings showed that problem recognition and desire for help were associated with cognitive indicators of therapeutic engagement, specifically confidence in and commitment to treatment. Increased focus on internal motivation for treatment may lead to more effective treatment for substance-using offenders. Pretreatment motivational interventions therefore are recommended for substance-using offenders with low internal motivation for treatment.     

Factors Predicting Unmet Health Services Needs Among Incarcerated Substance Users

Negative health consequences of illicit drug use, such as cardiovascular complications and infectious diseases, increase the likelihood of the need for health care. However, evidence suggests that, with the exception of emergency services, drug users generally are medically underserved. Furthermore, the effect of illicit drug use on health care utilization is becoming an especially important issue for the criminal justice system, because an increasing proportion of inmates in correctional institutions have a history of drug use. This 1998–1999 study of 661 incarcerated men in the Kentucky prison system focused on predictors of unmet physical, behavioral, and overall health care needs among chronic substance users. Analyses revealed that White incarcerated drug users were more likely to report unmet physical and overall health care needs than non-Whites and those with high school education or above were more likely to report unmet physical, behavioral, and overall health care needs. In addition, more episodes of serious illness, more mental health problems, and poorer self-rated health were predictive of all three types of unmet health care needs. A longer career of drug use emerged as a significant predictor of unmet behavioral health care needs, whereas more frequent drug use in the year before incarceration predicted unmet physical health care needs. Further research directions and implications for in-prison health care planning are discussed.     

Role of aberrant PI3K pathway activation in gallbladder tumorigenesis

The PI3K/AKT pathway governs a plethora of cellular processes, including cell growth, proliferation, and metabolism, in response to growth factors and cytokines. By acting as a unique lipid phosphatase converting phosphatidylinositol-3,4,5,-trisphosphate (PIP3) to phosphatidylinositol-4,5,-bisphosphate (PIP2), phosphatase and tensin homolog (PTEN) acts as the major cellular suppressor of PI3K signaling and AKT activation. Recently, PI3K mutations and loss/mutation of PTEN have been characterized in human gallbladder tumors; whether aberrant PTEN/PI3K pathway plays a causal role in gallbladder carcinogenesis, however, remains unknown. Herein we show that in mice, deregulation of PI3K/AKT signaling is sufficient to transform gallbladder epithelial cells and trigger fully penetrant, highly proliferative gallbladder tumors characterized by high levels of phospho-AKT. Histopathologically, these mouse tumors faithfully resemble human adenomatous gallbladder lesions. The identification of PI3K pathway deregulation as both an early event in the neoplastic transformation of the gallbladder epithelium and a main mechanism of tumor growth in Pten heterozygous and Pten mutant mouse models provides a new framework for studying in vivo the efficacy of target therapies directed against the PI3K pathway, as advanced metastatic tumors are often addicted to “trunkular” mutations.     

Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma

Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within two years of diagnosis. The available data suggest that simultaneous inactivation of critical nodes within the glioblastoma molecular circuitry will be required for meaningful clinical efficacy. We conducted parallel genome-wide shRNA screens to identify such nodes and uncovered a number of G-Protein Coupled Receptor (GPCR) neurotransmitter pathways, including the Dopamine Receptor D2 (DRD2) signaling pathway. Supporting the importance of DRD2 in glioblastoma, DRD2 mRNA and protein expression were elevated in clinical glioblastoma specimens relative to matched non-neoplastic cerebrum. Treatment with independent si-/shRNAs against DRD2 or with DRD2 antagonists suppressed the growth of patient-derived glioblastoma lines both in vitro and in vivo. Importantly, glioblastoma lines derived from independent genetically engineered mouse models (GEMMs) were more sensitive to haloperidol, an FDA approved DRD2 antagonist, than the premalignant astrocyte lines by approximately an order of magnitude. The pro-proliferative effect of DRD2 was, in part, mediated through a GNAI2/Rap1/Ras/ERK signaling axis. Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models. Our results suggest combined EGFR and DRD2 inhibition as a promising strategy for glioblastoma treatment.