Genome-wide association study identifies a novel locus for cannabis dependence.

Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

Genome-wide polygenic scores for age at onset of alcohol dependence and association with alcohol-related measures.

Age at onset of alcohol dependence (AO-AD) is a defining feature of multiple drinking typologies. AO-AD is heritable and likely shares genetic liability with other aspects of alcohol consumption. We examine whether polygenic variation in AO-AD, based on a genome-wide association study (GWAS), was associated with AO-AD and other aspects of alcohol consumption in two independent samples. Genetic risk scores (GRS) were created based on AO-AD GWAS results from a discovery sample of 1788 regular drinkers from extended pedigrees from the Collaborative Study of the Genetics of Alcoholism (COGA). GRS were used to predict AO-AD, AD and Alcohol dependence symptom count (AD-SX), age at onset of intoxication (AO-I), as well as maxdrinks in regular drinking participants from two independent samples-the Study of Addictions: Genes and Environment (SAGE; n=2336) and an Australian sample (OZ-ALC; n=5816). GRS for AO-AD from COGA explained a modest but significant proportion of the variance in all alcohol-related phenotypes in SAGE. Despite including effect sizes associated with large numbers of single nucleotide polymorphisms (SNPs; >110 000), GRS explained, at most, 0.7% of the variance in these alcohol measures in this independent sample. In OZ-ALC, significant but even more modest associations were noted with variance estimates ranging from 0.03 to 0.16%. In conclusion, there is modest evidence that genetic variation in AO-AD is associated with liability to other aspects of alcohol involvement.

Evidence of CNIH3 involvement in opioid dependence.

Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.

Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample.

Smoking is a major risk factor for several somatic diseases and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Previous large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed GWA analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked and ND. Our results highlight a locus on 16p12.3, with several single-nucleotide polymorphisms (SNPs) in the vicinity of CLEC19A showing association (P<1 × 10(-6)) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention-deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1 × 10(-5)) was detected between DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Recently, a significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice and an association between NRG3 SNPs and smoking cessation success was detected in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. In conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND.

Cough sensors. I. Physiological and pharmacological properties of the afferent nerves regulating cough.

The afferent nerves regulating cough have been reasonably well defined. The selective effects of general anesthesia on C-fiber-dependent cough and the opposing effects of C-fiber subtypes in cough have led to some uncertainty about their regulation of this defensive reflex. But a role for C-fibers in cough seems almost certain, given the unique pharmacological properties of these unmyelinated vagal afferent nerves and the ability of many C-fiber-selective stimulants to evoke cough. The role of myelinated laryngeal, tracheal, and bronchial afferent nerve subtypes that can be activated by punctate mechanical stimuli, inhaled particulates, accumulated secretions, and acid has also been demonstrated. These "cough receptors" are distinct from the slowly and rapidly adapting intrapulmonary stretch receptors responding to lung inflation. Indeed, intrapulmonary rapidly and slowly adapting receptors and pulmonary C-fibers may play no role or a nonessential role in cough, or might even actively inhibit cough upon activation. A critical review of the studies of the afferent nerve subtypes most often implicated in cough is provided.

Effects of systemic administration of mirtazapine on respiratory muscle activity in sleeping rats.

Mirtazapine (MIRT) is an antidepressant with mixed noradrenergic and serotonergic effects in central nervous system. The present study was undertaken to assess whether MIRT can stimulate genioglossus muscle (GG) activity in the conscious, behaving rat. Nine male rats were chronically instrumented with GG and neck muscle EMG electrodes. EEG electrodes were implanted to acquire sleep stage. Results demonstrated a dose-dependent effect of MIRT on GG activity during sleep, although no changes reached statistical significance. Low dose MIRT (0.1 mg/kg) showed a slight increase in GG phasic activity. In contrast, higher doses of MIRT (0.5-1.0 mg/kg) tended to decrease GG activity relative to vehicle, in addition to decreasing total sleep time.

Respiratory-related evoked potential elicited in tracheostomised lung transplant patients.

The present study investigated the role of removal of upper airway and lung vagal afferents in the respiratory-related evoked potential (RREP) response to inspiratory occlusions in two patients with a tracheostomy, who had undergone double lung transplantation (DLT). The patients were 1.5 and 3 months post-DLT and surgical placement of the tracheostomy. RREP recordings in response to inspiratory occlusions were obtained under four conditions: mouth breathing ignore trial; mouth breathing attend trial; tracheostomy breathing attend trial; and tracheostomy breathing ignore trial. The RREP peak components, Nf, P1 and N1, were present in both mouth and tracheostomy ignore breathing trials. The P300 was present in both mouth and tracheostomy attend trials. RREP peak latencies were similar between conditions. The peak amplitudes were greater with mouth breathing due to greater occlusion-related inspiratory pressure. These results demonstrate that the respiratory-related evoked potential can be elicited with inspiratory occlusion in the absence of mouth, upper airway and lung vagal afferent input. This suggests that inspiratory occlusion can elicit cortical activity with activation of inspiratory pump mechanoreceptors.

Movement of finger joints induced by synergistic wrist motion.

BACKGROUND: An experiment has recently been conducted to evaluate and compare the differences in tendon excursions between the flexor digitorum profundus and superficialis using three mobilization techniques. No previous studies deal with the total joint excursions with constant tendon length. The purpose of this study was to investigate the coordinated motion between the finger and wrist joints resulting from passive tension of the muscles while performing synergistic wrist motion. METHODS: The relative joint positions of the hand and wrist were measured using a three-dimensional motion analysis system with external retroreflective markers 2 mm in diameter placed on the dorsal surface of the hand. Fifty normal subjects, with a 1:1 gender ration, ranging in age from 20 to 40 years, and with no previous history of upper extremity injury, were recruited for the experiment. FINDINGS: The relationships of synergistic motion between the wrist and finger joints due to passive tension in the muscles were approximately linear. The ranges of wrist motion averaged 60 degrees extension and 60 degrees flexion. Moving the wrist from flexion into extension induced synergistic finger joint motion as follows: the distal interphalangeal joint angles changed from an average of 12 degrees of flexion to 31 degrees; proximal-interphalangeal joint angles changed from 19 degrees to 70 degrees; and metacarpal phalangeal joints changed from 27 degrees to 63 degrees of flexion. INTERPRETATION: The relationships of synergistic motion between the wrist and finger joints were systematically documented. Such a relationship could be considered in optimizing the design of dynamic splints used for rehabilitation in post-surgical tendon repair, as well as providing useful information about potential diagnoses of problems with the integrity of the flexor and extensor mechanisms.

Elbow load with various forearm positions during one-handed pushup exercise.

This is the first study of the one-handed pushup, and tries to show the effects of forearm rotations. Previous studies of elbow loading have focused on passive loading and small loads, because data from large loads during active exercise is not easy to obtain. In order to investigate the biomechanical impact of hand position on the elbow and the potential trauma mechanisms of outstretched elbow, joint loading across the elbow was analyzed for three forearm rotational positions, neutral, 90 degrees internal rotation and 90 degrees external rotation. Both kinematic and kinetic data were collected from eight volunteers by the Motion Analysis System and a Kistler Force Plate. Statistical analysis of the data delineates the relationship between elbow joint load and hand rotational position during one-handed pushup, and also provides useful biomechanical information for this challenging exercise. The axial and valgus stresses and forces are the major concerns. The peak axial forces exerted on the elbow joint averaged 65 % of the body weight when the hand position was neutral, and was significantly reduced with the hand rotated either internally or externally. The peak valgus shear force with the hand externally rotated was 50 % greater than the other two positions. Thus, outward rotation of the hand is a stressful position that should be avoided during one-handed pushup exercise or forward falls with outstretched hands in order to reduce the risk of elbow injuries.

Effect of elbow flexion on upper extremity impact forces during a fall.

OBJECTIVE: The overall objectives are to develop a biomechanical model for a simulated fall with outstretched hand. DESIGN: Cross-sectional study involving young healthy volunteers in a university research laboratory setting. BACKGROUND: Little is known about the factors which influence fracture risk during a fall on outstretched hand. METHODS: A group of 11 male subjects volunteered for this investigation. A set of eight reflective markers was placed bilaterally on selected anatomic landmarks. Subjects were suspended with both elbows extended and wrists dorsiflexed, preparing to impact the ground and force plates from two different fall heights: 3 and 6 cm. Two different postures for the elbows were employed. In the elbow extension experiment, the elbows were extended at all times. In the elbow flexion experiment, the elbows were extended at impact, but then flexed immediately, as though in the initial downward phase of a push-up exercise. RESULT: Increasing the fall height significantly increased the upper extremity axial forces by 10% and 5%. No significantly different differences were found in the axial forces applied to the wrist, elbow or shoulder between the elbow flexion and elbow extension trials, but the elbow mediolateral shear force was 68% larger (P=0.002) in the extension trials. CONCLUSIONS: Performing an elbow flexion movement at impact reduces the first peak impact force value and postpones the maximum peak value. Although changing the fall arrest strategy from elbow extension to elbow flexion did not affect the peak impact force on the hand, it did require substantially greater elbow and shoulder muscle strengths. RELEVANCE: This paper yields insights into how the physical demands of arresting mild falls may relate to upper extremity muscle capacity, joint dislocation and bony fracture.

The effect of changing the foot progression angle on the knee adduction moment in normal teenagers.

The effect of changing the foot progression angle on the peak knee adduction moment (KAM) during stance was investigated in 48 teenagers. They underwent gait analysis when walking in three different postures: normal walking, intentional in-toeing, and intentional out-toeing. The peak KAM when in-toeing was the highest and was statistically different from that seen in the normal walking or in the out-toeing posture. These findings may have clinical significance in adult life.

The effect of magnitudes and duration of pressure on cerebral cortex in a rat model.

The aim of this biomechanical study was to investigate the pressure-time-damage relationship on the cerebral cortex using a rat model. During brain surgery, additional cortical injuries induced by traction have been an important clinical issue. A total of 84 rats underwent a unilateral craniectomy, and conduction by hydrostatic pressure loading through a modified central venous pressure device with various combinations of magnitudes ranging from 0.5 to 10 cm H2O and duration from 0.5 to 20 minutes was then performed. Histopathological examination has exhibited three patterns of clustered, spotted damaged neurons and undamaged neuron. Two best-fitted exponential curves were derived from the data to establish the damaged, critical and tolerable loadings responsible for the neuron viability. This research provides information to enhance understanding of the additional cortex injuries induced by traction. Furthermore, the results may have implications in providing clinical guidance and/or development of alarm systems for minimising cortical damage during surgery.

Elbow load during pushup at various forearm rotations.

OBJECTIVE: Elbow joint loading was evaluated during pushup exercises at various forearm rotations. DESIGN: Subjects were asked to perform pushup in various forearm rotations: neutral, 90 degrees internal rotation, and 90 degrees external rotation. BACKGROUND: Training with pushup exercise is good for the muscles and joints of the upper extremities. However, excessive shear forces on the elbow might lead to injuries to either normal trainees or to handicapped people, especially for those who rely on elbow prosthesis. METHODS: The kinematics and kinetics of the elbow joint were investigated under various forearm rotations. RESULTS: The loading biomechanics of the elbow joint differed with various forearm rotations. It was noted that greater posterior and varus forces of the elbow are encountered with internal rotation of the hand position and, consequently, full forearm pronation. CONCLUSIONS: Pushup with hands in internally rotated position should be prevented so as to avoid excessive shear forces or moments. RELEVANCE: Knowledge of elbow kinematics and kinetics may be helpful in preventing injuries by reducing the elbow shear force with changes of forearm rotation.

Correlating factors and clinical significance of flexible flatfoot in preschool children.

To elucidate the correlating factors and clinical significance of flexible flatfoot (FF) in preschool children of Taiwan, a cross-sectional study was conducted in a research laboratory equipped with a gait analysis facility. Altogether, 377 preschool children (201 boys, 176 girls), ranging in age from 2 to 6 years, were enrolled in this investigation. The results show that age, height, weight, foot progression angle, occurrence of physical knock-knee, and joint laxity score correlate with FF. Children with FF, compared with children without, performed physical tasks poorly and walked slowly, as determined by gait parameters. The FF should not simply be regarded as a problem of static alignment of the ankle and foot complex, but may be the consequence of a dynamic functional change of the lower extremity. Better understanding of the correlating factors and the clinical relevance of FF may prove helpful in deciding on the most appropriate treatment for a particular patient.

Sit-to-stand at different periods of pregnancy.

OBJECTIVE: This study was performed to determine the biomechanics of chair rising by pregnant women. DESIGN: Relative body joint position and ground reaction forces were measured by a motion analysis system and one force plate. BACKGROUND: Physiological and psychological changes during pregnancy impose postural demands and limit the performance of daily living activities such as rising from sitting to standing position. METHODS: Twenty-four pregnant women, divided into three groups, were studied performing sit-to-stand transition from an armless and adjustable chair. By kinematic and kinetic analysis, the angles and moments of hip, knee and ankle joints were investigated. RESULTS: The chair height has great influence on knee joint and hip joint moments, but less on ankle joints. In the third trimester for all chair heights, because of a marked increase in abdominal depth, the maximum hip moment is significantly less than that in first trimester, while the maximum knee moment is significantly larger. Pregnant women in third trimester produced larger knee moment during sit-to-stand transition from lower chair height. CONCLUSIONS: The mechanism of sit-to-stand is affected by the physical changes of pregnant women at different periods of pregnancy, e.g. increased loading of knee joint and decreased hip joint moment, especially in the last trimester period of pregnancy.

Multiple actinomyces brain abscesses: case report.

A case of multiple cerebral abscesses caused by actinomyces is reported in a 37 year old male with mucoepidermoid carcinoma of the right lung. In conjunction with penicillin, sulfonamide and erythromycin, the patient underwent stereotactic surgery for aspiration of the brain abscesses under (CT). The bacteria, considered to originate from the right lung, were identified from the abscess material obtained at surgery. Using proper therapy to control infection and intracranial pressure is important. A lon g term follow up with frequent computerised tomography evaluation has been conducted and the patient outcome has been successful recovery.

Incidence of transitional cell carcinoma and arsenic in drinking water: a follow-up study of 8,102 residents in an arseniasis-endemic area in northeastern Taiwan.

A significant association between ingested arsenic and bladder cancer has been reported in an arseniasis-endemic area in southwestern Taiwan, where many households share only a few wells in their villages. In another arseniasis-endemic area in northeastern Taiwan, each household has its own well for obtaining drinking water. In 1991-1994, the authors examined risk of transitional cell carcinoma (TCC) in relation to ingested arsenic in a cohort of 8,102 residents in northeastern Taiwan. Estimation of each study subject's individual exposure to inorganic arsenic was based on the arsenic concentration in his or her own well water, which was determined by hydride generation combined with atomic absorption spectrometry. Information on duration of consumption of the well water was obtained through standardized questionnaire interviews. The occurrence of urinary tract cancers was ascertained by follow-up interview and by data linkage with community hospital records, the national death certification profile, and the cancer registry profile. Cox proportional hazards regression analysis was used to estimate multivariate-adjusted relative risks and 95% confidence intervals. There was a significantly increased incidence of urinary cancers for the study cohort compared with the general population in Taiwan (standardized incidence ratio = 2.05; 95% confidence interval (CI): 1.22, 3.24). A significant dose-response relation between risk of cancers of the urinary organs, especially TCC, and indices of arsenic exposure was observed after adjustment for age, sex, and cigarette smoking. The multivariate-adjusted relative risks of developing TCC were 1.9, 8.2, and 15.3 for arsenic concentrations of 10.1-50.0, 50.1-100, and >100 microg/liter, respectively, compared with the referent level of < or =10.0 microg/liter.

Potential of the genetic algorithm neural network in the assessment of gait patterns in ankle arthrodesis.

The aim of this study was to develop an empirical model of parameter-based gait data, based on an artificial neural network and a genetic algorithm, for the assessment of patients after ankle arthrodesis. Ground reaction force vectors were measured by force platforms during level walking. Nine force parameters expressed in percentage of body weight and their chronologic incidence of occurrence expressed in percentage of stance phase period were used in modeling. Ten healthy persons and ten patients who had solid arthrodesis of the ankle were recruited in this study for developing the model. By applying the genetic algorithm neural network, the percentage of correct classification was 98.8% and the subset of discriminant parameters was be reduced to 9 out of 18. These key parameters were mainly related to the loading response and propulsive phase. This indicates that there was a reduction in the abilities in cushion impact and push off in the patients after ankle arthrodesis. Finally, the relative distance (Dr) was defined in this study and used in two new patients' examinations to demonstrate its clinical utility.

Fatal and non-fatal chromobacterial septicemia: report of two cases.

Chromobacterium violaceum is frequently found in soil and water in tropical and subtropical regions. The organism rarely causes infection in humans, but is associated with a high mortality rate when it occurs. Septicemia associated with abscess in multiple organs such as the liver, skin, lungs, spleen, lymph nodes, and brain has been reported. We report on 2 patients with systemic infections with Chromobacterium violaceum. One presented with a fulminant course with multiple organ involvement and died 78 days later. The other presented with a milder course and survived after antibiotic therapy. In conclusion, infection with Chromobacterium violaceum is rare but its course is usually fulminant with high mortality especially in patients with sepsis and multiple organ involvement. We hope this report will provide additional information to physicians in the treatment of this disease.