The CLOCK gene and mood disorders: a case-control study and meta-analysis

The clock gene (CLOCK) is considered to be a good candidate gene for the pathophysiology of mood disorders, including bipolar disorder (BP) and major depressive disorder (MDD). rs1801260 (T3111C) has been detected at position 3111 in the CLOCK mRNA 3' untranslated region, and was reported to be associated with a substantial delay in preferred timing for activity and sleep in a human study. As for function, rs1801260 has been speculated to affect mRNA. Therefore, the authors investigated the association between the three tagging single-nucleotide polymorphisms (SNPs) (rs3736544, rs1801260, and rs3749474) in CLOCK and risk of BP (n=867) and MDD (n=139) compared to controls (n=889) in the Japanese population. In addition, we also performed an updated meta-analysis of nine published, genetic association studies investigating the relationship between rs1801260 and mood disorder risk, comprising 3321 mood disorders cases and 3574 controls. We did not detect any associations between tagging SNPs in CLOCK and BP or MDD in the allele, genotype, or haplotype analysis (global p(BP)=.605 and global p(MDD)=.211). Moreover, rs1801260 was also not associated with BP, MDD, or any mood disorders in the meta-analysis. In conclusion, these data suggest that CLOCK does not play a major role in the pathophysiology of mood disorders.     

Predicting treatment failure in patients with community acquired pneumonia: a case-control study

Introduction

Treatment failure in community-acquired-pneumonia (CAP) patients is associated with a high mortality rate, and therefore are a matter of great concern in clinical management. Those patients have increased mortality and are a target population for randomized clinical trials.

Methods

A case–control study was performed in patients with CAP (non-failure cases vs. failure cases, discriminating by late and early failure). CRP, PCT, interleukin 1, 6, 8 and 10 and TNF were determined at days 1 and 3 of hospitalization.

Results

A total of 253 patients were included in this study where 83 patients presented treatment failure. Of these, 40 (48.2%) had early failure. A discriminative effect was found for a higher CURB-65 score among late failure patients (p = 0.004). A significant increase on day 1 of hospitalization in CRP (p < 0.001), PCT (p = 0.004), IL-6 (p < 0.001) and IL-8 (p = 0.02), and a decrease in IL-1 (p = 0.06) in patients with failure was observed compared with patients without failure. On day 3, only the increase in CRP (p < 0.001), PCT (p = 0.007) and IL-6 (p < 0.001) remained significant. Independent predictors for early failure were higher IL-6 levels on day 1 (OR = 1.78, IC = 1.2-2.6) and pleural effusion (OR = 2.25, IC = 1.0-5.3), and for late failure, higher PCT levels on day 3 (OR = 1.60, IC = 1.0-2.5), CURB-65 score ≥ 3 (OR = 1.43, IC = 1.0-2.0), and multilobar involvement (OR = 4.50, IC = 2.1-9.9).

Conclusions

There was a good correlation of IL-6 levels and CAP failure and IL-6 & PCT with late CAP failure. Pleural effusion and multilobar involvement were simple clinical predictors of early and late failure, respectively.

Trial registration

IRB Register: http://2009/5451.     

Ischemic arterial events and atherosclerosis in patients with systemic sclerosis: a population-based case-control study

Introduction

While microvascular disease is well described in systemic sclerosis (SSc), it is still unclear whether the occurrence of ischemic macrovascular events and atherosclerosis is enhanced among patients with SSc.

Methods

In this study, 111 SSc patients (74% of prevalent cases in Stockholm County) and 105 age- and sex-comparable population controls were investigated. Previous ischemic arterial events were tabulated. As surrogate measures of atherosclerosis, plaque occurrence and intima-media thickness (IMT) were determined with carotid ultrasound and the ankle-brachial index (ABI) was calculated. Traditional cardiovascular risk factors were recorded and we also measured biomarkers indicating systemic inflammation and endothelial activation/dysfunction.

Results

Mean age was 62 ± 12 years for patients and controls. Ischemic arterial events were more common, due to increased occurrence of ischemic heart disease (IHD) and ischemic peripheral vascular disease (IPVD), in the patient group (12% vs. 4%, P = 0.03 and 9% vs. 0%, P = 0.003 respectively). On a group level, there was no difference regarding the occurrence of ischemic cerebrovascular disease, the frequency of plaques, IMT or ABI between SSc patients and controls. Subgroup analyses revealed that patients with anticentromere antibodies (ACA+) had more plaques and more ischemic arterial events compared to other SSc patients (67% vs. 39% and 32% vs. 11%; P = 0.006 and P = 0.01, respectively) and compared to controls (67% vs. 41% and 32% vs. 7%, P = 0.02 and P = 0.0003, respectively). Biomarkers of inflammation/endothelial activation were generally increased among SSc patients.

Conclusions

Patients with SSc are at enhanced risk for IHD and IPVD. The ACA+ SSc subgroup was particularly affected with both ischemic arterial events and premature atherosclerosis. The microvascular vulnerability of ACA+ patients is previously well documented. We demonstrate that ACA+ SSc patients have an enhanced risk of macrovascular injury as well. This group should be followed closely and modifiable cardiovascular risk factors should be treated at an early stage.     

Qualitative dermatoglyphic traits in ovarian cancer patients: a case-control study

The authors investigated the correlation between the occurrence of certain qualitative dermatoglyphic traits and the susceptibility to ovarian cancer, using the case-control design. A sample of 168 diseased cases, treated at the University Department of Gynecologic Oncology in Zagreb, Croatia between 1996-1997 was compared to 200 healthy females, investigated at the Institute for Anthropological Research in Zagreb. The results showed significant differences between ovarian cancer cases and healthy controls regarding the frequency of arches on the fingers of both hands (10-11% vs. 4-5%, respectively, p < 0.05), and of characteristic patterns on the palms of right hand (33% vs. 54% in 3rd interdigital space (IS), p < 0.001; 39% vs. 47% in 4th IS, p < 0.05) and of the left hand (42% vs. 58% in 4th IS, p < 0.001; 24% vs. 34% in hypothenar, p < 0.01). Although probably neither very sensitive nor specific, these findings could still be used in addition to other diagnostic procedures, as a rough screening method in early detecting of ovarian cancer.     

Attention-deficit/hyperactivity disorder and alexithymia: a pilot study

Although the relationship between alexithymia and psychopathology has been studied extensively in adults, research is lacking on alexithymia in childhood psychopathology. The aim of this study was to investigate the relationship between alexithymia and attention-deficit/hyperactivity disorder (ADHD). The Italian version of the Alexithymia Questionnaire for Children was administered to a sample of 50 children with a DSM-IV diagnosis of ADHD, as assessed by means of the K-SADS PL, and to 100 healthy, age- and sex-matched children without ADHD. The total alexithymia score as well as the difficulty in identifying feelings (DIF) and externally oriented thinking factors were significantly associated with ADHD. The total alexithymia score, the DIF, and the difficulty in describing feelings factors were also significantly associated with symptoms of hyperactivity/impulsivity. No significant relationship between alexithymia and inattentiveness symptoms emerged. Results provide preliminary data on the relationship between alexithymia and ADHD. Findings point to an association between difficulty in identifying emotions and hyperactivity/impulsivity. Future studies conducted on larger patient samples, as well as longitudinal designs, are warranted to confirm our findings.     

Activation of caspases in lymphocytes of patients with borderline personality disorders

Activities of caspases involved in cell death have been investigated in lymphocytes of patients with borderline personality disorders (BPD). In the group of patients with organic mental disorders (OMD) caspase activity decreased in a depressive disorder and increased in an anxiety disorder, thus suggesting activation of apoptosis in lymphocytes of patients with the anxiety disorder. Caspase activities differed in lymphocytes of OMD patients with the depressive disorder and a recurrent depressive disorder. In BPD patients with OMD lymphocyte caspase activity was higher thus indicating activation of apoptosis in these cells. Results can be used for specification of mechanisms of pathogenesis of mental disorders and search for new markers of these diseases.     

Deliberate self-poisoning: a study in London casualty departments.

During a prospective study of the whole spectrum of drug-related problems treated in one month by 62 casualty departments in the Greater London area, 949 cases of deliberate self-poisoning were identified. Nearly three-quarters of the patients were under the age of 40 years and in all age groups women outnumbered men. Psychoactive drugs of some sort were used in 673 incidents (71%) and ordinary analgesics and other drugs were used in 252 (27%). The incidence of polydrug overdose (423; 45%) was much higher than that found in other studies. In at least 256 incidents (27%) there was a history of repeated overdose in the previous 12 months. Comparison with other studies showed a steady decline in the use of barbiturates in deliberate self-poisoning but an increase in the use of non-barbiturate hypnotics, minor tranquilisers, and antidepressants.     

Wall stress of the cervical carotid artery in patients with carotid dissection: a case-control study

Spontaneous internal carotid artery (ICA) dissection (sICAD) results from an intimal tear located around the distal carotid sinus. The mechanisms causing the tear are unknown. This case-control study tested the hypotheses that head movements increase the wall stress in the cervical ICA and that the stress increase is greater in patients with sICAD than in controls. Five patients with unilateral, recanalized, left sICAD and five matched controls were investigated before and after maximal head rotation to the left and neck hyperextension after 45° head rotation to the left. The anatomy of the extracranial carotid arteries was assessed by magnetic resonance imaging and used to create finite element models of the right ICA. Wall stress increased after head movements. Increases above the 80th and 90th percentile were located at the intimal side of the artery wall from 7.4 mm below to 10 mm above the cranial edge of the carotid sinus, i.e., at the same location as histologically confirmed tears in patients with sICAD. Wall stress increase did not differ between patients and controls. The present findings suggest that wall stress increases at the intimal side of the artery wall surrounding the distal edge of the carotid bulb after head movements may be important for the development of carotid dissection. The lack of wall stress difference between the two groups indicates that the carotid arteries of patients with carotid dissection have either distinct functional or anatomical properties or endured unusually heavy wall stresses to initiate dissection.     

Reducing all-cause mortality among patients with psychiatric disorders: a population-based study

Background:

Among patients with psychiatric disorders, there are 10 times as many preventable deaths from physical disorders as there are from suicide. We investigated whether compulsory community treatment, such as community treatment orders, could reduce all-cause mortality among patients with psychiatric disorders.

Methods:

We conducted a population-based survival analysis of an inception cohort using record linking. The study period extended from November 1997 to December 2008. The cohort included patients from all community-based and inpatient psychiatric services in Western Australia (state population 1.8 million). We used a 2-stage design of matching and Cox regression to adjust for demographic characteristics, previous use of health services, diagnosis and length of psychiatric history. We collected data on successive cohorts for each year for which community treatment orders were used to measure changes in numbers of patients, their characteristics and outcomes. Our primary outcome was 2-year all-cause mortality. Our secondary outcomes were 1-and 3-year all-cause mortality.

Results:

The study population included 2958 patients with community treatment orders (cases) and 2958 matched controls (i.e., patients with psychiatric disorders who had not received a community treatment order). The average age for cases and controls was 36.7 years, and 63.7% (3771) of participants were men. Schizophrenia and other nonaffective psychoses were the most common diagnoses (73.4%) among participants. A total of 492 patients (8.3%) died during the study. Cox regression showed that, compared with controls, patients with community treatment orders had significantly lower all-cause mortality at 1, 2 and 3 years, with an adjusted hazard ratio of 0.62 (95% confidence interval 0.45–0.86) at 2 years. The greatest effect was on death from physical illnesses such as cancer, cardiovascular disease or diseases of the central nervous system. This association disappeared when we adjusted for increased outpatient and community contacts with psychiatric services.

Interpretation:

Community treatment orders might reduce mortality among patients with psychiatric disorders. This may be partly explained by increased contact with health services in the community. However, the effects of uncontrolled confounders cannot be excluded.Mortality among patients with psychiatric disorders is higher than in the general population.¹ Chronic physical disorders such as cardiovascular disease and cancer are the main causes of death in this population, with risks 10 times that of suicide; however, such causes receive far less attention than suicides.^1,2 Patients with schizophrenia die 15–20 years earlier than people in the general population, a difference that has increased over time.^1,3 Reasons for this difference include socioeconomic disadvantage, adverse effects of medication and reduced access to health care.^4,5There are limited data on possible interventions aimed at preventing such deaths, most of which stress regular monitoring of physical status, peer support and collaboration with primary care.^6,7 One study from Victoria, Australia, found that patients on conditional release from hospital had lower mortality than expected when use of community care, age, sex, inpatient experience and diagnosis were taken into account.⁸ However, 10% of these patients had dementia or other diseases of the nervous system, and patients with these diagnoses made up 29% of the deaths in the study. Dementia is not a typical indication for compulsory community treatment. In addition, Victoria has one of the highest levels of use of community treatment orders, about 60 per 100 000 population; thus, those results may not be generalizable to other locales.⁸ Although the authors controlled for time at risk, death could occur from 1 day to 11 years after the index date;⁹ most evaluations of community treatment orders are limited to 1 or 2 years after the order is issued.^9,10 Finally, the results were not adjusted for patients’ marital status, education, country of birth, indigenous status or use of health services before the introduction of community treatment orders. Adjusting for these variables could reduce the bias inherent in drawing cases and controls from the same jurisdiction given the difficulties in controlling for all possible reasons for issuing these orders once they have been introduced.We sought to assess the impact of community treatment orders on 1-, 2-, and 3-year survival in Western Australia. Community treatment orders provide a legal framework within which patients with a serious mental disorder are required to accept psychiatric treatment while living outside hospital. These orders are used across both Canada and Australia, are of similar duration in both countries, and are clinician-initiated rather than court-ordered (in contrast to the United States).^10,11 Unlike in Canada, patients in Australia can be given community treatment orders without having been previously admitted to hospital. In practice, patients in both countries spend similar amounts of time in hospital before being given a community treatment order.¹²We focused on deaths from physical illness, rather than suicides, as these are the most common causes of preventable death among people with severe mental illness.^1,2 We thought that patients with community treatment orders would have lower mortality because of improved engagement with health services, thus allowing greater monitoring and management of physical health. Greater engagement would be shown via increased outpatient contacts following the receipt of a community treatment order, which would influence any association between compulsory community treatment and mortality.     

Energy expenditure at rest and during walking in patients with chronic respiratory failure: a prospective two-phase case-control study

Background

Measurements of Energy Expenditure (EE) at rest (REE) and during physical activities are increasing in interest in chronic patients. In this study we aimed at evaluating the validity/reliability of the SenseWear®Armband (SWA) device in terms of REE and EE during assisted walking in Chronic Respiratory Failure (CRF) patients receiving long-term oxygen therapy (LTOT).

Methodology/Principal Findings

In a two-phase prospective protocol we studied 40 severe patients and 35 age-matched healthy controls. In phase-1 we determined the validity and repeatability of REE measured by SWA (REEa) in comparison with standard calorimetry (REEc). In phase-2 we then assessed EE and Metabolic Equivalents-METs by SWA during the 6-minute walking test while breathing oxygen in both assisted (Aid) or unassisted (No-Aid) modalities. When compared with REEc, REEa was slightly lower in patients (1351±169 vs 1413±194 kcal/day respectively, p<0.05), and less repeatable than in healthy controls (0.14 and 0.43 coefficient respectively). COPD patients with CRF patients reported a significant gain with Aid as compared with No-Aid modality in terms of meters walked, perceived symptoms and EE.

Conclusions/Significance

SWA provides a feasible and valid method to assess the energy expenditure in CRF patients on LTOT, and it shows that aided walking results in a substantial energy saving in this population.     

ABO blood group and the risk of hepatocellular carcinoma: a case-control study in patients with chronic hepatitis B

Background

Studies have observed an association between the ABO blood group and risk of certain malignancies. However, no studies of the association with hepatocellular carcinoma (HCC) risk are available. We conducted this hospital-based case-control study to examine the association with HCC in patients with chronic hepatitis B (CHB).

Methods

From January 2004 to December 2008, a total of 6275 consecutive eligible patients with chronic hepatitis B virus (HBV) infection were recruited. 1105 of them were patients with HBV-related HCC and 5,170 patients were CHB without HCC. Multivariate logistic regression models were used to investigate the association between the ABO blood group and HCC risk.

Results

Compared with subjects with blood type O, the adjusted odds ratio (AOR) for the association of those with blood type A and HCC risk was 1.39 [95% confidence interval (CI), 1.05–1.83] after adjusting for age, sex, type 2 diabetes, cirrhosis, hepatitis B e antigen, and HBV DNA. The associations were only statistically significant [AOR (95%CI) = 1.56(1.14–2.13)] for men, for being hepatitis B e antigen positive [AOR (95%CI) = 4.92(2.83–8.57)], for those with cirrhosis [AOR (95%CI), 1.57(1.12–2.20)], and for those with HBV DNA≤10⁵copies/mL [AOR (95%CI), 1.58(1.04–2.42)]. Stratified analysis by sex indicated that compared with those with blood type O, those with blood type B also had a significantly high risk of HCC among men, whereas, those with blood type AB or B had a low risk of HCC among women.

Conclusions

The ABO blood type was associated with the risk of HCC in Chinese patients with CHB. The association was gender-related.     

KIR and HLA loci are associated with hepatocellular carcinoma development in patients with hepatitis B virus infection: a case-control study

Background

Natural killer (NK) cells activation has been reported to contribute to inflammation and liver injury during hepatitis B virus (HBV) infection both in transgenic mice and in patients. However, the role of NK cells in the process of HBV-associated hepatocellular carcinoma (HCC) development has not been addressed. Killer cell immunoglobulin-like receptors (KIRs) are involved in regulating NK cell activation through recognition of specific human leukocyte antigen (HLA) class I allotypes.

Methodology/Principal Findings

To investigate whether KIR and HLA genes could influence the risk of HBV-associated HCC development, 144 HBV-infected patients with HCC and 189 well-matched HBV infectors with chronic hepatitis or cirrhosis as non-HCC controls were enrolled in this study. The presence of 12 loci of KIR was detected individually. HLA-A, -B, -C loci were genotyped with high-resolution. HLA-C group 1 homozygote (OR = 2.02; p = 0.005), HLA-Bw4-80I (OR = 2.67; p = 2.0E-04) and combination of full-length form and 22 bp-deleted form of KIR2DS4 (KIR2DS4/1D) (OR = 1.89; p = 0.017) were found associated with HCC incidence. When the combined effects of these three genetic factors were evaluated, more risk factors were observed correlating with higher odds ratios for HCC incidence (P trend = 7.4E-05). Because all the risk factors we found have been reported to result in high NK cell functional potential by previous studies, our observations suggest that NK cell activation may contribute to HBV-associated HCC development.

Conclusions/Significance

In conclusion, this study has identified significant associations that suggest an important role for NK cells in HCC incidence in HBV-infected patients. Our study is useful for HCC surveillance and has implications for novel personalized therapy strategy development aiming at HCC prevention in HBV-infected patients.     

Nonsuicidal self-harm in youth: a population-based survey

Background

Nonsuicidal self-harm includes cutting, scratching, burning and minor overdosing. There have been few studies that have examined the rate of self-harm and mental-health correlates among community-based youth. We performed a population-based study to determine the prevalence of nonsuicidal self-harm, its mental-health correlates and help-seeking behaviour.

Methods

We used data from the Victoria Healthy Youth Survey, a population-based longitudinal survey of youth aged 14–21 in Victoria, British Columbia. The survey included questions about the history, method, frequency, age of onset and help-seeking for nonsuicidal self-harm. Youth were interviewed between February and June 2005. Univariable group differences were analyzed using students t test for continuous data and χ² for binary or categorical data. Multivariate analyses were conducted by use of multivariate analysis of variance and logistic regression.

Results

Ninety-six of 568 (16.9%) youth indicated that they had ever harmed themselves. Self-injuries such as cutting, scratching and self-hitting were the most common forms of nonsuicidal self-harm (83.2%). The mean age of onset was 15.2 years. Of those who reported nonsuicidal self-harm, 56% had sought help for this behaviour. Participants who reported 5 or more symptoms (out of 6) in a given symptom category were more likely than those who reported less than 5 symptoms to report nonsuicidal self-harm for the following categories: depressive mood (odds ratio [OR] 2.18, confidence interval [CI] 1.28–3.7) and problems with regulation of attention, impulsivity and activity (OR 2.24, CI 1.33–3.76).

Interpretation

We found a high lifetime prevalence of nonsuicidal self-harm. Many mental-health symptoms were associated with this behaviour, particularly those with depressive mood and attention-related problems. Just over half of youth reported seeking help for nonsuicidal self-harm. Clinicians who encounter youth should be vigilant to assess for this behaviour in youth who present with mental health issues.Nonsuicidal self-harm includes behaviours such as self-cutting, scratching and burning, done without the conscious intent to take one''s life. Onset typically occurs between 14 and 24 years of age.^1,2 The most common reasons for this type of harm are regulation of affect (e.g., to reduce tension or relieve dysphoric feelings), but reasons may also include self-punishment, interpersonal reasons, sensation seeking and anti-dissociation mechanisms.³ Factors associated with nonsuicidal self-harm include being female, awareness of self harm in peers, family members who self harm, drug misuse, depression, anxiety, impulsivity, disruptive disorders and low self-esteem.^4,5 Suicide ideation and attempts are more likely to be reported among those with repeated nonsuicidal self-harm.⁶A definition of “deliberate self-harm,” which does not distinguish between suicidal and nonsuicidal intent, has been proposed by the Child and Adolescent Self-Harm in Europe research group and has been used in several school-based surveys of adolescents.^4,7 The prevalence self-harm has been studied in school-based surveys of adolescents and young adults.^4–6,8 The results of these surveys are of limited generalizability because the samples were restricted to schools in large urban centres. Thus, we performed a population-based survey of youth in western Canada to investigate nonsuicidal self-harm. Our objectives were to determine the rate of nonsuicidal self-harm among Canadian youth; to determine the mental-health factors associated with nonsuicidal self-harm; and to examine the help-seeking patterns for this behaviour.     

A new approach of personality and psychiatric disorders: a short version of the affective neuroscience personality scales

Background

The Affective Neuroscience Personality Scales (ANPS) is an instrument designed to assess endophenotypes related to activity in the core emotional systems that have emerged from affective neuroscience research. It operationalizes six emotional endophenotypes with empirical evidence derived from ethology, neural analyses and pharmacology: PLAYFULNESS/joy, SEEKING/interest, CARING/nurturance, ANGER/rage, FEAR/anxiety, and SADNESS/separation distress. We aimed to provide a short version of this questionnaire (ANPS-S).

Methodology/Principal Findings

We used a sample of 830 young French adults which was randomly split into two subsamples. The first subsample was used to select the items for the short scales. The second subsample and an additional sample of 431 Canadian adults served to evaluate the psychometric properties of the short instrument. The ANPS-S was similar to the long version regarding intercorrelations between the scales and gender differences. The ANPS-S had satisfactory psychometric properties, including factorial structure, unidimensionality of all scales, and internal consistency. The scores from the short version were highly correlated with the scores from the long version.

Conclusions/Significance

The short ANPS proves to be a promising instrument to assess endophenotypes for psychiatrically relevant science.     

Bone fragility in sarcoidosis and relationships with calcium metabolism disorders: a cross sectional study on 142 patients

Introduction

The prevention of fragility fractures in patients with sarcoidosis is a serious concern and the potential risk of hypercalcemia limits vitamin D and calcium supplementation. The objective of this study was to evaluate the risk factors for low bone mineral density (BMD) and fractures in sarcoidosis. In particular, we aimed to determine the link among bone fragility and calcium and vitamin D metabolism in this population.

Methods

We performed a cross-sectional analysis on 142 consecutive patients with histologically proven sarcoidosis. BMD and prevalence of vertebral fractures on X-rays were assessed and the association with potential risk factors was studied by regression analysis.

Results

Fragility fractures occurred in 23.5% of patients, despite a normal mean BMD in the study population. In a multivariate analysis, low dietary calcium, fracture, age, gender and menopause were associated with increased risk of low BMD. Low dietary calcium, high current corticosteroid dose and low creatinine clearance were associated with increased risk of fracture. Serum 25(OH)D between 10 and 20 ng/ml was significantly associated with higher BMD. Conversely, values greater than 20 ng/ml were associated with increased risk of fracture. Serum 25(OH)D level was inversely correlated with disease activity. Of note, vitamin D supplements increased serum 25(OH)D in a dose-dependent manner but had no effect on serum calcium level.

Conclusions

Sarcoidosis patients have a high risk of fracture despite not having a lowered BMD suggesting that other independent factors are involved. Current corticosteroid dose, low dietary calcium and serum 25(OH)D levels are associated with bone fragility. In sarcoidosis, calcium and vitamin D supplementation might be warranted, but desirable 25(OH)D serum levels might be lower than those advised for the general population.