The single-suture technique for anterior cruciate ligament graft preparation provides similar stability as a three-suture technique: a biomechanical in vitro study in a porcine model.

PURPOSE: Numerous techniques have been described for the tibial-sided graft preparation in anterior cruciate ligament (ACL) reconstruction. The use of less suture material for graft preparation is thought to improve ingrowth and to reduce the risk for infection. At the same time, the suture construct should be strong enough to resist the surgeon's pull during tensioning of the transplant. METHODS: In total, 39 fresh-frozen procine deep flexor tendons were used and prepared as four-strand grafts. In the three-suture group (n = 19), graft preparation was performed using three tibial-sided sutures, with each tendon end sutured separately. In the one-suture group (n = 20), a modified graft preparation using only one tibial-sided suture was applied. Each sample underwent load-to-failure testing (Nmax) after cyclic pre-loading. To estimate intraoperative tension forces acting on the tibial-sided suture constructs, the maximal tension force of 26 volunteers on such a construct was measured using a load cell. RESULTS: The biomechanical testing of the two different suture constructs showed a significantly higher load-to-failure for the three-suture group (711 N ± 91 N) compared to the one-suture group (347 N ± 24 N) (p = 0.0001). In both groups, the mode of failure was a tear of the suture in all samples. A failure of the suture-tendon interface was not observed in any case. The median maximal tension force on the construct applied by the 26 volunteers was 134 N (range 73-182 N). CONCLUSION: The presented single-suture tendon graft preparation resisted to smaller failure loads than the conventional three-suture technique. However, no failures in the suture-tendon interface were seen and the failure loads observed were far beyond the tension forces that can be expected intraoperatively. Hence, the single-suture graft preparation technique may be a valuable alternative to the conventional technique.

Tuning the Pseudospin Polarization of Graphene by a Pseudomagnetic Field.

One of the intriguing characteristics of honeycomb lattices is the appearance of a pseudomagnetic field as a result of mechanical deformation. In the case of graphene, the Landau quantization resulting from this pseudomagnetic field has been measured using scanning tunneling microscopy. Here we show that a signature of the pseudomagnetic field is a local sublattice symmetry breaking observable as a redistribution of the local density of states. This can be interpreted as a polarization of graphene's pseudospin due to a strain induced pseudomagnetic field, in analogy to the alignment of a real spin in a magnetic field. We reveal this sublattice symmetry breaking by tunably straining graphene using the tip of a scanning tunneling microscope. The tip locally lifts the graphene membrane from a SiO2 support, as visible by an increased slope of the I(z) curves. The amount of lifting is consistent with molecular dynamics calculations, which reveal a deformed graphene area under the tip in the shape of a Gaussian. The pseudomagnetic field induced by the deformation becomes visible as a sublattice symmetry breaking which scales with the lifting height of the strained deformation and therefore with the pseudomagnetic field strength. Its magnitude is quantitatively reproduced by analytic and tight-binding models, revealing fields of 1000 T. These results might be the starting point for an effective THz valley filter, as a basic element of valleytronics.

[The ICD-10 Symptom Rating (ISR): validation of the depression scale in a clinical sample]. / Das ICD-10 Symptomrating (ISR): Validierung der Depressionsskala an einer klinischen Stichprobe.

The ICD-10 Symptom Rating (ISR) 1 measures the severity of psychiatric disorders with 29 items on 5 subscales as comprehensively as possible. The following syndromes are measured: Depressive syndrome, anxiety syndrome, obsessive-compulsive syndrome, Somatoform syndrome, eating disorder syndrome as well as additional items that cover various mental syndromes, and an overall score. The study reports findings on the validity and sensitivity to change of the depression subscale (ISR-D). In a clinical sample of N=949 inpatients with depression spectrum disorders the convergent validity was determined by correlation with the Beck Depression Inventory (BDI) 3 and the subscale "depression" of the Symptom-Checklist-90-R (SCL-90-R) 4. The high correlation between the different instruments confirms the validity of the ISR-Depression Scale. The sensitivity to change of the ISR seems higher than that of the BDI and the SCL-90. Because of its economy and the good psychometric properties the ISR is recommended for use in clinical samples.

The DISC locus and schizophrenia: evidence from an association study in a central European sample and from a meta-analysis across different European populations.

Association studies, as well as the initial translocation family study, identified the gene Disrupted-In-Schizophrenia-1 (DISC1) as a risk factor for schizophrenia. DISC1 encodes a multifunctional scaffold protein involved in neurodevelopmental processes implicated in the etiology of schizophrenia. The present study explores the contribution of the DISC locus to schizophrenia using three different approaches: (i) systematic association mapping aimed at detecting DISC risk variants in a schizophrenia sample from a central European population (556 SNPs, n = 1621 individuals). In this homogenous sample, a circumscribed DISC1 interval in intron 9 was significantly associated with schizophrenia in females (P = 4 x 10(-5)) and contributed most strongly to early-onset cases (P = 9 x 10(-5)). The odds ratios (ORs) were in the range of 1.46-1.88. (ii) The same sample was used to test for the locus-specific SNP-SNP interaction most recently associated with schizophrenia. Our results confirm the SNP interplay effect between rs1538979 and rs821633 that significantly conferred disease risk in male patients with schizophrenia (P = 0.016, OR 1.57). (iii) In order to detect additional schizophrenia variants, a meta-analysis was performed using nine schizophrenia samples from different European populations (50 SNPs, n = 10 064 individuals maximum, n = 3694 minimum). We found evidence for a common schizophrenia risk interval within DISC1 intron 4-6 (P = 0.002, OR 1.27). The findings point to a complex association between schizophrenia and DISC, including the presence of different risk loci and SNP interplay effects. Furthermore, our phenotype-genotype results--including the consideration of sex-specific effects--highlight the value of homogenous samples in mapping risk genes for schizophrenia in general, and at the DISC locus in particular.

Genetic variation in G72 correlates with brain activation in the right middle temporal gyrus in a verbal fluency task in healthy individuals.

The D-amino acid oxidase activator gene (G72) has been found associated with several psychiatric disorders such as schizophrenia, major depression, and bipolar disorder. Impaired performance in verbal fluency tasks is an often replicated finding in the mentioned disorders. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal and lateral temporal areas and could possibly constitute an endophenotype. Therefore, it is of interest whether genes associated with the disorders, such as G72, modulate verbal fluency performance and its neural correlates. Ninety-six healthy individuals performed a semantic verbal fluency task while brain activation was measured with functional MRI. All subjects were genotyped for two single nucleotide polymorphisms (SNP) in the G72 gene, M23 (rs3918342) and M24 (rs1421292), that have previously shown association with the above-mentioned disorders. The effect of genotype on brain activation was assessed with fMRI during a semantic verbal fluency task. Although there were no differences in performance, brain activation in the right middle temporal gyrus (BA 39) and the right precuneus (BA 7) was positively correlated with the number of M24 risk alleles in the G72 gene. G72 genotype does modulate brain activation during language production on a semantic level in key language areas. These findings are in line with structural and functional imaging studies in schizophrenia, which showed alterations in the right middle temporal gyrus.

A systematic association mapping on chromosome 6q in bipolar affective disorder--evidence for the melanin-concentrating-hormone-receptor-2 gene as a risk factor for bipolar affective disorder.

Strong evidence of linkage between chromosomal region 6q16-q22 and bipolar affective disorder (BPAD) has previously been reported. We conducted a systematic association mapping of the 6q-linkage interval using 617 SNP markers in a BPAD case-control sample of German descent (cases = 330, controls = 325). In this screening step, 46 SNPs showed nominally significant BPAD-association (P-values between 0.0007 and 0.0484). Although none of the 46 SNPs survived correction for multiple testing, they were genotyped in a second and ethnically matched BPAD sample (cases = 328, controls = 397). At the melanin-concentrating-hormone-receptor-2 (MCHR2) gene, we found nominal association in both the initial and second BPAD samples (combined P = 0.008). This finding was followed up by the genotyping of 17 additional MCHR2-SNPs in the combined sample in order to define our findings more precisely. We found that the MCHR2-locus can be divided into three different haplotype-blocks, and observed that the MCHR2-association was most pronounced in BPAD male patients with psychotic symptoms. In two neighboring blocks, putative risk-haplotypes were found to be 7% more frequent in patients (block II: 23.3% vs. 16.2%, P = 0.005, block III: 39.2% vs. 32.0%, P = 0.024), whereas the putative protective haplotypes were found to be 5-8% less frequent in patients (block II: 11.6% vs. 16.4%, P = 0.041, block III: 30.0% vs. 38.8%, P = 0.007). The corresponding odds ratios (single-marker analysis) ranged between 1.25 and 1.46. Our findings may indicate that MCHR2 is a putative risk factor for BPAD. These findings should be interpreted with caution and replicated in independent BPAD samples.

Premorbid adjustment: a phenotype highlighting a distinction rather than an overlap between schizophrenia and bipolar disorder.

BACKGROUND: Premorbid adjustment (PMA) in schizophrenia (SZ) has been widely studied and shown to be worse in individuals who develop SZ as compared to controls. It has been proposed as a predictor of clinical presentation and outcome, and may delineate a specific SZ phenotype for genetic and other biological studies. Research into PMA in BD has been scarce and inconclusive. AIMS: The authors compared PMA in individuals suffering from BD with that of healthy controls and investigated whether levels of PMA in BD patients correlate with specific phenotypic features. METHODS: The authors investigated 344 BD patients and 137 population-based controls. Retrospective PMA assessment was performed using the Premorbid Adjustment Scale (PAS). An overall score as well as sub-scores for age ranges and functional domains were obtained. RESULTS: Patients had a better overall PAS score than controls and outperformed controls during early and late adolescence. They scored significantly better than controls in the functional domains "sociability and withdrawal" and "adaptation to school". No differences were observed for the other subscales and there were no differences between groups during childhood. No association was observed between PMA and any of the phenotype characteristics investigated. CONCLUSIONS: In the largest study to date on PMA in BD, PMA was shown to be better in bipolar patients than in healthy controls. PMA in BD is not a simple proxy for commonly studied phenotypic markers of severity. PMA emerges as a phenotype in its own right, and highlights an aspect of disparity rather than overlap between SZ and BD.

Variation in P2RX7 candidate gene (rs2230912) is not associated with bipolar I disorder and unipolar major depression in four European samples.

Two recent studies reported evidence for association between genetic variation of the positional candidate gene P2RX7 on chromosome 12q24 and bipolar I disorder (BPI) [Barden et al. (2006); Am J Med Genet Part B 141B:374-382; McQuillin et al. (2008); Mol Psychiatry 13:1-7] and one study found association with unipolar major depression (Mdd-UP) [Lucae et al. (2006); Hum Mol Genet 15:2438-2445]. In the present work, we aimed to replicate the SNP that showed the strongest association in the above-mentioned studies, namely rs2230912 (P2RX7-E13A) resulting in a change of the amino acid glutamine to arginine at position 460 (Gln460Arg), in four European bipolar I disorder samples from Germany, Poland, Romania, and Russia totaling 1,445 patients, in a German sample of recurrent Mdd-UP patients (N = 640), and a control sample of 2,006 subjects. We found no allelic or genotypic association between rs2230912 and BPI or Mdd-UP both in the national samples and in the combined European patient sample. Additional studies are needed to clarify the potential involvement of P2RX7 and of SNP rs2230912 in the etiology of major affective disorders.

Brief report: no association between premorbid adjustment in adult-onset schizophrenia and genetic variation in Dysbindin.

Whereas Dysbindin is considered a schizophrenia vulnerability gene, there is no consistency of findings. Phenotype refinement approaches may help to increase the genetic homogeneity and thus reconcile conflicting results. Premorbid adjustment (PMA) has been suggested to aid the phenotypic dissection. Gornick et al. (J Autism Dev Disord 35:831-838, 2005) reported an association between Dysbindin and PMA in US-Caucasian individuals with childhood-onset psychosis. In a sample of 222 adult-onset schizophrenia inpatients from Germany, we could not detect an association between PMA and 36 SNPs in Dysbindin. Our results suggest that genetic variation in Dysbindin may not contribute to the schizophrenia phenotype with an onset beyond childhood. Further studies including even larger samples and more SNPs may be warranted to clarify the relationship between Dysbindin and PMA.

Premorbid adjustment in schizophrenia--an important aspect of phenotype definition.

UNLABELLED: Schizophrenia is a heterogeneous disorder, and early signs of disorder such as poor premorbid adjustment (PMA) are often present before the onset of diagnosable illness. Differences in PMA between patients may be suggestive of differing aetiological pathways. Poor PMA in schizophrenia has repeatedly been reported to be associated with male sex, earlier age at onset, illness severity, negative symptoms, and poor outcome. Studies of schizophrenia patients systematically assessed for PMA have used small patient samples and have rarely used controls. OBJECTIVE: To investigate possible correlations of PMA, as measured with the Cannon-Spoor Premorbid Adjustment Scale (PAS), with such meaningful clinical characteristics as sex, age at onset, negative symptoms etc. using one of the largest samples of schizophrenia inpatients as well as controls characterised for PMA to date. METHOD: PMA, diagnosis and lifetime symptoms were assessed in 316 inpatients with schizophrenia and 137 population based controls using the PAS and the Structured Clinical Interview for DSM. RESULTS: Controls demonstrated better PAS scores than inpatients with schizophrenia. Earlier age at onset and negative symptoms were found to be associated with poorer PAS scores. There was no difference in PAS ratings between males and females in patients with schizophrenia. Among the control probands, females showed significantly better PAS scores than males. CONCLUSION: PAS scores are worse in individuals who eventually develop schizophrenia, and the distribution of these scores among schizophrenia inpatients is correlated with specific clinical features. Earlier findings, which had reported an association with age at onset and negative symptoms in small patient samples, were substantiated. The widely reported association of poor PMA with male sex, if genuinely present, does not appear to be disease specific. Our findings suggest that PMA is in itself a valuable phenotype characteristic and that it may represent a specific biological phenotype which may be of value in sub-sample selection.

Possible association between genetic variants at the GRIN1 gene and schizophrenia with lifetime history of depressive symptoms in a German sample.

Genetic variation in glutamatergic signalling pathways is believed to play a substantial role in the aetiology of schizophrenia. The N-methyl-D-aspartate receptor subunit gene GRIN1 has been proposed as a candidate gene for schizophrenia. We tested for a potential association between schizophrenia and four single nucleotide polymorphisms (rs4880213, rs11146020, rs6293, and rs10747050) and one microsatellite marker at GRIN1 in a German sample of 354 patients and 323 controls. We found significant associations in single-marker and haplotype-based analyses (P<0.05). Significance was more pronounced (P<0.01) in the subset of patients with a lifetime history of major depression, a subgroup of schizophrenia described previously as a promising phenotypic subtype in genetic studies of schizophrenia. Although significances did not withstand correction for multiple testing, the results of our exploratory analysis warrant further studies on GRIN1 and schizophrenia.

The startle reflex in alcohol-dependent patients: changes after cognitive-behavioral therapy and predictive validity for drinking behavior. A pilot study.

BACKGROUND: Previous studies demonstrated an attenuation of the affect-modulated startle reflex when alcohol-dependent patients were viewing alcohol-associated pictures. This indicates an appetitive valence of these stimuli. We used the affect-modulated startle reflex to assess the effects of behavioral treatment on the emotional processing of alcohol-associated stimuli. Further, we examined whether the affect-modulated startle reflex is a predictor of treatment success. METHODS: Forty-three alcohol-dependent patients (21 females, mean age 45.67 years, SD 9.45) were recruited consecutively from an inpatient alcohol detoxification facility where patients attended a 3-week detoxification program including cognitive-behavioral treatment to successfully handle high-risk situations. The eye blink component of the affect-modulated startle response, self-reported cue-induced craving and skin conductance responses to alcohol-associated and control slides were assessed before and after treatment. Changes were analyzed using repeated measures analysis of variance. Drinking behavior was assessed in the 6 months following treatment, and a regression analysis was performed to evaluate the predictive validity of the affect-modulated startle response for drinking behavior. RESULTS: Drinking behavior as well as craving and skin conductance responses decreased significantly over time. The pattern of the affective modulation of the startle reflex was not altered over time. However, startle modulation and relapse were related, and within the group of relapsers, startle modulation was a significant predictor of drinking behavior. CONCLUSIONS: Our results suggest that the modulation of the startle reflex may reflect more enduring and permanent processes of emotional responding to alcohol-related cues than autonomic arousal and self-reported craving, and that startle modulation by alcohol-associated cues may be a better predictor of drinking behavior for relapsers than other measures. Further studies including a control condition are necessary to validate these findings.

No association between genetic variants at the GRIN1 gene and bipolar disorder in a German sample.

Disturbed glutamatergic neurotransmission has been implicated in the pathogenesis of schizophrenia and bipolar disorder, with the N-methy-D-aspartate receptors being in the focus of research. The NR1 subunit, which is encoded by the gene GRIN1, plays a key role in the functionality of N-methy-D-aspartate receptors. We tested the association between GRIN1 and bipolar disorder in a sample of German descent, consisting of 306 bipolar disorder patients and 319 population-based controls. No significant association was found. In accordance with our recent findings, we hypothesized that restricting case definition to individuals with a history of persecutory delusions might clarify the relationship between bipolar disorder and GRIN1. This stratified analysis did not yield any significant association either. Our results do not support an association of the GRIN1 gene with bipolar disorder in the German population.

No association between genetic variants at the ASCT1 gene and schizophrenia or bipolar disorder in a German sample.

Altered glutamatergic neurotransmission is considered a potential etiological factor of schizophrenia (SCZ) and affective disorders. The gene ASCT1 (SLC1A4) coding for a Na+-dependent neutral aminoacid transporter is a member of the glutamate transporter superfamily and is located on 2p13-14, a region showing linkage to both SCZ and bipolar disorder (BD). ASCT1 can thus be considered a candidate gene for both disorders. In a German sample, we tested for association between ASCT1 and both SCZ and BD. Allele and haplotype frequencies, however, did not differ between cases and controls. Recent findings on the associations between brainderived neurotrophic factor (BDNF) and SCZ and between G72/G30 and BD suggest that SCZ patients with a history of major depressive episodes (MDE) outside psychotic episodes and BD cases with a history of persecutory delusions constitute genetically distinct subgroups of these disorders. Thus, we hypothesized that restricting case definition to those 95 SCZ individuals with MDE and to those 107 BD patients with a history of persecutory delusions might clarify the relationship between BD, SCZ and ASCT1. However, these stratification approaches did not yield any significant association either. Allele and haplotype frequencies did not differ between cases and controls. Our results do not support an association of the ASCT1 gene with BD or SCZ in the German population.

The Impact of Staff Turnover and Staff Density on Treatment Quality in a Psychiatric Clinic.

Intuition suggests that improving stability of the health workforce brings benefits to staff, the organization and, most importantly, the patients. Unfortunately, there is limited research available to support this, and how health workforce stability can contribute to reduced costs and better treatment outcomes. To help to rectify this situation, we investigated the effects of staff turnover and staff density (staff members per patient) on the treatment outcome of inpatients in a psychiatric clinic. Our data come from the standard assessment of 1429 patients who sought treatment in our clinic from January 2011 to August 2013. Correlation analysis shows no significant effect of raw staff turnover (the total number of psychiatrists, physicians and psychologists starting or quitting work per month) on treatment quality. However, we do find two significant beneficial effects: first, a higher staff consistency (time without staff turnover) and second, a higher staff density lead to an improvement of treatment quality. Our findings underline the dire need for an extended effort to achieve optimal staff retention, both to improve patient's outcomes and to reduce health expenses.

How does the ICD-10 symptom rating (ISR) with four items assess depression compared to the BDI-II? A validation study.

OBJECTIVE: The "ICD-10 Symptom-Rating" (ISR) is a novel 29-item self-rating questionnaire with scales for the assessment of depression, anxiety, OCD, somatisation and eating disorders and additional items. This study aims at the validation of the depression subscale. METHODS: Based on a sample of 1844 depressed inpatients, the ISR was correlated with the Beck-Depression-Inventory-II (BDI-II). To estimate the sensitivity to change, the effect sizes were also calculated. RESULTS: The correlation between ISR and BDI-II was r=0.79. The sensitivity to change for the BDI-II was d=1.44, for the ISR-depression scale d=1.64. LIMITATIONS: The studied sample shows a higher psychiatric and somatic comorbidity, a lower mean age and a higher level of education than comparable samples from other psychiatric or psychosomatic studies. Although we cannot find any effects of these differences on our results, they cannot be fully dismissed without further study. CONCLUSION: The ISR-depression scale correlates highly with the BDI-II. Being more sensitive to change than the BDI-II, the ISR is a useful tool to diagnose and measure the severity and course of depression.

Common and rare variant analysis in early-onset bipolar disorder vulnerability.

Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder.

Absence of edge states in covalently bonded zigzag edges of graphene on Ir(111).

The zigzag edges of graphene on Ir(111) are studied by ab initio simulations and low-temperature scanning tunneling spectroscopy, providing information about their structural, electronic, and magnetic properties. No edge state is found to exist, which is explained in terms of the interplay between a strong geometrical relaxation at the edge and a hybridization of the d orbitals of Ir atoms with the graphene orbitals at the edge.