Shiga Toxin (Stx) Phage-Encoded Lytic Genes Are Not Required for the Mouse Virulence of O157:H7 Escherichia coli Stx2-Producing Clinical Isolates.

Shiga toxin (Stx)-producing Escherichia coli (STEC) is a major cause of foodborne diarrheal illness in the United States and globally, and serotype O157:H7 is frequently associated with STEC outbreaks and sporadic cases in the United States. Severe systemic diseases associated with STEC are mediated by Stx types, particularly subtype Stx2a, encoded on inducible bacteriophages. We previously identified two STEC O157:H7 clinical isolates, JH2010 and JH2012, that exhibit a large difference in virulence in a streptomycin (Str)-treated mouse model. In this study, we aimed to identify a genetic basis for the difference in virulence between those strains. Comparison of the stx2a phage sequences showed that JH2012 lacks the lytic genes S and R on the phage genome. We also demonstrated that compared to JH2012 cultures, cultures of JH2010 released more Stx2 into the supernatant and were more sensitive to bacterial lysis during growth with ciprofloxacin (Cip), an inducer of stx phages. We therefore generated an stx2a phage SR deletion mutant strain of JH2010 to determine if those genes were responsible for the high virulence of that strain. We found that deletion of the SR genes from the stx2a phage in JH2010, and another O157:H7 strain, JH2016, resulted in increased cellular retention of Stx2, but there was no difference in virulence compared to the wild-type strains. Our results indicate that the stx2a phage SR genes are involved in Stx2 localization and phage-mediated cell lysis in vitro but that they are not required in wild-type STEC strains for virulence in a mouse model. IMPORTANCE The release of Stx from STEC has been thought to be tied to phage-mediated lysis of the host bacterial cell. In this study, we found that the stx2a phage lytic genes are not required for the virulence of pathogenic O157:H7 clinical isolates in a murine model of STEC infection or for release of Stx2a into the supernatant of bacterial cultures. These results point to an alternate mechanism for Stx2a release from STEC strains.

[Extensor tendon injuries of the hand]. / Strecksehnenverletzungen der Hand.

The extensor tendon apparatus is a network consisting of two different systems, an intrinsic and an extrinsic system, which are subdivided into eight different zones. Isolated injuries in zones 1 and 2 can be treated nonoperatively, whereas injuries in zones 3-8 usually require surgical treatment. A decision on the suture technique, suture material and postoperative follow-up care is made depending on the zone of the injury. The concomitant injuries of joints, bones, nerves and vessels must be taken into consideration and treated. The outcome of a tendon injury depends on the location and severity of the injury as well as the surgical technique and follow-up care. Exact knowledge of the anatomy with precise diagnostics, atraumatic, zone-dependent surgical and postoperative treatment, adequate rehabilitation and occupational therapy are essential for high quality management and preservation of fine motor skills and coordination of the whole hand.

New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation.

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin α9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.

Polyploidy as a chromosomal component of stochastic noise: variable scalar multiples of the diploid chromosome complement in the invertebrate species Girardia schubarti from Brazil / Poliploidia como componente cromossômico de ruído estocástico: variações escalares múltiplas do componente cromossômico diploide do invertebrado Girardia schubarti ocorrente no Brasil

Abstract Chromosome stoichiometry, a form of genetic plasticity, specifically refers to variation in the standard diploid genomic composition of an individual or species. In the present work, freshwater planarians (Girardia schubarti) were analyzed to recognize variations in chromosomal stoichiometry especially of complete ploidal change between specimens, within specimens and between cells within specimens and any relations they might have with selected components of phenotypic plasticity. Homoploid polyploids for the group reached rational scalar multiples (e.g. tetraploids) or irrational scalar multiples (e.g. triploids). Karyotypic mosaics emerged where individual cells presented polyploid multiples in arithmetic and geometric progressions. Ploidal multiplicity, a chromosomal component of stochastic noise, had positive phenotypic effects (increased dimensions) on morphologic criteria of body length, body width and dorsal surface reflecting a significant genotypic plasticity (GP) and robust phenotypic plasticity (PP). Variable but significant association of genotypic plasticity with robust phenotypic variance suggests kinetics of phenotypic homeostasis that is species-specific permitting phenotypic adaptability to environmental variables by means of GP. That association is diminished, deactivated or lost in more advanced and more complex organisms.

Resumo A estequiometria cromossômica, uma forma de plasticidade genotípica, representa variações na composição genômica diploide de um indivíduo ou espécie. Planárias límnicas (Girardia schubarti) foram analisadas para verificar a estequiometria cromossômica, especialmente alterações na ploidia entre espécimes, em cada espécime e entre células do mesmo espécime, além de relações dessas alterações com a plasticidade fenotípica. Espécimes poliploides homoploides apresentaram múltiplos escalares racionais ou irracionais, tais como triploides. Mosaicos cariotípicos ocorreram quando células apresentaram poliploides múltiplos em progressões aritméticas e geométricas. Nas planárias estudadas, a multiplicidade ploidal, um componente cromossômico de ruído estocástico, apresentou efeitos fenotípicos positivos, causando aumento das dimensões dos indivíduos, tais como comprimento corporal, largura do corpo e superfície dorsal, indicando plasticidade genotípica (GP) significativa e plasticidade fenotípica (PP) robusta. Associações significativas da plasticidade genotípica com variâncias fenotípicas robustas, embora variáveis, sugerem que a homeostase fenotípica, a qual é espécie-específica, possibilita adaptações a variáveis ambientais através da GP. Tal associação apresenta-se reduzida, desativada ou perdida em organismos mais complexos.

[The scaphoid fracture : Between pseudoarthrosis and possible anatomical variance]. / Die Skaphoidfraktur : Zwischen Pseudarthrose und möglicher anatomischer Varianz.

The diagnosis of a scaphoid fracture, especially in the differentiation of a fresh fracture, the nonunion or a possible anatomical norm variant, can be difficult. We report on two patients who presented with stress-related, radiocarpal pain in our department. In both cases, radiological abnormalities were observed in the scaphoideal area, with a scaphoideum bipartitum on both sides, as well as an approximately 25-year-old scaphoid pseudarthrosis.

Polyploidy as a chromosomal component of stochastic noise: variable scalar multiples of the diploid chromosome complement in the invertebrate species Girardia schubarti from Brazil.

Chromosome stoichiometry, a form of genetic plasticity, specifically refers to variation in the standard diploid genomic composition of an individual or species. In the present work, freshwater planarians (Girardia schubarti) were analyzed to recognize variations in chromosomal stoichiometry especially of complete ploidal change between specimens, within specimens and between cells within specimens and any relations they might have with selected components of phenotypic plasticity. Homoploid polyploids for the group reached rational scalar multiples (e.g. tetraploids) or irrational scalar multiples (e.g. triploids). Karyotypic mosaics emerged where individual cells presented polyploid multiples in arithmetic and geometric progressions. Ploidal multiplicity, a chromosomal component of stochastic noise, had positive phenotypic effects (increased dimensions) on morphologic criteria of body length, body width and dorsal surface reflecting a significant genotypic plasticity (GP) and robust phenotypic plasticity (PP). Variable but significant association of genotypic plasticity with robust phenotypic variance suggests kinetics of phenotypic homeostasis that is species-specific permitting phenotypic adaptability to environmental variables by means of GP. That association is diminished, deactivated or lost in more advanced and more complex organisms.

Personality traits as an endophenotype in genetic studies on suicidality in bipolar disorder.

Introduction The influence of personality traits on suicidal behaviour risk has been well documented. Personality traits and suicidal behaviour are partially genetically determined and personality has been described as an endophenotype of suicidal behaviour. The aim of this study was to investigate a possible association between personality traits with suicidal behaviour and selected serotonergic gene polymorphisms. METHODS: In the study we included 156 patients meeting DSM-IV criteria for bipolar disorder (BP) and 93 healthy controls. The personality dimensions were assessed using the Temperament and Character Inventory (TCI). We genotyped two selected polymorphisms of the tryptophan hydroxylase 1 (TPH1) gene (rs1800532 218A>C and rs1799913 779A>C) and polymorphism in the promoter region of serotonin transporter gene (5-HTTLPR, rs25531) related to serotoninergic neurotransmission. Multiple poisson regression, logistic regression and Kruskal-Wallis tests were applied. RESULTS: We found numerous differences between the BP patients and the control group in terms of their TCI dimensions/subdimensions. Significant differences were found between patients with, and without, suicidal attempts in fatigability and asthenia (Ha4), as well as in harm avoidance (Ha). We also found that the interactions between TCI subdimensions (the interaction of disordiness (Ns4) and spiritual acceptance (St3), disordiness (Ns4) and integrated conscience (C5), extravagance (Ns3) and resourcefulness (Sd3)) were significantly contributing for suicidal behaviour risk. We found association between all studied genetic polymorphisms and several TCI dimensions and subdimensions. CONCLUSION: Our results confirm that personality traits are partially determined by genes. Both personality traits and the interactions between temperament and character traits, may be helpful in predicting suicidal behaviour.

Thermal and near-infrared light induced spin crossover in a mononuclear iron(ii) complex with a tetrathiafulvalene-fused dipyridophenazine ligand.

A mononuclear Fe(ii) complex involving a tetrathiafulvalene-based ligand exhibits thermal spin-crossover (around 143 K) with pronounced hysteresis behaviour (48 K). The chromophoric and π-extended ligand allows Near-Infrared (NIR) sensitization for the light-induced excited spin-state trapping (LIESST) with T(LIESST) = 90 K.

[The medical dissertation in Germany : A quantitative analysis of promotion regulations in medical faculties]. / Die medizinische Doktorarbeit in Deutschland : Eine quantitative Analyse der Promotionsordnungen medizinischer Fakultäten.

BACKGROUND: The medical dissertation represents an independently processed scientific project. In the field of medicine this has for many years displayed the basis for controversial discussions. The aim of the study presented here was to evaluate the prerequisites of all current promotion regulations in German medical faculties in order to develop a comparability on the basis of a scoring system. METHOD: An independent analysis of all promotion regulations from German medical faculties for the year 2014 was carried out according to 12 primary outcome measures and a scoring system. RESULTS: The average total score of promotion regulations at 37 German medical faculties was 57.2 points (SD ±9.5) out of a possible 100 scoring points. The highest scores with 72-85 points were achieved by 3 faculties and 5 achieved scores of only 42-45 points. The range of the different criteria tested was broad. While the written thesis, the review process, the examination requirements as well as the grading of the thesis were defined in all regulations, the introduction into good clinical practice, knowledge of methodology as well as a check for plagiarism only seem to play minor roles. CONCLUSION: The promotion regulations at German medical faculties show a great variation using the scoring system presented here for the first time. Standardized federal promotion regulations might help to establish a structured transparency as well as a national equality of opportunity.

Place Cell Networks in Pre-weanling Rats Show Associative Memory Properties from the Onset of Exploratory Behavior.

Place cells are hippocampal pyramidal cells that are active when an animal visits a restricted area of the environment, and collectively their activity constitutes a neural representation of space. Place cell populations in the adult rat hippocampus display fundamental properties consistent with an associative memory network: the ability to 1) generate new and distinct spatial firing patterns when encountering novel spatial contexts or changes in sensory input ("remapping") and 2) reinstate previously stored firing patterns when encountering a familiar context, including on the basis of an incomplete/degraded set of sensory cues ("pattern completion"). To date, it is unknown when these spatial memory responses emerge during brain development. Here, we show that, from the age of first exploration (postnatal day 16) onwards, place cell populations already exhibit these key features: they generate new representations upon exposure to a novel context and can reactivate familiar representations on the basis of an incomplete set of sensory cues. These results demonstrate that, as early as exploratory behaviors emerge, and despite the absence of an adult-like grid cell network, the developing hippocampus processes incoming sensory information as an associative memory network.

High-Field High-Repetition-Rate Sources for the Coherent THz Control of Matter.

Ultrashort flashes of THz light with low photon energies of a few meV, but strong electric or magnetic field transients have recently been employed to prepare various fascinating nonequilibrium states in matter. Here we present a new class of sources based on superradiant enhancement of radiation from relativistic electron bunches in a compact electron accelerator that we believe will revolutionize experiments in this field. Our prototype source generates high-field THz pulses at unprecedented quasi-continuous-wave repetition rates up to the MHz regime. We demonstrate parameters that exceed state-of-the-art laser-based sources by more than 2 orders of magnitude. The peak fields and the repetition rates are highly scalable and once fully operational this type of sources will routinely provide 1 MV/cm electric fields and 0.3 T magnetic fields at repetition rates of few 100 kHz. We benchmark the unique properties by performing a resonant coherent THz control experiment with few 10 fs resolution.

[Postdoctoral lecturer thesis in medicine: academic competence or career booster?]. / Die medizinische Habilitation: akademische Befähigung oder Karriereinstrument?

BACKGROUND: The postdoctoral lecturer thesis in medicine represents an essential success factor for the career of a physician; however, there is controversial discussion on whether this reflects academic competence or is more a career booster. In this context we conducted a survey among postdoctoral medical lecturers with the aim to evaluate the significance of this qualification. MATERIAL AND METHODS: The online survey was performed using a questionnaire requesting biographical parameters and subjective ratings of topics concerning the postdoctoral lecturer thesis. RESULTS: Overall 628 questionnaires were included in the study. The significance of the postdoctoral qualification was rated high in 68.6 % and was seen to be necessary for professional advancement in 71.0 %. The chances of obtaining a full professorship after achieving a postdoctoral qualification were rated moderate to low (68.1 %); nevertheless, 92.3 % would do it again and 86.5 % would recommend it to colleagues. Accordingly, 78.8 % were against its abolishment. Wishes for reforms included standardized federal regulations, reduced dependency on professors and more transparency. CONCLUSION: The postdoctoral lecturer qualification in medicine is highly valued and the majority of responders did not want it to be abolished. Although the chances for a full professorship were only rated low, successful graduation seems to be beneficial for the career; however, there is a need for substantial structural and international changes.

Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder.

Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippocampal neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P-values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499, miR-708 and miR-1908. Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499, four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2. First results of functional analyses in rat hippocampal neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.

High-intensity functional training improves functional movement and body composition among cancer survivors: a pilot study.

This pilot study investigated feasibility and preliminary efficacy of a high-intensity functional training (HIFT) group-exercise programme among adult cancer survivors within 5 years of last cancer treatment. Eight participants were assigned to a 5-week, 3 days/week HIFT intervention with four testing sessions and 12 workouts along with mobility and stretching exercises. Feasibility was assessed by initiation, adherence, and acceptability. Efficacy was determined by changes from baseline to post-test in health-related quality of life, body composition and functional movement. The recruitment rate was 80% and the adherence rate was 75%. Significant improvements were found for emotional functioning (P = 0.042) and body composition (lean mass +3.8 ± 2.1 kg, P = 0.008; fat mass -3.3 ± 1.0 kg, P = 0.001; body fat percentage -4.7 ± 1.2%, P < 0.001). Participants also significantly improved on five of seven functional movements: balance (P = 0.032), carrying a weighted object (P = 0.004), lower body strength and power (P = 0.009), aerobic capacity and endurance (P = 0.039), and perceived difficulty for flexibility (P = 0.012). Five weeks of HIFT training was well-received and feasible for most cancer survivors, and effective for improving emotional functioning, body composition and functional movement.

[Sarcoma of the hand and wrist]. / Sarkome an Hand und Handgelenk.

Sarcomas of the hand and wrist are rare malignancies, which should be referred to high-volume comprehensive cancer centres providing multidisciplinary treatment options. The tumour board should propose patient-oriented oncological pathways as well as sophisticated hand and plastic reconstructive procedures. In Addition, isolated limb perfusion with TNF-alpha and melphalan is likely to lead to preoperative tumour shrinkage allowing for R0 resection in sano. Our clinical results in long-term survivors demonstrate reduced amputation rates and salvage of basic hand function when a risk-adapted treatment rationale is applied.

[Prefabrication of transplants in plastic surgery]. / Präfabrikation von Transplantaten in der plastischen Chirurgie.

Complex three-dimensional defects with destruction of the external form, loss of functional stability and inner lining are associated with tactical and technical challenges in reconstructive plastic surgery. Causative factors are mutilating infections, resection of malignant tumors and trauma, predominantly located at the aerodigestive junction, the urogenital region and the extremities. Three-dimensional tissue constructions are preformed distant to the defect site allowing safe pedicled or microsurgical transfer into the defect.

Familiality and SNP heritability of age at onset and episodicity in major depressive disorder.

BACKGROUND: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). METHOD: For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. RESULTS: Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. CONCLUSIONS: AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.

Investigation of blood mRNA biomarkers for suicidality in an independent sample.

Changes in the blood expression levels of SAT1, PTEN, MAP3K3 and MARCKS genes have been reported as biomarkers of high versus low suicidality state (Le-Niculescu et al.). Here, we investigate these expression biomarkers in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study, of patients with major depressive disorder on a 12-week antidepressant treatment. Blood gene expression levels were available at baseline and week 8 for patients who experienced suicidal ideation during the study (n=20) versus those who did not (n=37). The analysis is well powered to detect the effect sizes reported in the original paper. Within either group, there was no significant change in the expression of these four genes over the course of the study, despite increasing suicidal ideation or initiation of antidepressant treatment. Comparison of the groups showed that the gene expression did not differ between patients with or without treatment-related suicidality. This independent study does not support the validity of the proposed biomarkers.

[Sternal osteomyelitis. Etiology, diagnostics and operative therapy concepts]. / Sternumosteomyelitis. Ätiologie, Diagnostik und operative Therapiekonzepte.

Deep sternal infections with sternal osteomyelitis are rare conditions with extensive consequences for the patient. The incidence of complications after median sternotomy is as high as 0.4-8 %. Wound and sternal dehiscence and a septic course with mediastinitis leading to septic shock is a feared complication with a high mortality next to the chronic course of the infection with the clinical correlation of presternal fistulas. An early diagnosis and surgical intervention is decisive to enhance the prognosis of the disease, leading to a significant increase in the survival rate of patients.

[Long-term functional results after sarcoma resection]. / Funktionelle Langzeitergebnisse nach Sarkomresektionen.

Multimodal treatment of malignant tumors of the musculoskeletal system with R0 in sano resection plays a key role in prevention of local recurrence in soft tissue and bone sarcoma. In cases of unavoidable neuromuscular or osseous defects, current plastic and orthoplastic reconstruction techniques avoid limb amputation in the majority of patients. Clinical long-term results demonstrate that large resection defects do not necessarily result in impaired limb function if multidisciplinary procedures are integrated. In oncologically necessary major limb amputation, segmental resection and replantation of distal limb parts should be considered which provide end-bearing long stump formation. The functional conditions of long-term surviving elderly patients should be integrated into surgical decision-making and rehabilitation efforts.