Impact of NNLO QED corrections on lepton-proton scattering at MUSE.

We present the complete next-to-next-to-leading order (NNLO) pure pointlike QED corrections to lepton-proton scattering, including three-photon-exchange contributions, and investigate their impact in the case of the MUSE experiment. These corrections are computed with no approximation regarding the energy of the emitted photons and taking into account lepton-mass effects. We contrast the NNLO QED corrections to known next-to-leading order corrections, where we include the elastic two-photon exchange (TPE) through a simple hadronic model calculation with a dipole ansatz for the proton electromagnetic form factors. We show that, in the low-momentum-transfer region accessed by the MUSE experiment, the improvement due to more sophisticated treatments of the TPE, including inelastic TPE, is of similar if not smaller size than some of the NNLO QED corrections. Hence, the latter have to be included in a precision determination of the low-energy proton structure from scattering data, in particular for electron-proton scattering. For muon-proton scattering, the NNLO QED corrections are considerably smaller.

Tumor repolarization by an advanced liposomal drug delivery system provides a potent new approach for chemo-immunotherapy.

Immunosuppressive cells in the tumor microenvironment allow cancer cells to escape immune recognition and support cancer progression and dissemination. To improve therapeutic efficacy, we designed a liposomal oxaliplatin formulation (PCL8-U75) that elicits cytotoxic effects toward both cancer and immunosuppressive cells via protease-mediated, intratumoral liposome activation. The PCL8-U75 liposomes displayed superior therapeutic efficacy across all syngeneic cancer models in comparison to free-drug and liposomal controls. The PCL8-U75 depleted myeloid-derived suppressor cells and tumor-associated macrophages in the tumor microenvironment. The combination of improved cancer cell cytotoxicity and depletion of immunosuppressive populations of immune cells is attractive for combination with immune-activating therapy. Combining the PCL8-U75 liposomes with a TLR7 agonist induced immunological rejection of established tumors. This combination therapy increased intratumoral numbers of cancer antigen-specific cytotoxic T cells and Foxp3- T helper cells. These results are encouraging toward advancing liposomal drug delivery systems with anticancer and immune-modulating properties into clinical cancer therapy.

Clinical relevance of Scedosporium spp. and Exophiala dermatitidis in patients with cystic fibrosis: A nationwide study.

An increased prevalence of various filamentous fungi in sputum samples of patients with cystic fibrosis (CF) has been reported. The clinical significance, however, is mostly unclear. The aim of this study was to investigate the clinical relevance of Scedosporium spp. and Exophiala dermatitidis from sputum samples of patients with CF in the Netherlands. In this cross-sectional study, all CF patients of the Dutch national CF registry who were treated at five of the seven recognized CF centers during a 3-year period were included. We linked clinical data of the national CF registry with the national Dutch filamentous fungal database. We investigated the association between clinical characteristics and a positive sputum sample for Scedosporium spp. and E. dermatitidis, using logistic regression. Positive cultures for fungi were obtained from 3787 sputum samples from 699 of the 1312 patients with CF. Scedosporium spp. was associated with severe genotype, CF-related diabetes, several microorganisms, and inhaled antibiotics. E. dermatitidis was associated with older age, female sex, and Aspergillus spp. CF patients with and without Scedosporium spp. or E. dermatitidis seemed comparable in body mass index and lung function. This study suggests that Scedosporium spp. and E. dermatitidis are probably no major pathogens in CF patients in the Netherlands. Greater understanding of epidemiologic trends, risk factors, and pathogenicity of filamentous fungi in the respiratory tracts of patients with CF is needed.

Refining the dermatological spectrum in primary immunodeficiency: mucosa-associated lymphoid tissue lymphoma translocation protein 1 deficiency mimicking Netherton/Omenn syndromes.

The proteinase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), which forms part of the caspase recruitment domain-containing protein 11-B-cell lymphoma 10-MALT1 signalosome complex, plays a direct role in nuclear factor kappa B activation. Here, we describe the case of a female infant with severe immune dysregulation leading to recurrent systemic infections, failure to thrive and severe crises of ichthyosiform erythroderma with high levels of serum IgE. Hence, initial symptoms indicated Netherton syndrome or Omenn syndrome. Surprisingly, sequence analyses of SPINK5 and RAG1/RAG2, respectively, excluded these diseases. During the hospital stay the patient's health deteriorated, despite intensive care therapy, and she died. In order to delineate the diagnosis, whole-exome sequencing was performed. Two compound heterozygous mutations in MALT1 were found and verified by Sanger sequencing (exon 2 c.245T>C, exon 2 c.310dup), which led to a MALT1 deficiency at the protein level. Based on these results, an immunological analysis was performed, as was immunofluorescence staining of key skin proteins, to confirm a diagnosis of MALT1 deficiency. This case report provides a closer description of the clinical and histological skin phenotype of MALT1 deficiency, and we conclude that MALT1 deficiency must be considered a possible differential diagnosis of Netherton and Omenn syndromes. What's already known about this topic? Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) deficiency is a combined immunodeficiency. MALT1 is part of the caspase recruitment domain-containing protein 11-B-cell lymphoma 10-MALT1 signalosome complex, which is essential for nuclear factor kappa B activation. Current publications describe a phenotype of recurrent systemic infections; only in a few cases has an inflammatory involvement of the integument been described. What does this study add? A closer description of the cutaneous phenotype of MALT1 deficiency in a patient with two novel MALT1 mutations. Immune mapping of follicular epidermis shows lympho-epithelial Kazal-type-related inhibitor is reduced in MALT1 deficiency and absent on interfollicular staining. Clinically, MALT1 deficiency mimics Netherton syndrome and Omenn syndrome, and should be considered a differential diagnosis.

Reversible helical electromagnetic launcher used as an electrically programmable shock tester.

The performance of a reversible helical electromagnetic launcher (RHEML) is reported and discussed. The results demonstrate the feasibility of using the RHEML as an electrically programmable shock tester (EPST). The data show that the reversible helical electromagnetic launcher can be operated with parallel-connected armatures that share current and force. This report is also the first-ever successful demonstration of iron-cored HEML stators. The electrical programmability of the EPST has been demonstrated by varying the shock pulse width in approximately 30 ms increments. The armature assembly has a total mass of approximately 25 kg (55 lbs). The stators are approximately 100 mm (4 in.) in diameter and 2.3 m (90 in.) long. The large mass reversible helical electromagnetic launcher is powered by a 1 MJ capacitive pulse forming network. The armature assembly has a measured minimum velocity of 0.4 m/s and a maximum velocity of 8.3 m/s. The minimum acceleration/deceleration force is 4.3 gees, while the maximum acceleration/deceleration force is 30.7 gees. The minimum shock pulse width is 16 ms, and the maximum shock pulse width is 150 ms.

Re-phrasing the question: A simple tool for evaluation of adherence to therapy in patients with inflammatory bowel disease.

BACKGROUND: Non-adherence to medication in patients with inflammatory bowel disease (IBD) is a challenging problem which is often overlooked or under-estimated by the physician or denied by the patient. We aimed to examine if re-phrasing the wording of the question used by the physician could help in revealing more patients who are non-adherent, and for whom appropriate counseling may be instituted. METHODS: A cross-sectional questionnaire-based study of IBD patients treated in a tertiary center was conducted. Patients received a questionnaire detailing their treatments and disease course, as well as their perceptions about disease. Two forms of questions about adherence were deliberately placed in two separate parts of the questionnaire: One was 'are you taking your medications regularly as prescribed?' (Standard question), and the second, more emphatic question, was 'how often does it happen that you miss a drug dosing?' (Re-phrased question). The rate of non-adherence disclosed by each of these questions was compared. Sensitivity, specificity and predicative values were computed for each question against the conventional definition of non-adherence as taking of less than 80% of prescribed medication doses disclosed by any of the methods. Predictors of non-compliance and of denying non-compliance were also explored. RESULTS: Overall, 165 patients were included (49% female, mean age 33.7 ± 12.7 SD, median age 30 years, 29.6% with ulcerative colitis, 62.4% with Crohn's disease). Upon questioning, 50 (30.3%) of the patients admitted to non-adherence in the last month when asked by the emphatic re-phrased question format, compared with only 10 patients (6%) reporting non-adherence when asked directly by the standard question (OR 7.4, 95%CI 3.6-15.2, p < 0.001). Thus, a 'Do you take your medicine regularly' question format disclosed only 20% of genuinely non-compliant patients and had 16% sensitivity and 98.2% specificity for revealing non-adherence (PPV 80%, NPV 72.9%) compared with the reference re-phrased question. The leading cause for non-adherence was skepticism about drug efficacy or safety (20.5%), followed by vacation or weekend (15%), problems with prescription or pharmacy (13.5%) and forgetfulness (10%). No single demographic or clinical factor correlated with non-adherence. The only factor which correlated with higher probability for non-adherence was biological and combination treatment. CONCLUSION: Non-compliance with treatment is much more common than patients admit. Asking patients how often does it happen that they miss a drug dosing is a simple, practical tool which performs significantly better in disclosing non-adherence compared with asking patients if they take their medication as they should.

A multi-centre prospective evaluation of the Check-Direct ESBL Screen for BD MAX as a rapid molecular screening method for extended-spectrum beta-lactamase-producing Enterobacteriaceae rectal carriage.

OBJECTIVE: A multiplex extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) quantitative polymerase chain reaction (qPCR), performed directly on rectal swabs, was compared with a culture-based protocol to study the discrepancies between the two methods, and identify existing challenges to apply this assay in routine clinical practice. The secondary objective was to assess the performance of the qPCR. MATERIALS AND METHODS: In two Dutch teaching hospitals, 573 rectal swabs were collected prospectively. Culture with additional testing with the Check-MDR CT103XL (Check-Points) was compared with the Check-Direct ESBL Screen for BD MAX (Check-Points), which detects the presence of the ESBL gene families CTX-M1, CTX-M2, CTX-M9 and SHV2/5-ESBL. The culture-based protocol (with Brilliance agar) was considered as the gold standard to assess the performance of the qPCR. RESULTS: Of the 573 rectal swabs, 74 (12.9%) were culture-positive. Eighty-four (14.7%) were qPCR-positive. There were eight culture-positive/qPCR-negative discrepancies and 18 culture-negative/qPCR-positive discrepancies. Sensitivity and specificity of qPCR vs culture were 87.7% [95% confidence interval (CI) 79.7-95.7] and 96.3% (95% CI 94.6-98.0), respectively. CONCLUSION: The Check-Direct ESBL Screen for the BD MAX is an easy-to-perform, quick molecular diagnostic test with the potential to significantly speed up screening for rectal ESBL-E carriage. Discrepancies were observed between the culture-based protocol and the qPCR in 4.5% of tested samples. Existing challenges for implementing qPCR are its limited sensitivity, the need for thorough knowledge of the local ESBL-E genes, and interpretation of culture-negative but qPCR-positive samples. It is believed that the limited sensitivity of qPCR could be optimized by including blaTEM as a molecular target, and improving the limit of detection.

Addition of an immunomodulator can reverse antibody formation and loss of response in patients treated with adalimumab.

BACKGROUND: Anti-adalimumab antibodies (AAA) are associated with loss of clinical response (LOR). Addition of an immunomodulator has been shown to reverse immunogenicity and regain response with infliximab monotherapy. Similar data on adalimumab are lacking. AIM: To study the impact of immunomodulator addition on the emergence of AAA and LOR among adalimumab therapy patients. METHODS: The databases of three tertiary medical centres were reviewed to identify patients who developed AAA during adalimumab monotherapy with resultant LOR, and received an immunomodulator as a salvage combination therapy. All sera were prospectively analysed using previously described ELISA assays. Clinical response was determined using appropriate clinical scores. Elimination of AAA, designated as 'sero-reversal', elevation of drug levels and regained clinical response were the sought outcomes. RESULTS: Twenty-three patients (21 Crohn's disease, and 2 ulcerative colitis) developed AAA with subsequent LOR and were thereafter prescribed an immunomodulator as salvage therapy (thiopurine n = 14, methotrexate n = 9). Eleven patients (48%) underwent sero-reversal with gradual elimination of AAA, increase in drug trough levels and restoration of clinical response (median time to sero-reversal 5 months). In 12 patients (52%), immunogenicity and loss of response could not be reversed. There was no difference between responders and nonresponders in the type of immunomodulators used or baseline clinical characteristics. CONCLUSIONS: In almost half of inflammatory bowel disease patients developing anti-adalimumab antibodies and loss of response, established immunogenicity of adalimumab can be gradually reversed by the addition of immunomodulator therapy with restoration of a clinico-biological response. However, these observations need to be confirmed with larger studies.

Driving while using a smartphone-based mobility application: Evaluating the impact of three multi-choice user interfaces on visual-manual distraction.

Innovative in-car applications provided on smartphones can deliver real-time alternative mobility choices and subsequently generate visual-manual demand. Prior studies have found that multi-touch gestures such as kinetic scrolling are problematic in this respect. In this study we evaluate three prototype tasks which can be found in common mobile interaction use-cases. In a repeated-measures design, 29 participants interacted with the prototypes in a car-following task within a driving simulator environment. Task completion, driving performance and eye gaze have been analysed. We found that the slider widget used in the filtering task was too demanding and led to poor performance, while kinetic scrolling generated a comparable amount of visual distraction despite it requiring a lower degree of finger pointing accuracy. We discuss how to improve continuous list browsing in a dual-task context.

Ultrasound Applied to Subcutaneous Fat Tissue Measurements in International Elite Canoeists.

Subcutaneous adipose tissue (SAT) measurements with ultrasound have recently been introduced to assess body fat in elite athletes. However, appropriate protocols and data on various groups of athletes are missing. We investigated intra-rater reliability of SAT measurements using ultrasound in elite canoe athletes. 25 international level canoeists (18 male, 7 female; 23±4 years; 81±11 kg; 1.83±0.09 m; 20±3 training h/wk) were measured on 2 consecutive days. SAT was assessed with B-mode ultrasound at 8 sites (ISAK): triceps, subscapular, biceps, iliac crest, supraspinal, abdominal, front thigh, medial calf, and quantified using image analysis software. Data was analyzed descriptively (mean±SD, [range]). Coefficient of variation (CV%), intraclass correlation coefficient (ICC, 2.1) and absolute (LoA) and ratio limits of agreement (RLoA) were calculated for day-to-day reliability. Mean sum of SAT thickness was 30.0±19.4 mm [8.0, 80.1 mm], with 3.9±1.8 mm [1.2 mm subscapular, 8.0 mm abdominal] for individual sites. CV for the sum of sites was 4.7%, ICC 0.99, LoA 1.7±3.6 mm, RLoA 0.940 ( * /÷1.155). Measuring SAT with ultrasound has proved to have excellent day-to-day reliability in elite canoe athletes. Recommendations for standardization of the method will further increase accuracy and reproducibility.

Bmf upregulation through the AMP-activated protein kinase pathway may protect the brain from seizure-induced cell death.

Prolonged seizures (status epilepticus, SE) can cause neuronal death within brain regions such as the hippocampus. This may contribute to impairments in cognitive functioning and trigger or exacerbate epilepsy. Seizure-induced neuronal death is mediated, at least in part, by apoptosis-associated signaling pathways. Indeed, mice lacking certain members of the potently proapoptotic BH3-only subfamily of Bcl-2 proteins are protected against hippocampal damage caused by status epilepticus. The recently identified BH3-only protein Bcl-2-modifying factor (Bmf) normally interacts with the cytoskeleton, but upon certain cellular stresses, such as loss of extracellular matrix adhesion or energy crisis, Bmf relocalizes to mitochondria, where it can promote Bax activation and mitochondrial dysfunction. Although Bmf has been widely reported in the hematopoietic system to exert a proapoptotic effect, no studies have been undertaken in models of neurological disorders. To examine whether Bmf is important for seizure-induced neuronal death, we studied Bmf induction after prolonged seizures induced by intra-amygdala kainic acid (KA) in mice, and examined the effect of Bmf-deficiency on seizures and damage caused by SE. Seizures triggered an early (1-8 h) transcriptional activation and accumulation of Bax in the cell death-susceptible hippocampal CA3 subfield. Bmf mRNA was biphasically upregulated beginning at 1 h after SE and returning to normal by 8 h, while again being found elevated in the hippocampus of epileptic mice. Bmf upregulation was prevented by Compound C, an inhibitor of adenosine monophosphate-activated protein kinase, indicating Bmf expression may be induced in response to bioenergetic stress. Bmf-deficient mice showed normal sensitivity to the convulsant effects of KA, but, surprisingly, displayed significantly more neuronal death in the hippocampal CA1 and CA3 subfields after SE. These are the first studies investigating Bmf in a model of neurologic injury, and suggest that Bmf may protect neurons against seizure-induced neuronal death in vivo.

[Clinical and radiological mid-term results after autologous osteochondral transplantation under consideration of quality of life]. / Mittelfristige klinische und radiologische Ergebnisse nach autologer osteochondraler Transplantation unter Berücksichtigung der Lebensqualität.

BACKGROUND: Treatment of full-thickness cartilage defects remains a challenge in musculoskeletal surgery. Autologous osteochondral transplantation represents a possible solution for the repair of affected areas. However, some problems like degenerative changes of the transplanted cylinders and the surrounding cartilage or lack of cylinder integration to the surrounding cartilage arise with this method. Thus mid-term results respecting the quality of life are useful for assessment of the method. PATIENTS/MATERIAL AND METHODS: We investigated 22 patients with a mean follow-up of 88 ± 14.5 months after autologous osteochondral transplantation due to a full-thickness cartilage defect of the medial femoral condyle. Beside clinical scores we assessed at follow-up the quality of life using the SF-36 health survey and the EQ-5D. Furthermore, radiological changes were detected and MRI was performed in 21 patients. A control group of 19 patients, treated with microfracture, was matched in terms of BMI, gender and age. Exclusion criteria for this group were tibial kissing lesion, ligament instability, arthrosis and malalignment. RESULTS: In a longitudinal comparison with results 13.5 months after operation, no difference in Lysholm score was found. In plain radiographs higher degrees of arthritic changes in the medial compartment compared to the unaffected knee were observed. MRI revealed a mean modified MOCART score of 41.2 ± 7.7 for the OAT group and of 39.4 ± 16.1 for the microfracture group, without being significant. For OAT patients all cylinders showed an osseous integration. However, cylinder oedema was found in 9 patients. Those patients had a higher intensity of pain on a visual analogue scale. Quality of life was better for OAT patients in the physical scale of SF-36, but not in the mental scale. CONCLUSION: Autologous osteochondral transplantation has an unaltered significance in treating full-thickness cartilage defects and leads to satisfying mid-term results. The development of early arthritic changes might not be preventable by this method. Oedema of the transplanted cylinders is attended by higher pain intensity and might be an indirect sign of cartilage degeneration.

Assessing the potential for post-copulatory sexual selection in elasmobranchs.

This review highlights the potential role that post-copulatory sexual selection plays in elasmobranch reproductive systems and the utility of this group to further understanding of evolutionary responses to the post-copulatory processes of sperm competition and cryptic female choice. The growing genetic evidence for female multiple mating (polyandry) in elasmobranchs is summarized. While polyandry appears to be common in this group, rates of multiple paternity are highly variable between species suggesting that there is large variance in the strength of post-copulatory sexual selection among elasmobranchs. Possible adaptations of traits important for post-copulatory sexual selection are then considered. Particular emphasis is devoted to explore the potential for sperm competition and cryptic female choice to influence the evolution of testes size, sperm morphology, genital morphology and sperm storage organs. Finally, it is argued that future work should take advantage of the wealth of information on these reproductive traits already available in elasmobranchs to gain a better understanding of how post-copulatory sexual selection operates in this group.

Application of PCA and SIMCA statistical analysis of FT-IR spectra for the classification and identification of different slag types with environmental origin.

In the past, different slag materials were often used for landscaping and construction purposes or simply dumped. Nowadays German environmental laws strictly control the use of slags, but there is still a remaining part of 35% which is uncontrolled dumped in landfills. Since some slags have high heavy metal contents and different slag types have typical chemical and physical properties that will influence the risk potential and other characteristics of the deposits, an identification of the slag types is needed. We developed a FT-IR-based statistical method to identify different slags classes. Slags samples were collected at different sites throughout various cities within the industrial Ruhr area. Then, spectra of 35 samples from four different slags classes, ladle furnace (LF), blast furnace (BF), oxygen furnace steel (OF), and zinc furnace slags (ZF), were determined in the mid-infrared region (4000-400 cm(-1)). The spectra data sets were subject to statistical classification methods for the separation of separate spectral data of different slag classes. Principal component analysis (PCA) models for each slag class were developed and further used for soft independent modeling of class analogy (SIMCA). Precise classification of slag samples into four different slag classes were achieved using two different SIMCA models stepwise. At first, SIMCA 1 was used for classification of ZF as well as OF slags over the total spectral range. If no correct classification was found, then the spectrum was analyzed with SIMCA 2 at reduced wavenumbers for the classification of LF as well as BF spectra. As a result, we provide a time- and cost-efficient method based on FT-IR spectroscopy for processing and identifying large numbers of environmental slag samples.

17 novel polymorphic microsatellite markers for the giant water bug, Abedus herberti (Belostomatidae).

The giant water bug (Abedus herberti) is a large flightless insect that is a keystone predator in aridland aquatic habitats. Extended droughts, possibly due to climate change and groundwater pumping, are causing once-perennial aquatic habitats to dry, resulting in serious conservation concern for some populations. A. herberti also exhibits exclusive male parental care, which has made it a model organism for studying mating systems evolution. Here we describe 17 novel polymorphic microsatellite loci developed for A. herberti. Number of alleles per locus ranged from 2 to 15, and average observed and expected heterozygosities were 0.579 and 0.697, respectively. These loci can successfully resolve both population genetic structure among sites separated by 3-100 km (FST = 0.08-0.21, P < 0.0001), and divergent mating strategies within local populations, making them highly useful for conservation genetics studies of this vulnerable species.

Deletion of Puma protects hippocampal neurons in a model of severe status epilepticus.

Prolonged seizures (status epilepticus) can activate apoptosis-associated signaling pathways. The extent to which such pathways contribute to cell death might depend on the insult intensity, whereby the programmed or apoptotic cell death component is reduced when seizures are more severe or protracted. We recently showed that mice lacking the pro-apoptotic Bcl-2 homology domain 3-only protein Puma (Bbc3) were potently protected against damage caused by status epilepticus. In the present study we examined whether Puma deficiency was protective when the seizure episode was more severe. Intra-amygdala microinjection of 1 microg kainic acid (KA) into C57BL/6 mice triggered status epilepticus that lasted about twice as long as with 0.3 microg KA prior to lorazepam termination. Hippocampal damage was also significantly greater in the higher-dose group. Over 80% of degenerating neurons after seizures were positive for DNA fragmentation assessed by terminal deoxynucleotidyl dUTP nick end labeling (TUNEL). Microscopic analysis of neuronal nuclear morphology in TUNEL-positive cells revealed the proportion displaying large rounded clumps of condensed chromatin was approximately 50% lower in the high-dose versus low-dose KA group. Nevertheless, compared to heterozygous and wild-type mice subject to status epilepticus by high-dose KA, neuronal death was reduced by approximately 50% in the hippocampus of Puma-deficient mice. These data suggest aspects of the apoptotic component of seizure-induced neuronal death are insult duration- or severity-dependent. Moreover, they provide further genetic evidence that seizure-induced neuronal death is preventable by targeting so-called apoptosis-associated signaling pathways and Puma loss likely disrupts caspase-independent or non-apoptotic seizure-induced neuronal death.

BH3-only proteins BIM and PUMA in the regulation of survival and neuronal differentiation of newly generated cells in the adult mouse hippocampus.

Neurogenesis persists in the adult hippocampus, where several thousand neurons are born every day. Most of the newly generated cells are eliminated by apoptosis, possibly because of their failure to integrate properly into neural networks. The BH3-only proteins Bim and Puma have been shown to mediate trophic factor withdrawal- and anoikis-induced apoptosis in various systems. We therefore determined their impact on proliferation, survival, and differentiation of adult-generated cells in the mouse hippocampus using gene-deficient mice. Wild-type, bim-, and puma-deficient mice showed similar rates of precursor cell proliferation, as evidenced by 5-bromo-2-deoxyuridine (BrdU)-incorporation. Deficiency in either bim or puma significantly increased the survival of adult-born cells in the dentate gyrus (DG) after 7 days. Consistently, we detected increased numbers of doublecortin (DCX)-positive and fewer terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelled-positive cells in the DG of bim- and puma-deficient mice. Bim and puma deficiency did not change early markers of neuronal differentiation, as evidenced by BrdU/DCX double-labelling. However, BrdU/NeuN double-labelling revealed that deficiency of bim, but not puma, accelerated the differentiation of newly generated cells into a neuronal phenotype. Our data show that Bim and Puma are prominently involved in the regulation of neuronal progenitor cell survival in the adult DG, but also suggest that Bim has an additional role in neuronal differentiation of adult-born neural precursor cells.

Loss of p53 results in protracted electrographic seizures and development of an aggravated epileptic phenotype following status epilepticus.

The p53 tumor suppressor is a multifunctional protein, which regulates cell cycle, differentiation, DNA repair and apoptosis. Experimental seizures up-regulate p53 in the brain, and acute seizure-induced neuronal death can be reduced by genetic deletion or pharmacologic inhibition of p53. However, few long-term functional consequences of p53 deficiency have been explored. Here, we investigated the development of epilepsy triggered by status epilepticus in wild-type and p53-deficient mice. Analysis of electroencephalogram (EEG) recordings during status epilepticus induced by intra-amygdala kainic acid (KA) showed that seizures lasted significantly longer in p53-deficient mice compared with wild-type animals. Nevertheless, neuronal death in the hippocampal CA3 subfield and the neocortex was significantly reduced at 72 h in p53-deficient mice. Long-term continuous EEG telemetry recordings after status epilepticus determined that the sum duration of spontaneous seizures was significantly longer in p53-deficient compared with wild-type mice. Hippocampal damage and neuropeptide Y distribution at the end of chronic recordings was found to be similar between p53-deficient and wild-type mice. The present study identifies protracted KA-induced electrographic status as a novel outcome of p53 deficiency and shows that the absence of p53 leads to an exacerbated epileptic phenotype. Accordingly, targeting p53 to protect against status epilepticus or related neurologic insults may be offset by deleterious consequences of reduced p53 function during epileptogenesis or in chronic epilepsy.

Contrasting patterns of Bim induction and neuroprotection in Bim-deficient mice between hippocampus and neocortex after status epilepticus.

Prolonged seizures (status epilepticus) are associated with brain region-specific regulation of apoptosis-associated signaling pathways. Bcl-2 homology domain 3-only (BH3) members of the Bcl-2 gene family are of interest as possible initiators of mitochondrial dysfunction and release of apoptogenic molecules after seizures. Previously, we showed that expression of the BH3-only protein, Bcl-2 interacting mediator of cell death (Bim), increased in the rat hippocampus but not in the neocortex after focal-onset status epilepticus. In this study, we examined Bim expression in mice and compared seizure damage between wild-type and Bim-deficient animals. Status epilepticus induced by intra-amygdala kainic acid (KA) caused extensive neuronal death within the ipsilateral hippocampal CA3 region. Hippocampal activation of factors associated with transcriptional and posttranslational activation of Bim, such as CHOP and c-Jun NH(2)-terminal kinases, was significant within 1 h. Upregulation of bim mRNA was evident after 2 h and Bim protein increased between 4 and 24 h. Hippocampal CA3 neurodegeneration was reduced in Bim-deficient mice compared with wild-type animals after seizures in vivo, and short interfering RNA molecules targeting bim reduced cell death after KA treatment of hippocampal organotypic cultures. In contrast, neocortical Bim expression declined after status epilepticus, and neocortex damage in Bim-deficient mice was comparable with that in wild-type animals. These results show region-specific differential contributions of Bim to seizure-induced neuronal death.

[Joint reconstruction with autologous bone cylinder and locked intramedullary nail: proximal humeral shaft fracture with ipsilateral reverse Hill-Sachs lesion]. / Gelenkrekonstruktion mit autologem Knochenzylinder und winkelstabilem Marknagel: Proximale Humerusschaftfraktur mit ipsilateraler Reverse-Hill-Sachs-Läsion.

The case of a 51-year-old patient is presented, with a humeral shaft fracture in combination with an ipsilateral reverse Hill-Sachs lesion, presumably after posterior shoulder dislocation as a result of an electrical accident followed by a fall from a ladder. After corresponding diagnostics, osteosynthesis of the shaft fracture was performed with a locked antegrade intramedullary nail. Simultaneously the reverse Hill-Sachs lesion was elevated und supplemented with the bone core that accrues during drilling of the nail entrance. In the follow-up period good fragment alignment, persistent joint stability and freedom of pain could be observed. On the basis of this case and the current literature the injury mechanism and potential therapy alternatives are discussed.