Searching for Hidden Neutrons with a Reactor Neutrino Experiment: Constraints from the STEREO Experiment.

Different extensions of the standard model of particle physics, such as braneworld or mirror matter models, predict the existence of a neutron sterile state, possibly as a dark matter candidate. This Letter reports a new experimental constraint on the probability p for neutron conversion into a hidden neutron, set by the STEREO experiment at the high flux reactor of the Institut Laue-Langevin. The limit is p<3.1×10^{-11} at 95% C.L. improving the previous limit by a factor of 13. This result demonstrates that short-baseline neutrino experiments can be used as competitive passing-through-walls neutron experiments to search for hidden neutrons.

Accurate Measurement of the Electron Antineutrino Yield of

We report a measurement of the antineutrino rate from the fission of ^{235}U with the STEREO detector using 119 days of reactor turned on. In our analysis, we perform several detailed corrections and achieve the most precise single measurement at reactors with highly enriched ^{235}U fuel. We measure an IBD cross section per fission of σ_{f}=(6.34±0.06[stat]±0.15[sys]±0.15[model])×10^{-43} cm^{2}/fission and observe a rate deficit of (5.2±0.8[stat]±2.3[sys]±2.3[model])% compared to the model, consistent with the deficit of the world average. Testing ^{235}U as the sole source of the deficit, we find a tension between the results of lowly and highly enriched ^{235}U fuel of 2.1 standard deviations.

McLeod syndrome: Five new pedigrees with novel mutations.

OBJECTIVE: To present five new McLeod Syndrome (MLS) pedigrees with novel XK gene mutations, review the literature of this disorder, and discuss the typical and atypical clinical features noted with these new mutations. METHODS: This is a multi-center retrospective review of five MLS cases with novel gene mutations. Genotypic and phenotypic information has been obtained from each center. RESULTS: Five novel mutations are reported in this Case series. New clinical findings include prolonged asymptomatic elevated creatine kinase (CK) levels, vocal tics, presence of obstructive sleep apnea (OSA), and one patient of Vietnamese ethnicity. CONCLUSIONS: We expand on the clinical and genetic spectrum of MLS demonstrating the clinical variability of MLS.

Sterile Neutrino Constraints from the STEREO Experiment with 66 Days of Reactor-On Data.

The reactor antineutrino anomaly might be explained by the oscillation of reactor antineutrinos toward a sterile neutrino of eV mass. In order to explore this hypothesis, the STEREO experiment measures the antineutrino energy spectrum in six different detector cells covering baselines between 9 and 11 m from the compact core of the ILL research reactor. In this Letter, results from 66 days of reactor turned on and 138 days of reactor turned off are reported. A novel method to extract the antineutrino rates has been developed based on the distribution of the pulse shape discrimination parameter. The test of a new oscillation toward a sterile neutrino is performed by comparing ratios of cells, independent of absolute normalization and of the prediction of the reactor spectrum. The results are found to be compatible with the null oscillation hypothesis and the best fit of the reactor antineutrino anomaly is excluded at 97.5% C.L.

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

SPAG7 is a candidate gene for the periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome.

Periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome is an auto-inflammatory disease for which a genetic basis has been postulated. Nevertheless, in contrast to the other periodic fever syndromes, no candidate genes have yet been identified. By cloning, following long insert size paired-end sequencing, of a de novo chromosomal translocation t(10;17)(q11.2;p13) in a patient with typical PFAPA syndrome lacking mutations in genes associated with other periodic fever syndromes we identified SPAG7 as a candidate gene for PFAPA. SPAG7 protein is expressed in tissues affected by PFAPA and has been functionally linked to antiviral and inflammatory responses. Haploinsufficiency of SPAG7 due to a microdeletion at the translocation breakpoint leading to loss of exons 2-7 from one allele was associated with PFAPA in the index. Sequence analyses of SPAG7 in additional patients with PFAPA point to genetic heterogeneity or alternative mechanisms of SPAG7 deregulation, such as somatic or epigenetic changes.

Proof testing of ceramic femoral heads for hip joint implants.

A proof test procedure for the rejection of defective ceramic hip ball heads in the production line is presented. The procedure consists of applying a load to each ceramic ball head. This load, being somewhat higher than the maximum physiological load, should not cause any damage in cases where the highly stressed areas are free of flaws. In this procedure, a polymer ring is positioned inside the ball head bore between a socket and the head of a tie bolt. Once the tie bolt is pulled downwards, the ring creates a radial pressure on the inner bore surface of the ball head. With an iterative approach based on finite element analysis, the proof test design was optimized in order to obtain a stress distribution in the ball head similar to that resulting in in vivo conditions. The calculated results were validated by strain gauge measurements performed on an assembled proof test apparatus. Several polymers were considered for the ring. Ultrahigh-molecular-weight polyethylene (UHMWPE grade RCH 1000) showed the best durability properties and lowest wear rates. The requirement to perform 1000 reruns without significant reduction of stress in the ball head was fulfilled. Although other proof test procedures for ceramic femoral heads already exist, the procedure presented in this article shows advantages concerning maintenance and operating costs.

Optimization of the stress distribution in ceramic femoral heads by means of finite element methods.

Ceramic ball heads for total hip replacement are highly loaded in vivo and must meet the sternest requirements concerning strength and safety. High stresses inside the ball head originate from the press fit between the conical stem (made of titanium alloy or steel) and the borehole of the ball. The aim of this study was the development of an optimized contour at the fillet inside the ball head by means of numerical methods, in order to reduce local stress concentrations. The computer-aided optimization method was applied on the customary engineering fillet radius to reduce local stress peaks. The local notch stress of the examined ball head design was reduced by up to 27 per cent for the relevant load cases. Verification by rupture testing of prototypes turned out to be difficult for axisymmetric load cases, since the static fracture load is governed by the hoop stresses in the contact area of the taper (global maximum), thus making it difficult to prove a local improvement. The sensitivity of the design to asymmetric loading was clearly shown (varying the load angle and bearing type). Stress relocation in the ball-stem interface at higher burst loads indicated the necessity of optimizing each ceramic femoral head design individually (i.e. for different borehole depths).

Influence of contaminants in the stem-ball interface on the static fracture load of ceramic hip joint ball heads.

The probability of in-vivo failure of ceramic hip joint implants is very low (0.05-0.004 per cent). Besides material flaws and overloading, improper handling during implantation may induce fractures of the ceramic ball head in the long term. This study focuses on the influence of contaminants located in the stem-ball interface and on the use of damaged metal tapers on the strength of ceramic ball heads. Mechanical tests on alumina ball heads according to the standard ISO 7206-10 were performed to identify their effect on the static fracture load. A decrease of up to 90 per cent with respect to the reference static fracture load was found when contaminants such as bone chips, soft tissue, or blood were present. Reductions of 57 per cent and 27 per cent were observed for deformed stem cross-sections (from circular to elliptical) and for flattened stems respectively, making deformed stems another influential parameter. Since any alteration of the interface between the metal taper and the ceramic ball head yields a nonuniform load introduction and hence results in stress concentrations, its presence has to be avoided.

[Sacral fracture as a rare early complication of lumbosacral spondylodesis]. / Sakrumfraktur als seltene Frühkomplikation nach lumbosakraler Spondylodese.

A 57 year old patient with secondary cortisone induced osteoporosis war surgically treated by means of posterior lumbar interbody fusion with internal fixation from L4-S1 for symptomatic instability in the level L4/5 after previous dorsal stabilisation L5/S1. After an unapparent initial postoperative phase, the patient complained of severe pain in the low back and gluteal region 9 day after surgery. Radiographs as well as CT-scans showed a horizontal fracture of the sacrum. After a short period of immobilisation the patient was carefully remobilised with an orthesis and the pain gradually subsided. Conventional radiographs one year later showed complete consolidation of the fracture and a good clinical result. There are only two literature reports with together 3 cases of patients attaining an early sacral fracture after spondylodesis. The main cause seems to be the unphysiological biomechanical stress placed on the osteoporotic sacrum after moresegmental spondylodesis. Further risk factors seem to be adipositas, female gender and age. Despite the rarity of sacral fractures after lumbosacral fusion, this complication should at least be considered in the differential diagnosis in patients who complain of persisting or sudden-onset pain after surgery.

[Invasive chondrosarcoma of the thoracic spine as a rare cause of acute paraplegia]. / Invasives Chondrosarkom der Brustwirbelsäule als seltene Ursache einer akuten Querschnittssymptomatik.

We report on the case of a invasive chondrosarcoma of the thoracic spine in a 65-year-old woman as a rare cause of acute paraplegia.

Coccygectomy for coccygodynia: does pathogenesis matter?

BACKGROUND: Severity of vertical impact to the coccyx can range from mere contusion to a dislocated fracture of the coccyx. With early conservative management, most patients have a good prognosis and heal within weeks to months after the initial trauma. Occasionally, persisting symptoms make a surgical intervention with coccygectomy necessary. METHODS: We report on the results of patients surgically managed for traumatically induced, persisting coccygodynia and compare these to patients operatively treated for idiopathic coccygodynia. Sixteen patients with an average follow-up of 7.3 years were evaluated. Of these, eight were surgically treated for traumatic and eight for idiopathic coccygodynia. The clinical results were assessed by means of the Hambly Score and the Oswestry Low Back Pain Disability questionnaire. Patient satisfaction with the postoperative result was assessed by a visual analog scale. RESULTS: Seven of eight (88%) patients treated for traumatically induced coccygodynia had a good or excellent postoperative result, in contrast to only three of eight (38%) patients with idiopathic coccygodynia. The former group had better results in terms of sitting tolerance and general pain intensity as represented by the Oswestry Low Back Pain Disability questionnaire. According to the significantly better clinical results, personal satisfaction was clearly higher in the traumatic group. CONCLUSION: These results suggest that, in patients where all conservative treatment methods work to no avail, particularly those with traumatically induced persisting coccygodynia benefit from surgical intervention with coccygectomy.

[Effectiveness of interscalene plexus block for open subacromion decompression]. / Effektivität der interskalenären Plexusblockade nach offener subakromialer Dekompression.

AIM: The aim of this study was to assess the influence of interscalene brachial plexus blocks on the functional outcome, subjective pain appraisal and patient satisfaction after open shoulder surgery. These results were compared with patients treated by conventional analgesic measures. METHOD: 23 patients with interscalene brachial plexus block (ISB) and 21 patients without ISB were evaluated preoperatively as well as 1, 7, 12 and 90 days after open surgery of the shoulder. By means of a visual analogue scale (VAS) subjective postoperative pain intensity was assessed. Using the Constant score preoperatively and 6 months after surgery the functional status of the treated shoulder was evaluated. At discharge from hospital patients were asked whether they were satisfied with the analgesic measures taken. RESULTS: The range of motion of the shoulder of patients treated with an ISB was significantly higher 1 and 7 days after surgery than those without ISB. 12 and 90 days postoperatively the range of motion in the ISB group was still higher, but no longer statistically significant. Assessment of the postoperative subjective pain status showed that patients with an ISB had significantly lower values and required less additional analgesia. In both groups the Constant score was significantly higher 6 months after surgery, compared to the preoperative condition. Compared to the control group, patients treated with ISB were clearly more satisfied with the postoperative pain management. CONCLUSION: By implementing ISB sufficient analgesia in the early postoperative period after open shoulder surgery is attained, allowing for early physiotherapy. This positively influences convalescence and the outcome of the surgical procedure. Furthermore, patients are visibly more satisfied with the postoperative pain management.

Pimecrolimus does not affect Langerhans cells in murine epidermis.

BACKGROUND: Langerhans cells (LCs) function as specialized antigen-presenting cells in the epidermis, and therefore play a critical role in cutaneous immunological reactions. Topical treatment with corticosteroids is associated with a decrease in epidermal LC number and antigen-presenting capacity in laboratory animals and humans. OBJECTIVES: To examine whether pimecrolimus, a nonsteroidal inflammatory cytokine inhibitor recently introduced for the topical treatment of atopic dermatitis, differs from corticosteroids in effects on LCs. METHODS: Groups of BALB/c mice were treated twice daily on one to five consecutive days on the inner surface of the right ear with 10 micro L of ethanolic solutions of the test compounds at their clinically used concentrations (1% pimecrolimus, 0.1% betamethasone-17-valerate, 1% hydrocortisone and 0.05% clobetasol propionate) or with the vehicle (controls) alone. At selected time points after the treatment epidermal sheets were prepared and examined histomorphometrically for LCs immunolabelled with antibodies to major histocompatibility complex (MHC) class II and DEC 205, and adenosine diphosphatase staining. RESULTS: No changes in number or morphology of LCs were observed in epidermal sheets of mice treated for 5 days with pimecrolimus. In contrast, an almost complete depletion of LCs was observed in skin samples treated with hydrocortisone, betamethasone or clobetasol. Even a single-day treatment schedule with hydrocortisone, betamethasone or clobetasol caused a significant reduction in MHC class II+ LCs, by 31%, 62% and 87%, respectively. CONCLUSIONS: It is therefore unlikely that topically applied pimecrolimus affects epidermal LCs, in contrast to corticosteroids.

[Development and pre-clinical aspects of pimecrolimus]. / Entstehungsgeschichte und präklinisches Profil von Pimecrolimus.

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, inhibits the phosphatase calcineurin and blocks the production of inflammatory cytokines in T cells. In contrast to corticosteroids, pimecrolimus has a cell selective mode of action, exerting e.g. no effect on dendritic cells, which have a central function in the skin-associated immune system. Pimecrolimus shows less permeation through skin than corticosteroids and tacrolimus which indicates a lower potential for systemic side effects after topical application. In animal models pimecrolimus has a marked dose-dependent anti-inflammatory activity. However, treatment with pimecrolimus does not induce skin atrophy in contrast to corticosteroids. In contrast to tacrolimus, pimecrolimus does not impair the primary immune reaction in the sensitization phase of allergic contact dermatitis and has generally less effect on systemic immune reactions. In summary, the pharmacological profile of pimecrolimus suggests high clinical efficacy together with excellent safety.

Iminosugars and relatives as antiviral and potential anti-infective agents.

Iminosugars have emerged in the literature during mid-1960's as synthetic compounds. Around the same time, the first examples were found in Nature and their interesting enzyme inhibitory properties were recognised. Due to their powerful interference with glycohydrolases (glycosidases) as well as glycosyltransferases, quite a few representatives exhibit notable biological activities. These range from anti-diabetic, insect antifeedant, nematicidal, plant growth regulating to immunomodulating, anti-cancer as well as - in selected cases - anti-infective properties. The latter will be the focus of the following survey.

A draft annotation and overview of the human genome.

BACKGROUND: The recent draft assembly of the human genome provides a unified basis for describing genomic structure and function. The draft is sufficiently accurate to provide useful annotation, enabling direct observations of previously inferred biological phenomena. RESULTS: We report here a functionally annotated human gene index placed directly on the genome. The index is based on the integration of public transcript, protein, and mapping information, supplemented with computational prediction. We describe numerous global features of the genome and examine the relationship of various genetic maps with the assembly. In addition, initial sequence analysis reveals highly ordered chromosomal landscapes associated with paralogous gene clusters and distinct functional compartments. Finally, these annotation data were synthesized to produce observations of gene density and number that accord well with historical estimates. Such a global approach had previously been described only for chromosomes 21 and 22, which together account for 2.2% of the genome. CONCLUSIONS: We estimate that the genome contains 65,000-75,000 transcriptional units, with exon sequences comprising 4%. The creation of a comprehensive gene index requires the synthesis of all available computational and experimental evidence.

Powerful probes for glycosidases: novel, fluorescently tagged glycosidase inhibitors.

Amino-1,2,5-trideoxy-2,5-imino-D-mannitol was fluorescently tagged by reaction with dansyl chloride at N-1 or by attachment of a dansyl amide bearing spacer to this centre. Compounds obtained are highly potent inhibitors of beta-glucosidase exhibiting Ki values in the single figure nanomolar range. The 1-N-dansyl substituted inhibitor was successfully exploited for binding studies with beta-glucosidase from Agrobacterium sp. employing fluorescence spectrometric methods.

Ethambutol analogues as potential antimycobacterial agents.

A range of new ethambutol analogues was synthesised and their inhibitory potencies were probed with Mycobacterium smegmatis. Interestingly, apparently even minor deviation from the structure of the parent compound resulted in reduced antimycobacterial activity.