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Non-steroidal anti-inflammatory drugs (NSAID) are used to alleviate pain sensations during orthodontic therapy but are also assumed to interfere with associated pseudo-inflammatory reactions. In particular, the effects of partially selective COX-2 inhibition over the constitutively expressed COX-1 (11:1) on periodontal cells and tissue, as induced by the NSAID meloxicam, remain unclear. We investigate possible adverse side-effects and potentially useful beneficial effects during orthodontic therapy and examine underlying cellular and tissue reactions. We randomly assigned 63 male Fischer344 rats to three consecutive experiments of 21 animals each (cone-beam computed tomography; histology/serology; reverse-transcription quantitative real-time polymerase chain reaction) in three experimental groups ( n  = 7; control; orthodontic tooth movement [OTM] of the first/second upper left molars [NiTi coil spring, 0.25 N]; OTM with a daily oral meloxicam dose of 3 mg/kg). In vitro, we stimulated human periodontal ligament fibroblasts (hPDL) with orthodontic pressure (2 g/cm 2 ) with/without meloxicam (10 μM). In vivo, meloxicam significantly reduced serum C-reactive protein concentration, tooth movement velocity, orthodontically induced dentine root resorption (OIRR), osteoclast activity and the relative expression of inflammatory/osteoclast marker genes within the dental-periodontal tissue, while presenting good gastric tolerance. In vitro, we observed a corresponding significant decrease of prostaglandin E 2 /interleukin-6/RANKL(−OPG) expression and of hPDL-mediated osteoclastogenesis. By inhibiting prostaglandin synthesis, meloxicam seems to downregulate hPDL-mediated inflammation, RANKL-induced osteoclastogenesis and, consequently, tooth movement velocity by about 50%, thus limiting its suitability for analgesia during orthodontic therapy. However, its protective effects regarding OIRR and good tolerance profile suggest future prophylactic application, which merits its further investigation.

Heterozygous pathogenic variants in ADAR have been associated with dyschromatosis symmetrica hereditaria, while biallelic pathogenic variants have been associated with Aicardi-Goutières syndrome 6 (AGS6). However, the heterozygous variant c.3019G>A, (p.Gly1007Arg) has been described to cause neurological manifestations, which resemble AGS6 and are associated with an upregulation of interferon-stimulated genes. We report a four-generation family with two symptomatic family members and five unaffected carriers of the heterozygous pathogenic ADAR variant c.3019G>A. The index (patient 1) manifested a gait disorder at three years of age (weakness in his legs, a tendency to fall and hyperreflexia), dyslalia, and mild cognitive developmental delay. A paternal half-brother (patient 4) to patient´s father (patient 2) presented with irritability and regression of previous skills at the age of 6 months after a fever reaction, following the second routine hexavalent vaccination at the age of 4 months. At 20 years of age, the patient was wheelchair-bound, had spasticity and severe global development delay. A blood test in both patients showed increased interferon signature with activation of type 1-interferon. Five asymptomatic carriers were identified in this family (age range 2–81 years of age) nearly all of them (except the 81-year old patient) showed a strong activation of type 1 interferon response in peripheral blood. Affected individuals had higher interferon signature than asymptomatic, underlining the possible role of interferon activation in disease mechanism. To our knowledge, this is the biggest family reported to date, encompassing a wide age-range of carriers, including an asymptotic carrier of advanced age (81 years of age).

This study investigates the influence of pre-corrosion damage on the fatigue behavior of AlSi10MgMn high-pressure die-cast specimens, using the statistical distribution of corrosion depths. The analysis is conducted on two different surface conditions: an unmachined rough surface (Ra=5.05μm) and a machined, polished surface (Ra=0.25μm). For the unmachined specimens, the corrosive damage manifests as homogeneously spread localized corrosion, whereas the polished specimens exhibit less uniform but deeper corrosion. The average corrosion depth of the polished specimens is found to be slightly higher (313 μm compared to 267 μm) with a broader depth distribution. Specimens are tested under a constant bending load amplitude in laboratory conditions at a stress ratio of R=0 until fracture. A fracture mechanics-based methodology is developed to assess the remaining fatigue life of corroded specimens, utilizing short and long crack fracture mechanical parameters derived from SENB specimens. This model incorporates a thickness reduction of the critical specimen cross-section based on the corrosion depth distribution and combines it with a small initial crack of the intrinsic defect size (aeff=14μm). Regardless of the surface condition, using the most frequent corrosion depth for thickness reduction provides a good estimate of the long-life fatigue strength, while using the 90th percentile depth allows for a conservative assessment.

Background As society ages, the need for nursing home care is steadily increasing and end-of-life care of nursing home residents has become increasingly more important. End-of-life care differs between Germany and the neighbouring Netherlands. For example, a much higher proportion of German compared to Dutch nursing home residents is hospitalized at the end of life. Therefore, the aim of this study was to evaluate end-of-life care in German and Dutch nursing homes. Methods In this cross-sectional study, a postal survey was sent to 600 randomly selected German and Dutch nursing homes each and addressed to the nursing staff management. Participants were asked to estimate the percentage of nursing home residents whose wishes for emergency situations (e.g. cardiopulmonary resuscitation) are known and to indicate whether facilities offer advanced care planning (ACP). They were also asked to estimate whether general practitioners (GPs)/elder care physicians (ECPs) and nursing home staff are usually well trained for end-of-life care. Finally, participants were asked to estimate the proportion of nursing home residents who die in hospital rather than in the nursing home and to rate overall end-of-life care provision. Results A total of 301 questionnaires were included in the analysis; 199 from German and 102 from Dutch nursing homes (response 33.2% and 17.0%). German participants estimated that 20.5% of residents die in the hospital in contrast to the Dutch estimation of 5.9%. In German nursing homes, ACP is offered less often (39.2% in Germany, 75.0% in the Netherlands) and significantly fewer wishes for emergency situations of residents were known than in Dutch nursing homes. GPs were considered less well-trained for end-of-life care in Germany. The most important measures to improve end-of-life care were comparable in both countries. Conclusion Differences in (the delivery and knowledge of) end-of-life care between Germany and the Netherlands could be observed in this study. These could be due to structural differences (ECPs available 24/7 in the majority of Dutch nursing homes) and cultural differences (more discussion on quality of life versus life-sustaining treatments in the Netherlands). Due to these differences, a country-specific approach is necessary to improve end-of-life care.

Colorectal cancer (CRC) is one of the most common cancers worldwide and demands more effective treatments. We sought to identify tumor selective CRC antigens and their therapeutic potential for cytotoxic T-cell targeting by transcriptomic and immunohistochemical analysis. LY6G6D was identified as a tumor selectively expressed CRC antigen, mainly in the microsatellite stable (MSS) subtype. A specific anti LY6G6D/CD3 T cell engager (TcE) was generated and demonstrated potent tumor cell killing and T cell activation in vitro . Ex vivo treatment of primary patient-derived CRC tumor slice cultures with the LY6G6D/CD3 TcE led to IFNγ secretion in LY6G6D positive tumor samples. In vivo , LY6G6D/CD3 TcE monotherapy demonstrated tumor regressions in pre-clinical mouse models of engrafted human CRC tumor cells and PBMCs. Lastly, 2D and 3D cocultures of LY6G6D positive and negative cells were used to explore the bystander killing of LY6G6D negative cells after specific activation of T cells by LY6G6D positive cells. LY6G6D/CD3 TcE treatment was shown to lyse target negative cells in the vicinity of target positive cells through a combined effect of IFNγ, TNFα and Fas/FasL. In summary, LY6G6D was identified as a selectively expressed CRC antigen that can be utilized to potently re-direct and activate cytotoxic T-cells to lyse LY6G6D expressing CRC using a TcE. This effect can be spread to target negative neighboring tumor cells, potentially leading to improved therapeutic efficacy.

Background: Namibia, a middle-income country in sub-Saharan Africa (SSA), plans to use the Maternal Near Miss (MNM) approach. Adaptations of the World Health Organization (WHO) MNM defining criteria ('WHO MNM criteria') were previously proposed for low-income settings in sub-Saharan Africa ('SSA MNM criteria'), but whether these adaptations are required in middle-income settings is unknown. Objective: To establish MNM criteria suitable for use in Namibia, a middle-income country in SSA. Methods: Cross-sectional study from 1 March 2018 to 31 May 2018 in four Namibian hospitals. Pregnant women or within 42 days of termination of pregnancy or birth, fulfilling at least one WHO or SSA MNM criterion were included. Records of women identified by either only WHO criteria or only SSA criteria were assessed in detail. Results: 194 Women fulfilled any MNM criterion. WHO criteria identified 61 MNM, the SSA criteria 184 MNM. Of women who only fulfilled any of the unique SSA MNM criteria, 18 fulfilled the criterion 'eclampsia', one 'uterine rupture' and five 'laparotomy'. These women were assessed to be MNM. Thresholds for blood transfusion to define MNM due to haemorrhage were two units in the SSA and five in WHO set. Two or three units were given to 95 women for mild/moderate haemorrhage or chronic anaemia who did not fulfil any WHO criterion and were not considered MNM. Fourteen women who were assessed to be MNM from severe haemorrhage received four units. Conclusions: WHO MNM criteria may underestimate and SSA MNM criteria overestimate the prevalence of MNM in a middle-income country such as Namibia, where MNM criteria 'in between' may be more appropriate. Namibia opts to apply a modification of the WHO criteria, including eclampsia, uterine rupture, laparotomy and a lower threshold of four units of blood to define MNM. We recommend that other middle-income countries validate our criteria for their setting.

Purpose Psychopathological changes and dysfunction in emotion processing have been described for anorexia nervosa (AN). Yet, findings are applicable to adult patients only. Furthermore, potential for discriminative power in clinical practice in relation to clinical parameters has to be discussed. The aim of this study was to investigate psychopathology and emotional face processing in adolescent female patients with AN. Methods In a sample of 15 adolescent female patients with AN (16.2 years, SD ± 1.26) and 15 age and sex matched controls we assessed alexithymia, depression, anxiety and empathy in addition to emotion labelling and social information processing. Results AN patients had significantly higher alexithymia, higher levels of depression, and state and trait anxiety compared to controls. There was a trend for a lower ability to recognize disgust. Happiness as a positive emotion was recognized better. All facial expressions were recognized significantly faster by AN patients. Associations of pathological eating behaviour and trait anxiety were seen. Conclusion In accordance with the stress reduction hypothesis, typical psychopathology of alexithymia, anxiety and depression is prevalent in female adolescent AN patients. It is present detached from physical stability. Pathogenesis of AN is multifactorial and already fully present in adolescence. An additional reinforcement process can be discussed. For clinical practice, those parameters might have a better potential for early prognostic factors related to AN than physical parameters and possible implication for intervention is given.

Background Multimorbidity is common in advanced age, and is usually associated with negative – yet to some extent preventable – health outcomes. Detecting comorbid conditions is especially difficult in individuals with dementia, as they might not always be able to sufficiently express discomfort. This study compares relevant comorbidity complexes in elderly people with and without dementia, with a particular look at gender- and living environment-specific differences. Moreover, associations between selected comorbid conditions and dementia are reviewed more closely. Methods Using 2006 claims data from a large German Statutory Health Insurance fund, 9,139 individuals with dementia and 28,614 age- and gender-matched control subjects aged 65 years and older were identified. A total of 30 comorbidity complexes were defined based on ICD-10 codes. Corresponding prevalence rates were calculated, and the association between a distinct condition and dementia was evaluated via logistic regression in the overall sample as well as in analyses stratified by gender and living environment. Results Individuals with dementia were more likely to be diagnosed with 15 comorbidity complexes, including Parkinson’s, stroke, diabetes, atherosclerosis (supposed dementia risk factors) or fluids and electrolyte disorders, insomnia, incontinence, pneumonia, fractures and injuries (supposed sequelae). In contrast, they were less likely to be diagnosed with 11 other conditions, which included vision and hearing problems, diseases of the musculoskeletal system, lipoprotein disorders and hypertension. In a gender-stratified analysis, the patterns remained largely the same, but a bigger comorbidity gap between cases and control subjects emerged in the male population. Restricting the analysis to community-living individuals did not lead to any substantial changes. Conclusion Besides strengthening the evidence on accepted dementia risk factors and sequelae, the analyses point to particular conditions that are likely to remain untreated or even undiagnosed. This issue seems to affect male and female individuals with dementia to varying degrees. Raising awareness of these conditions is important to possibly preventing comorbidity-associated complications and disease progression in dementia patients. To more comprehensively understand the mutual interactions between dementia and comorbidity, further research on diagnostic and treatment attitudes regarding comorbidity in dementia patients and on their gender-specific health-seeking behaviour seems to be required.

Besides being expressed on professional antigen-presenting cells, HLA class II antigens are expressed on various tumors of non-lymphoid origin, including a subset of colorectal cancers (CRC). Information about the regulation of HLA class II antigen expression is important for a better understanding of their role in the interactions between tumor and immune cells. Whether lack of HLA class II antigen expression in tumors reflects the selective immune destruction of HLA class II antigen-expressing tumor cells is unknown. To address this question, we tested whether lack of HLA class II antigen expression in CRC was associated with immune cell infiltration. We selected microsatellite-unstable (MSI-H) CRC, because they show pronounced tumor antigen-specific immune responses and, in a subset of tumors, lack of HLA class II antigen expression due to mutations inactivating HLA class II-regulatory genes. We examined HLA class II antigen expression, mutations in regulatory genes, and CD4-positive T cell infiltration in 69 MSI-H CRC lesions. Mutations in RFX5, CIITA , and RFXAP were found in 13 (28.9 %), 3 (6.7 %), and 1 (2.2 %) out of 45 HLA class II antigen-negative tumors. CD4-positive tumor-infiltrating lymphocyte counts were significantly higher in HLA class II antigen-negative tumors harboring mutations in HLA class II-regulatory genes (107.4 T cells per 0.25 mm 2 ) compared to tumors without mutations (55.5 T cells per 0.25 mm 2 , p  = 0.008). Our results suggest that the outgrowth of tumor cells lacking HLA class II antigen expression due to mutations of regulatory genes is favored in an environment of dense CD4-positive T cell infiltration.