[One-year outcomes after proximal humeral fractures : A risk-adjusted regression analysis of routine data based on 17,322 cases]. / Einjahresverläufe nach proximalen Humerusfrakturen : Eine risikoadjustierte Regressionsanalyse mittels Routinedaten anhand von 17.322 Fällen.

BACKGROUND: Proximal humeral fractures (PHF) are the third most common fracture in geriatric traumatology. No standard evidence-based treatment has been established so far. The epidemiology and economic burden highlight the importance of a targeted treatment strategy. OBJECTIVE: Epidemiology of PHF and analysis of the influence of preoperative length of stay, comorbidities and quality of patient life. Additionally, a comparison to the more frequently studied proximal femoral fractures. MATERIAL AND METHODS: A routine data analysis of 17,322 cases admitted for inpatient treatment with an observational period of 1 year was performed following an established model. Descriptive statistics included comorbidities, treatment procedures and mortality. Analytical statistics using logistic regression with the primary endpoints of early revision, mortality and decubitus within 1 year. RESULTS: In the investigated PHFs there was a mortality of 13% within 1 year, which is increased three-fold in patients with comorbidities such as cancer. There was an increase of 57% in patients who first received a care level following PHF. A preoperative care level in general significantly decreased survival. The most frequently used surgical procedure was fixation via stable-angle plate (used in 43%). The preoperative length of stay did not impact survival. DISCUSSION: Intrinsic factors such as preoperative comorbidities are crucial for the mortality after PHF. The PHF affects patients' lives less than proximal femoral fractures. With comparable comorbidity profiles, possible reasons are the lower levels of immobilization and less dependency on care before the fracture in comparison to proximal femoral fractures.

Whole-Body and Forearm Muscle Protein Metabolism in Patients With Acromegaly Before and After Treatment.

BACKGROUND: Active acromegaly is characterized by increased lean body mass, but the mechanisms underlying the protein anabolic effect are unclear. AIM: To study if active acromegaly induces reversible changes in whole-body and skeletal muscle protein kinetics. PATIENTS AND METHODS: Eighteen patients with acromegaly were investigated before and 47 ± 10 weeks after disease control by surgery (n = 8) and/or medical treatment (n = 10). Labeled phenylalanine and tyrosine tracers were employed to assess whole-body and regional forearm muscle protein kinetics. Intramyocellular protein signaling was assessed in skeletal muscle biopsies, and whole-body dual-energy X-ray absorptiometry scan and indirect calorimetry assessed lean body mass (LBM) and resting energy expenditure, respectively. RESULTS: Disease control induced a 7% decrease in lean body mass (P < .000) and a 14% decrease in LBM-adjusted energy expenditure. Whole-body phenylalanine breakdown decreased after disease control (P = .005) accompanied by a decrease in the degradation of phenylalanine to tyrosine (P = .005) and a decrease in whole-body phenylalanine synthesis (P = .030). Skeletal muscle protein synthesis tended to decrease after disease control (P = .122), whereas the muscle protein breakdown (P = .437) and muscle protein loss were unaltered (P = .371). Unc-51 like autophagy activating kinase 1 phosphorylation, an activator of protein breakdown, increased after disease control (P = .042). CONCLUSIONS: Active acromegaly represents a reversible high flux state in which both whole-body protein breakdown and synthesis are increased, whereas forearm muscle protein kinetics are unaltered. Future studies are needed to decipher the link between protein kinetics and the structure and function of the associated growth hormone-induced increase in lean body mass.

Ectopic lipid deposition and insulin resistance in patients with GH disorders before and after treatment.

OBJECTIVES: Insulin resistance is associated with ectopic lipid deposition. Growth hormone (GH) status also modulates ectopic lipid accumulation, but how this associates with insulin resistance in patients with GH disorders is not well established. DESIGN AND METHODS: Twenty-one patients diagnosed with acromegaly and 12 patients with adult GH deficiency (GHD) were studied at diagnosis and after treatment. A reference group of 12 subjects was included. Each study day comprised assessment of body composition with dual-energy X-ray absorptiometry, ectopic lipid deposition in the liver by MR spectroscopy, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). RESULTS: Disease control of acromegaly decreased lean body mass (LBM) (P < .000) and increased the percentage of total body fat (TBF) (P < .000). GH replacement increased LBM in the GHD patients (P = .007) and decreased the percentage of TBF (P = .010). The intrahepatic lipid (IHL) content increased after disease control in acromegaly (P = .004), whereas IHL did not change significantly after GH replacement in GHD (P = .34). Insulin resistance (HOMA-IR) improved after disease control of acromegaly (P < .000) and remained unaltered after GH replacement in the GHD patients (P = .829). CONCLUSIONS: GH status is a significant modulator of body composition and insulin sensitivity.GH excess reduces total fat mass and intrahepatic lipid content together with induction of insulin resistance.The data support the notion that GH-induced insulin resistance is unassociated with hepatic lipid accumulation.

Human visceral and subcutaneous adipose stem and progenitor cells retain depot-specific adipogenic properties during obesity.

Abdominal obesity associates with cardiometabolic disease and an accumulation of lipids in the visceral adipose depot, whereas lipid accumulation in the subcutaneous depot is more benign. We aimed to further investigate whether the adipogenic properties where cell-intrinsic, or dependent on a depot-specific or obesity-produced microenvironment. We obtained visceral and subcutaneous biopsies from non-obese women (n = 14) or women living with morbid obesity (n = 14) and isolated adipose stem and progenitor cells (ASPCs) from the stromal vascular fraction of non-obese (n = 13) and obese (n = 13). Following in vitro differentiation into mature adipocytes, we observed a contrasting pattern with a lower gene expression of adipogenic markers and a higher gene expression of immunogenic markers in the visceral compared to the subcutaneous adipocytes. We identified the immunogenic factor BST2 as a marker for visceral ASPCs. The effect of obesity and insulin resistance on adipogenic and immunogenic markers in the in vitro differentiated cells was minor. In contrast, differentiation with exogenous Tumor necrosis factor resulted in increased immunogenic signatures, including increased expression of BST2, and decreased adipogenic signatures in cells from both depots. Our data, from 26 women, underscore the intrinsic differences between human visceral and subcutaneous adipose stem and progenitor cells, suggest that dysregulation of adipocytes in obesity mainly occurs at a post-progenitor stage, and highlight an inflammatory microenvironment as a major constraint of human adipogenesis.

[Development of the inpatient quality of care of surgically treated patients with a proximal femoral fracture in North Rhine-Westphalia : Analysis of 61,249 treatment courses based on data from external inpatient quality assurance]. / Entwicklung der stationären Versorgungsqualität operativ behandelter Patienten mit einer proximalen Femurfraktur in Nordrhein-Westfalen : Eine Analyse über 61.249 Behandlungsverläufe auf Grundlage der Daten der externen stationären Qualitätssicherung.

BACKGROUND AND OBJECTIVE: Every year in Germany over 100,000 people, mostly of older age, suffer a proximal femoral fracture. Increasing case numbers in connection with an aging population and a relatively large number of concomitant diseases requiring treatment make everyday care more difficult. It is therefore of great importance to observe the quality of care for these patients using relevant quality parameters in order to be able to derive implications for everyday treatment practice. MATERIAL AND METHODS: The data of the external inpatient quality assurance from North Rhine-Westphalia for the years 2007-2008 and 2017-2018 were analyzed and the time periods compared. In addition, based on the documented secondary diagnosis and other influencing parameters, a risk adjustment was carried out with the aid of a logistic regression model with respect to the outcomes of general and surgical complications and mortality. Both osteosynthetically and endoprosthetically treated patients were taken into account. A total of 61,249 cases were included in the study. RESULTS: Positive developments could be observed in the area of surgical complications and wound infections with decreases of 1.2% and 0.8%, respectively. Patients with cardiovascular diseases had a particularly poor outcome. Here, improvements in the subcategory of cardiovascular events were found for general complications. The mortality remained unchanged at 6%. Operative activity on the weekends increased significantly. Patients whose hospital admission was related to the weekend did not show an increased risk of complications or mortality. Although the proportion of patients who were operated on after more than 48 h was reduced from 11.4% to 8.2%, the operation (> 24 h) was still delayed in 26.8% of cases. CONCLUSION: Against the background of increasing performance demands on the healthcare system, the results document improvements in some central areas of inpatient treatment. Nevertheless, the development of strategies for the further reduction of the preoperative waiting times in a medically justifiable manner is required. Internal concomitant diseases have a decisive influence on patient outcome. Thus, an adequate treatment of the multimorbid patient collective is to be established in everyday practice on the basis of close cooperation between geriatric traumatology and geriatric internal medicine departments.

Reversible insulin resistance in muscle and fat unrelated to the metabolic syndrome in patients with acromegaly.

BACKGROUND: Patients with active acromegaly exhibit insulin resistance despite a lean phenotype whereas controlled disease improves insulin sensitivity and increases fat mass. The mechanisms underlying this paradox remain elusive, but growth hormone (GH)-induced lipolysis plays a central role. The aim of the study was to investigative the molecular mechanisms of insulin resistance dissociated from obesity in patients with acromegaly. METHODS: In a prospective study, twenty-one patients with newly diagnosed acromegaly were studied at diagnosis and after disease control obtained by either surgery alone (n=10) or somatostatin analogue (SA) treatment (n=11) with assessment of body composition (DXA scan), whole body and tissue-specific insulin sensitivity and GH and insulin signalling in adipose tissue and skeletal muscle. FINDINGS: Disease control of acromegaly significantly reduced lean body mass (p<0.001) and increased fat mass (p<0.001). At diagnosis, GH signalling (pSTAT5) was constitutively activated in fat and enhanced expression of GH-regulated genes (CISH and IGF-I) were detected in muscle and fat. Insulin sensitivity in skeletal muscle, liver and adipose tissue increased after disease control regardless of treatment modality. This was associated with enhanced insulin signalling in both muscle and fat including downregulation of phosphatase and tensin homolog (PTEN) together with reduced signalling of GH and lipolytic activators in fat. INTERPRETATION: In conclusion, the study support that uncontrolled lipolysis is a major feature of insulin resistance in active acromegaly, and is characterized by upregulation of PTEN and suppression of insulin signalling in both muscle and fat. FUNDING: This work was supported by a grant from the Independent Research Fund, Denmark (7016-00303A) and from the Alfred Benzon Foundation, Denmark.

The decrease of endothelial progenitor cells caused by high altitude may lead to coronary heart disease.

OBJECTIVE: The purpose of this study was to explore the relationship between the number of endothelial progenitor cells (EPCs) and coronary heart disease (CHD). PATIENTS AND METHODS: A total of 24 patients with CHD were chosen from Lanzhou City and Xianyang City, and then, 24 healthy controls who matched the CHD group in gender, age and address were chosen as control group. C-reactive protein (CRP) and c-reaction protein (hs-CRP) were detected. The levels of interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), homocysteine (Hcy), hypoxia-inducible factor-1 (HIF-1α) and stromal cell-derived factor 1 (SDF-1α) were detected. RESULTS: The number of EPCs in control groups was both increased compared with CHD group (p<0.05). The number of EPCs in Xianyang control group was increased compared with Lanzhou control group (p<0.05). Compared with the control group, the levels of TC, LDL and CRP in the CHD group were higher (p<0.05). Compared with Lanzhou control group, Hcy level was decreased in Lanzhou CHD group (p<0.05). Compared with Xianyang control group, the levels of IL-8 and VEGF were increased, but the levels of HIF-1α and Hcy were decreased in the Xianyang CHD group (p<0.05). The expressions of IL-8, VEGF, Hcy and HIF-1α were increased in Lanzhou control group than the Xianyang control group (p<0.05). In Lanzhou CHD group, Spearman correlation analysis showed that the number of EPCs was negatively related to hs-CRP content (r=-0.631, p<0.05). CONCLUSIONS: The decrease of EPCs caused by high altitude may increase the expressions of various cytokines, leading to the occurrence of CHD.

Shared goals, communication and mutual respect in multicultural staff teams: A relational coordination perspective.

AIM: Task interdependence among staff in nursing homes is high, and staff teams are typically composed of employees from different cultural backgrounds with varying levels of skills and qualifications. By applying relational coordination theory as an analytic lens, we investigated how communication and cooperation challenges are experienced and dealt with. DESIGN: This is a qualitative study. METHOD: In-dept interviews with 31 members of staff in two nursing homes and thematic analysis of the material. RESULTS: The study identified challenges in direct communication and collaboration difficulties related to understanding how to use professional discretion in daily care practices in both nursing homes. The management in one of the two nursing homes arranged frequent meetings to share knowledge about the residents, their care status and introduced initiatives to build competence among all members of staff, including substitute and temporary staff. This contributed to ensuring shared goals and mutual respect at the workplace.

[Subtrochanteric femur fractures-epidemiology, surgical procedures, influence of time to surgery and comorbidities on complications : A risk-adjusted regression analysis of routine data from 2124 cases]. / Subtrochantäre Femurfrakturen ­ Epidemiologie, Operationsverfahren sowie Einfluss der präoperativen Verweildauer und von Nebendiagnosen auf Komplikationen : Eine risikoadjustierte Regressionsanalyse mittels Routinedaten anhand von 2124 Fällen.

BACKGROUND: There are approximately 12,000 subtrochanteric femur fractures in Germany per year with a rising trend but studies about the epidemiology and the surgical outcome are rare. Furthermore, there are no guidelines from expert societies and there is no adequate quality assurance. OBJECTIVE: Presentation of the epidemiology and the current treatment situation with respect to the patient collective, comorbidities, time to surgery and surgical procedures used as well as the identification of modifiable risk factors with respect to complications. MATERIAL AND METHODS: Analysis of routine data based on an established data model in 2124 cases. The descriptive statistics contain data on basic patient characteristics, such as age, comorbidities, surgical procedure, time to surgery and mortality. In the analytical statistics the impact of risk factors (surgical procedure, time to surgery etc.) on the endpoints mortality, complications and decubitus was investigated by logistical regression analyses. RESULTS: Of the patients 55% were operated on within the first 24h. Intramedullary osteosynthesis (89%) is the most frequently used surgical method (prostheses 2%, extramedullary procedures 5%). Within the first postoperative year 37% of the patients received a higher level of care, where the care was moved from outpatient to inpatient treatment. The mortality in the first postoperative year was 26%, while early complications were observed in 6%. A delay in surgical treatment was associated with an increased mortality and intrinsic factors, which were difficult to influence. Intramedullary osteosynthesis had the lowest mortality and revision rates. CONCLUSION: Concerning the epidemiological data, the patient collectives of subtrochanteric fractures and femoral neck or pertrochanteric fractures were very similar. Major delays in the time to surgery of subtrochanteric fractures can be associated with increased complication rates and mortality. Therefore, programs to prevent older patients from falling have a high priority.

Human Brown Adipocyte Thermogenesis Is Driven by ß2-AR Stimulation.

Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the ß3-adrenergic receptor (ß3-AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of ß3-AR. Oral administration of the ß3-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to ß1-AR and ß2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. ADRB2 was co-expressed with UCP1 in human brown adipocytes. Pharmacological stimulation and inhibition of the ß2-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through ß2-AR signaling in humans (ClinicalTrials.govNCT02811289).

Wearable electromyography recordings during daily life activities in children with cerebral palsy.

AIM: To test whether wearable textile electromyography (EMG) recording systems may detect differences in muscle activity levels during daily activities between children with cerebral palsy (CP) and age-matched typically developing children. METHOD: Wearable textile EMG recording systems were used to obtain leg muscle activity in 10 children with spastic CP (four females, six males; mean age 9y 6mo, standard deviation [SD] 2y 4mo, range: 6-13y; Gross Motor Function Classification System [GMFCS] level I and II) and 11 typically developing children (four females, seven males; mean age 9y 9mo, SD 1y 11mo, 7-12y) at rest and while performing seven daily activities. RESULTS: Children with CP showed significantly lower absolute EMG levels during maximal voluntary contractions (MVCs) of muscles on the most affected side as compared to the least affected side and to typically developing children. None of the typically developing children or children with CP showed detectable EMG activity in resting situations. EMG activity relative to MVC was greater in children with CP during walking, jumping, and kicking on the most affected side as compared to the least affected side and to typically developing children. INTERPRETATION: Wearable textile EMG recording systems may be used to determine differences in muscle activity during daily activities in children with CP. Children with CP showed reduced muscle activity during daily activities compared to their peers, but used a significantly larger part of their maximal voluntary muscle strength to perform these activities. WHAT THIS PAPER ADDS: Wearable textile electromyography (EMG) systems are feasible for measurement of daily muscle activity in children with cerebral palsy (CP). Children with CP showed reduced EMG levels during maximal voluntary contractions. Neither typically developing children or children with CP showed EMG activity in resting situations. Children with CP used a larger part of their voluntary muscle strength during daily activities.

Grabaciones de electromiografía portátil durante las actividades de la vida diaria en niños con parálisis cerebral OBJETIVO: Probar si los sistemas de registro de electromiografía textil portátil (EMG) pueden detectar diferencias en los niveles de actividad muscular durante las actividades diarias entre los niños con parálisis cerebral (PC) y los niños de desarrollo típico de la misma edad. MÉTODO: Se utilizaron sistemas de registro de EMG textiles portátiles para obtener actividad muscular de las piernas en 10 niños con PC espástica (cuatro mujeres, seis varones; edad media 9 años y 6 meses, desviación estándar [ED] 2 años y 4 meses, rango: 6-13 años; Escala de clasificación de función motora gruesa [GMFCS] nivel I y II) y 11 niños típicamente en desarrollo (cuatro mujeres, siete varones; edad media 9 años y 9 meses, DE 1 años y 11 meses, 7-12 años) en reposo y mientras realizan siete actividades diarias. RESULTADOS: Los niños con PC mostraron niveles de EMG absolutos significativamente más bajos durante las contracciones voluntarias máximas (CVM) de los músculos en el lado más afectado en comparación con el lado menos afectado y en los niños con desarrollo típico. Ninguno de los niños con desarrollo típico o niños con PC mostró actividad EMG detectable en situaciones de reposo. La actividad EMG en relación con CVM fue mayor en niños con PC al caminar, saltar y patear en el lado más afectado en comparación con el lado menos afectado y en los niños con desarrollo típico. INTERPRETACIÓN: Los sistemas de registro de EMG textiles portátiles pueden usarse para determinar las diferencias en la actividad muscular durante las actividades diarias en niños con PC. Los niños con PC mostraron una actividad muscular reducida durante las actividades diarias en comparación con sus compañeros, pero utilizaron una parte significativamente mayor de su fuerza muscular voluntaria máxima para realizar estas actividades.

Registros vestíveis de eletromiografia durante atividades de vida diária em crianças com paralisia cerebral OBJETIVO: Testar se registros têxteis vestíveis de eletromiografia (EMG) podem detector diferenças nos níveis de atividade muscular durante atividades de vida diária entre crianças com paralisia cerebral (PC) e crianças com desenvolvimento típico da mesma idade. MÉTODO: Sistemas têxteis vestíveis de EMG foram usados para obter a atividade muscular em 10 crianças com PC espástica (quatro do sexo feminino, seis do sexo masculino; média de idade 9a6m, desvio padrão [DP] 2a 4m, variação: 6-13a; Sistema de Classificação da Função Motora Grossa [GMFCS] nível I e II) e 11 crianças com desenvolvimento típico (quatro do sexo feminino, sete do sexo masculino; média de idade 9a 9m, DP 1a 11m, 7-12a) em repouso e durante a realização de sete atividades de vida diária. RESULTADOS: Crianças com PC mostraram níveis de EMG significativamente menores durante contrações voluntárias máximas (CVMs) de músculos no lado mais afetado, em comparação com o lado menos afetado e com crianças típicas. Nenhuma das crianças típicas ou com PC mostrou atividade de EMG detectável nas situações de repouso. A atividade de EMG relativa a CVM foi maior em crianças com PC durante a marcha, salto e chutes no lado mais afetado em comparação com o lado menos afetado e com crianças típicas. INTERPRETAÇÃO: Sistemas têxteis vestíveis para registro de EMG podem ser usados para determinar diferenças na atividade muscular durante atividades de vida diária em crianças com PC. Crianças com PC mostraram reduzida atividade muscular durante atividades diárias comparadas com seus pares, mas usaram uma porção significativamente maior de sua força voluntária máxima para realizar estas atividades.

Multivalent HER2-binding polymer conjugates facilitate rapid endocytosis and enhance intracellular drug delivery.

Incorporating targeting moieties that recognize cancer-specific cellular markers can enhance specificity of anticancer nanomedicines. The HER2 receptor is overexpressed on numerous cancers, making it an attractive target. However, unlike many receptors that trigger endocytosis upon ligand binding, HER2 is an internalization-resistant receptor. As most chemotherapeutics act on intracellular targets, this presents a significant challenge for exploiting HER2 overexpression for improved tumor killing. However, hyper-crosslinking of HER2 has been shown to override the receptor's native behavior and trigger internalization. This research co-opts this crosslinking-mediated internalization for efficient intracellular delivery of an anticancer nanomedicine - specifically a HPMA copolymer-based drug delivery system. This polymeric carrier was conjugated with a small (7 kDa) HER2-binding affibody peptide to produce a panel of polymer-affibody conjugates with valences from 2 to 10 peptides per polymer chain. The effect of valence on surface binding and uptake was evaluated separately. All conjugates demonstrated similar (nanomolar) binding affinity towards HER2-positive ovarian carcinoma cells, but higher-valence conjugates induced more rapid endocytosis, with over 90% of the surface-bound conjugate internalized within 4 h. Furthermore, this enhancement was sensitive to crowding - high surface loading reduced conjugates' ability to crosslink receptors. Collectively, this evidence strongly supports a crosslinking-mediated endocytosis mechanism. Lead candidates from this panel achieved high intracellular delivery even at picomolar treatment concentrations; untargeted HPMA copolymers required 1000-fold higher treatment concentrations to achieve similar levels of intracellular accumulation. This increased intracellular delivery also translated to a more potent nanomedicine against HER2-positive cells; incorporation of the chemotherapeutic paclitaxel into this targeted carrier enhanced cytotoxicity over untargeted polymer-drug conjugate.

Fibroblast Activation Protein is a GH Target: A Prospective Study of Patients with Acromegaly Before and After Treatment.

BACKGROUND: Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM: To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS: Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, ß-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: Total FGF21, active FGF21 and ß-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION: 1) Circulating FGF21 and ß-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION: NCT00647179.

Proteomics-Based Comparative Mapping of the Secretomes of Human Brown and White Adipocytes Reveals EPDR1 as a Novel Batokine.

Adipokines secreted from white adipose tissue play a role in metabolic crosstalk and homeostasis, whereas the brown adipose secretome is less explored. We performed high-sensitivity mass-spectrometry-based proteomics on the cell media of human adipocytes derived from the supraclavicular brown adipose and from the subcutaneous white adipose depots of adult humans. We identified 471 potentially secreted proteins covering interesting categories such as hormones, growth factors, extracellular matrix proteins, and proteins of the complement system, which were differentially regulated between brown and white adipocytes. A total of 101 proteins were exclusively quantified in brown adipocytes, and among these was ependymin-related protein 1 (EPDR1). EPDR1 was detected in human plasma, and functional studies suggested a role for EPDR1 in thermogenic determination during adipogenesis. In conclusion, we report substantial differences between the secretomes of brown and white human adipocytes and identify novel candidate batokines that can be important regulators of human metabolism.

LncRNA Lethe protects sepsis-induced brain injury via regulating autophagy of cortical neurons.

OBJECTIVE: To investigate the role of long non-coding RNA (lncRNA) Lethe in mediating autophagy of cortical neurons in mice with sepsis-induced brain injury (SIBI). MATERIALS AND METHODS: A total of 60 wild-type C57BL/6 mice were divided into sham-operated wild-type (SWT) group and wild-type model (MWT) group. Sixty Lethe-/- mice were divided into sham-operated knockout (SKO) group and model knockout (MKO) group. Each group had 30 mice. Sepsis model in mice was established by cecal ligation and puncture (CLP). Neurobiological score was recorded at 6 h after CLP. Mice with lower than 6 scores of neurobehavioral tests were diagnosed with SIBI. Quantitative Real-time polymerase chain reaction (qRT-PCR) was performed to determine mRNA levels of Lethe and interferon-γ (INF-γ) in cortical neurons of SIBI mice. Western blot was conducted to detect protein levels of LC3-II, LC3-I and SQSTM1 in mice. Neuronal impairment in mouse brain was evaluated by hematoxylin and eosin (HE) staining. RESULTS: Expressions of LC3-I and LC3-II in cerebral cortex of MWT group began to increase at 6 h after CLP, and remained at high levels until 96 h. On the contrary, SQSTM1 expression in cerebral cortex of MWT group began to decrease at 6 h after CLP. Compared with SWT group, expressions of Lethe and IFN-γ were remarkably upregulated in cortex of MWT group at 12 h after CLP. Expression of LC3-II in MWT group was remarkably upregulated, while SQSTM1 was downregulated at 12 h after CLP, which were contrary to those in MKO group. At 12 h after CLP, the neurobiological scores of the MKO group (4.97±0.71) were markedly lower than those of the MWT group (5.43±0.86). HE staining showed worse damage in cerebral cortex and fewer neurons of MKO group relative to MWT group. CONCLUSIONS: Lethe has a protective effect on SIBI mice by regulating autophagy in mouse cortical neurons.

[Clinical characteristics and risk factors in pregnancy with severe community-acquired pneumonia].

Objective: To analyze clinical characteristics of severe community-acquired pneumonia during pregnancy and its outcomes, and to explore the relevant risk factors. Methods: From September 2012 to September 2017, 324 398 pregnancies admitted in 7 tertiary hospitals were included. Clinical data of 33 cases of pregnancies with severe community-acquired pneumonia (severe pneumonia group) and 214 cases of pregnancies with common community-acquired pneumonia (control group) were reviewed retrospectively, including the clinical information, manifestations, laboratory examinations and pregnancy outcomes. Relevant risk factors were analyzed by multivariate logistic regression analysis. Results: (1) General data: pregnancies with severe community-acquired pneumonia accounted for 0.010% (33/324 398) of hospitalized pregnancies, the gestational age of two groups were (28±8) and (23±8) weeks, body mass index were (21.7±2.1) and (25.5±3.4) kg/m(2), rate of low income were 54.5% (18/33) and 31.8% (68/214) , respectively. The differences between two groups were all statistically significant (all P<0.05). No significant differences were found in age, pregnancy and parity times, rate of main pregnant complications such as diabetes and hypertension, educational level, asthma and onset seasons between two groups (all P>0.05). (2) Clinical data: the severe pneumonia group had significantly higher incidence of fever [100.0% (33/33) vs 75.2% (161/214) ], shortness of breath (90.9% vs 16.8%) compared with the control group (all P<0.05) .The median peripheral leukocytes counts were 12.3×10(9)/L and 10.2×10(9)/L, the hemoglobin level were (84±18) and (107±14) g/L,the albumin level were (26±4) and (37±3) g/L, the median serum urea nitrogen level were 3.7 and 2.4 mmol/L, the serum creatinine level were (72±25) and (45±11) µmol/L, respectively in two groups. The differences were all statistically significant (all P<0.05). No significantly statistical differences were found in coagulation indicator and cardiac function between two groups (all P>0.05). (3) Treatments: in severe pneumonia group, 12 patients (36.4%,12/33) needed invasive mechanical ventilation, 9 patients (27.3%,9/33) needed non-invasive mechanical ventilation, average time of mechanical ventilation was (7±4) days;8 patients (24.2%,8/33) with septic shock needed vasoactive drugs. However, there was no patient in control group needing mechanical ventilation and vasoactive drugs. (4) Pregnant outcomes: one patient (3.0%,1/33) died in the severe pneumonia group, while no death occurred in the control group. The hospital stay between two groups were (15.1±4.1) and (7.0±1.9) days, the rates of abortion and stillbirth between two groups were 42.4% (14/33) and 3.3% (7/214) , the rates of premature were 10/19 and 6.3% (13/207) , the rates of cesarean were 15/19 and 43.0% (89/207) , the rates of low birth weight newborn were 17/19 and 14.0% (29/207) , the rates of infected newborn were 15/19 and 10.1% (21/207) , the birth weights were (2 165±681) and (3 102±400) g, respectively. The differences between two groups were all statistically significant (all P<0.05). (5) Multivariate logistic regression analysis demonstrated that anemia, low body mass index, hypoproteinemia were risk factors for severe pneumonia in pregnancy (all P<0.05) . Conclusions: Pregnancy with severe community-acquired pneumonia may be complicated by multiple organ dysfunctions, lead to adverse outcomes. Anemia, malnutrition are risk factors for pregnancy with severe pneumonia. Active and effective treatment may improve its prognosis.

Major TCR Repertoire Perturbation by Immunodominant HLA-B*44:03-Restricted CMV-Specific T Cells.

Lack of disease during chronic human cytomegalovirus (CMV) infection depends on the maintenance of a high-frequency CMV-specific T cell response. The composition of the T cell receptor (TCR) repertoire underlying this response remains poorly characterised, especially within African populations in which CMV is endemic from infancy. Here we focus on the immunodominant CD8+ T cell response to the immediate-early 2 (IE-2)-derived epitope NEGVKAAW (NW8) restricted by HLA-B*44:03, a highly prevalent response in African populations, which in some subjects represents >10% of the circulating CD8+ T cells. Using pMHC multimer staining and sorting of NW8-specific T cells, the TCR repertoire raised against NW8 was characterised here using high-throughput sequencing in 20 HLA-B*44:03 subjects. We found that the CD8+ T cell repertoire raised in response to NW8 was highly skewed and featured preferential use of a restricted set of V and J gene segments. Furthermore, as often seen in immunity against ancient viruses like CMV and Epstein-Barr virus (EBV), the response was strongly dominated by identical TCR sequences shared by multiple individuals, or "public" TCRs. Finally, we describe a pair "superdominant" TCR clonotypes, which were germline or nearly germline-encoded and produced at remarkably high frequencies in certain individuals, with a single CMV-specific clonotype representing up to 17% of all CD8+ T cells. Given the magnitude of the NW8 response, we propose that this major skewing of CMV-specific immunity leads to massive perturbations in the overall TCR repertoire in HLA-B*44:03 individuals.

Immunodominant cytomegalovirus-specific CD8+ T-cell responses in sub-Saharan African populations.

More than 90% of children in Africa are infected with cytomegalovirus (CMV) by the age of 12 months. However, the high-frequency, immunodominant CD8+ T-cell responses that control CMV infection have not been well studied in African populations. We therefore sought to define the immunodominant CMV-specific CD8+ T-cell responses within sub-Saharan African study subjects. Among 257 subjects, we determined the CD8+ T-cell responses to overlapping peptides spanning three of the most immunogenic CMV proteins, pp65, IE-1 and IE-2, using IFN-γ ELISpot assays. A bioinformatics tool was used to predict optimal epitopes within overlapping peptides whose recognition was statistically associated with expression of particular HLA class I molecules. Using this approach, we identified 16 predicted novel CMV-specific epitopes within CMV-pp65, IE-1 and IE-2. The immunodominant pp65-specific, IE-1, IE-2 responses were all either previously well characterised or were confirmed using peptide-MHC tetramers. The novel epitopes identified included an IE-2-specific epitope restricted by HLA*B*44:03 that induced high-frequency CD8+ T-cell responses (mean 3.4% of CD8+ T-cells) in 95% of HLA-B*44:03-positive subjects tested, in one individual accounting for 18.8% of all CD8+ T-cells. These predicted novel CMV-specific CD8+ T-cell epitopes identified in an African cohort will facilitate future analyses of immune responses in African populations where CMV infection is almost universal during infancy.

Ambient and at-the-ear occupational noise exposure and serum lipid levels.

OBJECTIVES: Occupational and residential noise exposure has been related to increased risk of cardiovascular disease. Alteration of serum lipid levels has been proposed as a possible causal pathway. The objective of this study was to investigate the relation between ambient and at-the-ear occupational noise exposure and serum levels of total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and triglycerides when accounting for well-established predictors of lipid levels. METHODS: This cross-sectional study included 424 industrial workers and 84 financial workers to obtain contrast in noise exposure levels. They provided a serum sample and wore portable dosimeters that every 5-s recorded ambient noise exposure levels during a 24-h period. We extracted measurements obtained during work and calculated the full-shift mean ambient noise level. For 331 workers who kept a diary on the use of a hearing protection device (HPD), we subtracted 10 dB from every noise recording obtained during HPD use and estimated the mean full-shift noise exposure level at the ear. RESULTS: Mean ambient noise level was 79.9 dB (A) [range 55.0-98.9] and the mean estimated level at the ear 77.8 dB (A) [range 55.0-94.2]. Ambient and at-the-ear noise levels were strongly associated with increasing levels of triglycerides, cholesterol-HDL ratio, and decreasing levels of HDL-cholesterol, but only in unadjusted analyses that did not account for HPD use and other risk factors. CONCLUSION: No associations between ambient or at-the-ear occupational noise exposure and serum lipid levels were observed. This indicates that a causal pathway between occupational and residential noise exposure and cardiovascular disease does not include alteration of lipid levels.