Why do some trauma patients die while others survive? A matched-pair analysis based on data from Trauma Register DGU®.
The mortality rate for severely injured patients with the injury severity score (ISS) ≥16 has decreased in Germany. There is robust evidence that mortality is influenced not only by the acute trauma itself but also by physical health, age and sex. The aim of this study was to identify other possible influences on the mortality of severely injured patients. In a matched-pair analysis of data from Trauma Register DGU®, non-surviving patients from Germany between 2009 and 2014 with an ISS≥16 were compared with surviving matching partners. Matching was performed on the basis of age, sex, physical health, injury pattern, trauma mechanism, conscious state at the scene of the accident based on the Glasgow coma scale, and the presence of shock on arrival at the emergency room. We matched two homogeneous groups, each of which consisted of 657 patients (535 male, average age 37 years). There was no significant difference in the vital parameters at the scene of the accident, the length of the pre-hospital phase, the type of transport (ground or air), pre-hospital fluid management and amounts, ISS, initial care level, the length of the emergency room stay, the care received at night or from on-call personnel during the weekend, the use of abdominal sonographic imaging, the type of X-ray imaging used, and the percentage of patients who developed sepsis. We found a significant difference in the new injury severity score, the frequency of multi-organ failure, hemoglobine at admission, base excess and international normalized ratio in the emergency room, the type of accident (fall or road traffic accident), the pre-hospital intubation rate, reanimation, in-hospital fluid management, the frequency of transfusion, tomography (whole-body computed tomography), and the necessity of emergency intervention. Previously postulated factors such as the level of care and the length of the emergency room stay did not appear to have a significant influence in this study. Further studies should be conducted to analyse the identified factors with a view to optimising the treatment of severely injured patients. Our study shows that there are significant factors that can predict or influence the mortality of severely injured patients.


Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser glycogen synthase kinase-3beta.
Glycogen synthase kinase-3beta (GSK-3beta) is a multifunctional enzyme involved in a variety of biological events including development, glucose metabolism and cell death. Its activity is inhibited by phosphorylation of the Ser9 residue and up-regulated by Tyr216 phosphorylation. Activated GSK-3beta increases phosphorylation of tau protein and induces cell death in a variety of cultured neurons, whereas phosphorylation of phosphatidylinositol-3 (PI-3) kinase-dependent protein kinase B (Akt), which inhibits GSK-3beta activity, is one of the best characterized cell survival signaling pathways. In the present study, the cholinergic immunotoxin 192 IgG-saporin was used to address the potential role of GSK-3beta in the degeneration of basal forebrain cholinergic neurons, which are preferentially vulnerable in Alzheimer's disease (AD) brain. GSK-3beta co-localized with a subset of forebrain cholinergic neurons and loss of these neurons was accompanied by a transient decrease in PI-3 kinase, phospho-Ser473Akt and phospho-Ser9GSK-3beta levels, as well as an increase in phospho-tau levels, in the basal forebrain and hippocampus. Total Akt, GSK-3beta, tau and phospho-Tyr216GSK-3beta levels were not significantly altered in these brain regions in animals treated with 192 IgG-saporin. Systemic administration of the GSK-3beta inhibitor LiCl did not significantly affect cholinergic marker or phospho-Ser9GSK-3beta levels in control rats but did preclude 192-IgG saporin-induced alterations in PI-3 kinase/phospho-Akt, phospho-Ser9GSK-3beta and phospho-tau levels, and also partly protected cholinergic neurons against the immunotoxin. These results provide the first evidence that increased GSK-3beta activity, via decreased Ser9 phosphorylation, can mediate, at least in part, 192-IgG saporin-induced in vivo degeneration of forebrain cholinergic neurons by enhancing tau phosphorylation. The partial protection of these neurons following inhibition of GSK-3beta kinase activity suggests a possible therapeutic role for GSK-3beta inhibitors in attenuating the loss of basal forebrain cholinergic neurons observed in AD.


Causal Inference with Case-Only Studies in Injury Epidemiology Research.
We review the application and limitations of two implementations of the "case-only design" in injury epidemiology with example analyses of Fatality Analysis Reporting System data. The term "case-only design" covers a variety of epidemiologic designs; here, two implementations of the design are reviewed: (1) studies to uncover etiological heterogeneity and (2) studies to measure exposure effect modification. These two designs produce results that require different interpretations and rely upon different assumptions. The key assumption of case-only designs for exposure effect modification, the more commonly used of the two designs, does not commonly hold for injuries and so results from studies using this design cannot be interpreted. Case-only designs to identify etiological heterogeneity in injury risk are interpretable but only when the case-series is conceptualized as arising from an underlying cohort. The results of studies using case-only designs are commonly misinterpreted in the injury literature.


Intracellular recordings from interneurons and motoneurons in intact flying locusts.
A preparation is described in which it is possible to record intracellularly from identified motoneurons and interneurons during flight in intact tethered locusts. Intracellular recordings could be obtained from either the large somata of the motoneurons or from the neuropil processes of interneurons and motoneurons in either the meso- or metathoracic ganglion. Intracellular recordings from motoneuron somata were sufficiently stable to allow surgical manipulations, e.g. deafferentation, of the nervous system without the loss of penetration. Recordings from neuropil processes required stabilizing the ganglion by sandwiching it between two supports. The preparation is suitable for the cellular analysis of many aspects of motor patterning in the flight system of the locust. So far we have used it to make a direct comparison between the patterns of synaptic activity in intact and deafferented animals. This comparison shows that sensory feedback from wing proprioceptors strongly influences the activity in elevator motoneurons and flight interneurons. From these and other observations we conclude that proprioceptive feedback is essential for generating important features of the intact motor pattern and that wing receptors are integral elements of the intact flight pattern generator.


Radiology of external ear: indications, normal anatomy, and pathological processes.
The external ear is accessible to direct examination; the clinical history and otoscopy are sufficient to diagnose and treat most diseases of the external ear. We aim to describe the normal anatomy of the external ear, specify the indications for imaging tests, and review the clinical and radiological manifestations of the most common diseases affecting the external ear. We classify these diseases according to their origin into congenital, inflammatory, infectious, or traumatic disease or benign bone tumors or malignant tumors. Imaging does not play an important role in diseases of the external ear, but in certain clinical scenarios it can be crucial for reaching a concrete diagnosis and establishing the best treatment. Computed tomography is the first-choice technique for most diseases. Magnetic resonance imaging complements computed tomography and makes it possible to differentiate among different tissue types and to evaluate the extension of disease accurately.


Buprenorphine as a stimulus in drug discrimination learning: an assessment of mu and kappa receptor activity.
Using the conditioned taste aversion baseline of drug discrimination learning, different groups of animals were trained to discriminate either buprenorphine or morphine from distilled water. Specifically, animals were injected with buprenorphine or morphine prior to a saccharin-LiCl pairing and the drug vehicle prior to saccharin alone. By the fifth conditioning trial, animals differentially consumed saccharin on the basis of administration of the drug or its vehicle. In subsequent generalization tests, buprenorphine stimulus control generalized completely to the mu agonist morphine in four of the five subjects tested, while morphine stimulus control completely generalized to buprenorphine in two of five subjects and partially generalized in the remaining three. Buprenorphine failed to generalize to the relatively selective kappa antagonist MR2266 and the broad-based antagonist diprenorphine. Morphine also failed to generalize to MR2266, but did generalize to diprenorphine. That morphine and buprenorphine displayed some degree of cross-generalization suggests that these compounds share some stimulus property, presumably their agonist activity at the mu receptor, and that the mu activity of these compounds was used in the establishment of the discrimination, a conclusion supported by the fact that compounds with mu antagonist activity (e.g., naloxone, MR2266) blocked both buprenorphine and morphine stimulus control. That buprenorphine failed to generalize to compounds with kappa antagonist activity suggests that animals trained to discriminate buprenorphine from its vehicle do not use the kappa antagonist activity of the drug in the establishment of the discrimination. The basis for the differential ability of various receptor subtypes to mediate the discriminative properties of compounds with mixed receptor activity was discussed.


Neuronal death in the central nervous system during development.
About half the neurons in the brain die at the time when their connections are being formed. This neuronal death is regulated by anterograde and retrograde signals that reflect both electrical activity and the uptake of trophic factors. Our recent data on the isthmo-optic projection indicate that there are in fact two different retrograde signals: a slow-acting survival signal mediated by a neurotrophin, and a fast-acting death signal mediated by calcium entry due to electrical activity in the presynaptic terminals. The developmental roles of the cell death are not well understood, but they appear to include the elimination of aberrant connections. The intracellular mechanisms of the cell death may not always correspond to the apoptotic ones so thoroughly investigated in vitro, because only one of the three morphological types occurring regularly in vivo resembles apoptosis. However, our experiments on retinal ganglion cells indicate that several apoptotic mechanisms apply in this particular in vivo situation: these include an involvement of oxygenated free radicals and glutathione, cell cycle-related events, and probably the synthesis of proteins promoting neuroprotection or cell death.


An Ascendant Challenge: Central Nervous System Metastases in ALK+ Lung Cancers.
Central nervous system (CNS) metastases constitute a challenge for the design of anaplastic lymphoma kinase (ALK) fusion-positive lung cancer trials. The ASCEND-7 study of ceritinib demonstrates the feasibility of broadening CNS eligibility criteria to include symptomatic brain and leptomeningeal disease and highlights design features that contemporary trials will need to incorporate. See related article by Chow et al., p. 2506.


Sputum carcinoembryonic antigen, neuron-specific enolase and cytokeratin fragment 19 levels in lung cancer diagnosis.
The aim of the present study was to examine the impact of sputum carcinoembryonic antigen (CEA), neuron-specific enolase (NSE) and cytokeratin fragment 19 (CYFRA 21-1) levels in lung cancer diagnosis and to compare the diagnostic usefulness of sputum assays with that of serum assays. Forty-seven patients with lung cancer and 62 with benign lung disease were studied. Tumour marker levels in sputum (sp.) and serum (ser) were measured by immunoradiometric assays. Sputum and serum tumour marker levels were significantly higher in lung cancer than in benign disease. When the specificity was 95%, the sensitivity was 57%, 43%, 36%, 30%, 28% and 19%, for spCEA, serCYFRA 21-1, spCYFRA 21-1, serCEA, serNSE, and spNSE, respectively. Bayesian analysis showed that the best predictive values correspond to spCEA and serCYFRA 21-1. The maximum overall gain was obtained in pretest probability of 0.35 for both spCEA and serCYFRA 21-1, with predictive values of 84% and 80% for spCEA and serCYFRA 21-1, respectively. Sputum tumour marker levels were no more useful than the serum levels in lung cancer diagnosis. SpCEA offered the best predictive values but these were still not sufficiently satisfactory for spCEA to be proposed for routine use.


Effect of repeat unit structure and molecular mass of lactic acid bacteria hetero-exopolysaccharides on binding to milk proteins.
Interactions of exopolysaccharides and proteins are of great importance in food science, but complicated to analyze and quantify at the molecular level. A surface plasmon resonance procedure was established to characterize binding of seven structure-determined, branched hetero-exopolysaccharides (HePSs) of 0.14-4.9MDa from lactic acid bacteria to different milk proteins (β-casein, κ-casein, native and heat-treated β-lactoglobulin) at pH 4.0-5.0. Maximum binding capacity (RUmax) and apparent affinity (KA,app) were HePS- and protein-dependent and varied for example 10- and 600-fold, respectively, in the complexation with native β-lactoglobulin at pH 4.0. Highest RUmax and KA,app were obtained with heat-treated β-lactoglobulin and β-casein, respectively. Overall, RUmax and KA,app decreased 6- and 20-fold, respectively, with increasing pH from 4.0 to 5.0. KA,app was influenced by ionic strength and temperature, indicating that polar interactions stabilize HePS-protein complexes. HePS size as well as oligosaccharide repeat structure, conferring chain flexibility and hydrogen bonding potential, influence the KA,app.


Obesity causes PGC-1α deficiency in the pancreas leading to marked IL-6 upregulation via NF-κB in acute pancreatitis.
Obesity is associated with local and systemic complications in acute pancreatitis. PPARγ coactivator 1α (PGC-1α) is a transcriptional coactivator and master regulator of mitochondrial biogenesis that exhibits dysregulation in obese subjects. Our aims were: (1) to study PGC-1α levels in pancreas from lean or obese rats and mice with acute pancreatitis; and (2) to determine the role of PGC-1α in the inflammatory response during acute pancreatitis elucidating the signaling pathways regulated by PGC-1α. Lean and obese Zucker rats and lean and obese C57BL6 mice were used first; subsequently, wild-type and PGC-1α knockout (KO) mice with cerulein-induced pancreatitis were used to assess the inflammatory response and expression of target genes. Ppargc1a mRNA and protein levels were markedly downregulated in pancreas of obese rats and mice versus lean animals. PGC-1α protein levels increased in pancreas of lean mice with acute pancreatitis, but not in obese mice with pancreatitis. Interleukin-6 (Il6) mRNA levels were dramatically upregulated in pancreas of PGC-1α KO mice after cerulein-induced pancreatitis in comparison with wild-type mice with pancreatitis. Edema and the inflammatory infiltrate were more intense in pancreas from PGC-1α KO mice than in wild-type mice. The lack of PGC-1α markedly enhanced nuclear translocation of phospho-p65 and recruitment of p65 to Il6 promoter. PGC-1α bound phospho-p65 in pancreas during pancreatitis in wild-type mice. Glutathione depletion in cerulein-induced pancreatitis was more severe in KO mice than in wild-type mice. PGC-1α KO mice with pancreatitis, but not wild-type mice, exhibited increased myeloperoxidase activity in the lungs, together with alveolar wall thickening and collapse, which were abrogated by blockade of the IL-6 receptor glycoprotein 130 with LMT-28. In conclusion, obese rodents exhibit PGC-1α deficiency in the pancreas. PGC-1α acts as selective repressor of nuclear factor-κB (NF-κB) towards IL-6 in pancreas. PGC-1α deficiency markedly enhanced NF-κB-mediated upregulation of Il6 in pancreas in pancreatitis, leading to a severe inflammatory response. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


[Clinical significance of preoperative B-ultrasonography for traumatic cataract].
To approach the clinical significance of B-ultrasonography in detection of the break of posterior lens capsule in traumatic cataract. 30 patients (30 eyes) of traumatic cataract underwent preoperative B-ultrasonography and intraoperative microscopic examination to evaluate the status of posterior lens capsule. 14 eyes showed posterior lens capsule unbroken in B-ultrasonography. Of them, 12 eyes were confirmed by surgery. 16 eyes showed rupture of the posterior lens capsule in B-ultrasonography. Among them 14 eyes were confirmed by surgery and in 2 eyes there was no break at the posterior lens capsule. B-ultrasonography for preoperative traumatic cataract is harmless, painless, simple in operative procedure and accurate, thus it can be used as a routine examination to show the status of posterior lens capsule in traumatic cataract.


Cancer; Pathophysiology and Stress Modulation (Cancer, Therapeutic Interventions).
The purpose of this review is to describe the myriad complications of cancer and its therapies to emphasize the pathophysiological need for prehabilitation. The information presented in this review is from applicable, peer-reviewed scientific articles. Cancer itself renders negative effects on the body, most notably unintentional weight loss and fatigue. Cancer treatments, especially surgical interventions, can cause detrimental short- and long-term impacts on patients, which translate to suboptimal treatment outcomes. Prehabilitation can be used to improve patient health prior to anticancer therapies to improve treatment tolerance and efficacy. Nurses play an important role in the treatment of patients with cancer throughout the cancer care continuum. Many nurses are already aiding their patients in cancer prehabilitation through education. By describing common impairments amenable to multimodal prehabilitation, nurses may better advocate for their patients and can become even more involved in this aspect of care.


Liquid resorbable nanofibrous surgical mesh: a proof of a concept.
Surgical mesh is widely used not only to treat but also to prevent incisional hernia formation. Despite much effort by material engineers, the 'ideal' mesh mechanically, biologically and surgically easy to use remains elusive. Advances in tissue engineering and nanomedicine have allowed new concepts to be tested with promising results in both small and large animals. Abandoning the concept of a pre-formed mesh completely for a 'pour in liquid mesh' has never been tested before. Thirty rabbits underwent midline laparotomy with closure using an absorbable suture and small stitch small bites technique. In addition, their abdominal wall closure was reinforced by a liquid nanofibrous scaffold composed of a fibrin sealant and nanofibres of poly-ε-caprolactone with or without hyaluronic acid or the sealant alone, poured in as an 'onlay' over the closed abdominal wall. The animals were killed at 6 weeks and their abdominal wall was subjected to histological and biomechanical evaluations. All the animals survived the study period with no major complication. Histological evaluation showed an eosinophilic infiltration in all groups and foreign body reaction more pronounced in the groups with nanofibres. Biomechanical testing demonstrated that groups treated with nanofibres developed a scar with higher tensile yield strength. The use of nanofibres in a liquid form applied to the closed abdominal wall is easy to use and improves the biomechanical properties of healing fascia at 6 weeks after midline laparotomy in a rabbit model.


Association between vitamin D receptor (FokI) genetic variant rs2228570 and iron profile in hemodialysis patients.
Iron deficiency is a common etiology of anemia that causes suboptimal response to erythropoietin therapy in hemodialysis (HD) patients. This study investigated the association between vitamin D receptor (VDR) genetic variant (FokI) rs2228570 with iron indices (serum iron, transferrin, transferrin saturation, and ferritin). Sixty adequately hemodialyzed patients subdivided into two groups; 31 patients with transferrin saturation (TSAT) < 20% and 29 with TSAT > 20% who received I.V sodium ferric gluconate, calcium, and vitamin D. Sixty normal healthy were selected as the control group.. VDR genetic variant (SNP rs2228570) was genotyped in all subjects using PCR/RFLP. HD patients showed a higher frequency of rs2228570 FF genotype (38.3%) than controls (31.7%). The frequency of ff genotype and f allele in patients (8.4 and 35% respectively) were significantly lower than controls (25 and 46.7% respectively). Allele model (f vs. F): OR 0.721, 95% CI 0.521-0.998, P = 0.049. While (ff vs. FF): OR 0.452, 95% CI 0.223-0.917, P = 0.028. The distribution of Ff + ff genotypes in HD cases with TSAT > 20% was higher than in HD cases with TSAT < 20%, Dominant model (Ff +ff vs FF): OR 2.753, 95% CI 1.902-3.409, P = 0.048. f allele showed lower frequency in low TSAT group than high TSAT group (27.4 vs. 43.1%) with significant P value (P = 0.042) with allele model (f vs. F): OR 2.012, 95% CI 1.923-4.226, P = 0.042. Fok-1 ff, Ff + ff genotypes were significantly associated with TSAT > 20% with a protective effect against low TSAT in HD patients.


Patterns of care in community-based oncology practices for anemia associated with myelosuppressive chemotherapy.
Use of erythropoiesis-stimulating agents in the treatment of myelosuppresive chemotherapy-induced anemia has been shown to increase hemoglobin levels and reduce the need for transfusions in patients with cancer.


Residual disease in lymph nodes has no influence on survival in patients with incidental gallbladder cancer - institution experience with literature review.
A better appreciation of the course and factors that influence incidental gallbladder cancer (iGBC) is needed to develop treatment strategies aimed to improve outcomes. The purpose of the study was to determine the influence of residual disease in the liver and lymph nodes on overall survival in re-resected patients with iGBC. Patients undergoing radical re-resection for iGBC from January 2012 to December 2018 were retrospectively identified. Patients with a 5-year follow-up and submitted to complete resection with stage I, II and III disease were analysed. The influence of residual disease (RD) in liver and lymph nodes on survival was assessed using the Kaplan-Meier curves. In addition, the rest of the group was assessed based on type of primary/secondary procedure, number of harvested lymph nodes and RD in liver and/or lymph nodes. In this retrospective study 48 out of 58 (83%) patients underwent re-resection. Among the group with a 5-year follow-up (re-operation between 2012-2014), 22 patients out of 28 (79%) were re-resected. Survival analysis showed that patients with no RD in the liver and lymph nodes had statistically significant better 5-year survival than those with RD. Comparing 5-year survival rate in patients with RD in the liver or lymph nodes against no RD group, patients with RD in the liver had statistically significantly worse 5-year survival, while lymph node metastases did not show any statistically significant different in 5-year survival. Besides, a statistically significant better prognosis was found in stage II disease compared to stage III, as expected. The most important predictors of a 5-year survival in our study were RD in liver and stage of the disease. Lymph node metastases did not have any impact on the overall 5-year survival rate.


Determination of the food dye indigotine in cream by near-infrared spectroscopy technology combined with random forest model.
Artificial pigment is a common food additive in cream products. If added in excess, it will do harm to human body. At present, there is no research on the detection of cream pigment by Near Infrared (NIR) spectroscopy. In this paper, a method based on random forest was applied to determine the indigotine in cream. Weighting in the experiments was accomplished using analytical balances with precision as low as 0.0001 g. The NIR spectra data of cream with different concentration of indigotine were recorded. The original spectra was pretreated by SG smoothing, mean centering and second derivative. Random forest was applied to establish a quantitative analysis model for cream pigment content, and multiple evaluation criteria were selected to comprehensively evaluate the model. The R2 was 0.9402, RMSEP was 0.2509 and RPD was 4.0893. Consequently, NIR spectroscopy, combined with data pretreatments and random forest model, was confirmed to be an interesting tool for non-destructive evaluation of pigment content in cream.


EEG cartography before and after visual stimulation: a group study with descriptive non-parametric analysis of EEG data.
Ten right-handed students were submitted to a protocol of cognitive visual stimulations based on six successive sequences: EC1, EO, B1, B2, B3, EC2. Following a first "eyes closed" (EC1) multiple EEG recording (16 EEG leads, plus polygraphy), and an "eyes-open" recording (EO) with central visual fixation, 60 computer-controlled slides were presented successively for each of three successive recordings (B1, B2, B3) before the last "eyes-closed" recording (EC2). In B1, the subjects were asked to look at the meaningful black and white drawings presented without comment. In B2, a second set of similar pictures was presented, with the advice to try to remember later on the visually projected slides. In B3, a memory recognition task was introduced with 20 slides coming from the B1 set, 20 from the B2 set, completed by 20 new slides. Each slide was presented for 10.24s. followed by a beep audio-signal indicating that the subjects should press electronic mouse knobs alternatively in B1, B2, and for indicating their answers in B3. After artifact rejection, EEG spectral analysis was followed by parametrization and group studies applying Fisher non-parametric paired exact probability tests. Nine comparisons were computed: EC1-EC2, EC1-EO, EC2-EO, EO-B1, EO-B2, EO-B3, B1-B2, B1-B3, B2-B3. A statistical strategy of descriptive inter-individual non-parametric. Fisher tests was undertaken, together with computation and mapping of averaged spectral parameter differences (mean amplitudes and frequencies, mean amplitudes %, resonance coefficients) for raw EEG, delta, theta, alpha, alpha 1, alpha 2, beta 1 and beta 2 frequency bands and probability maps.(ABSTRACT TRUNCATED AT 250 WORDS)


Empowerment for people living with dementia: An integrative literature review.
Although the concept of empowerment seems useful for good care and support for people living with dementia, there is a lack of understanding of the process of empowerment. Therefore, more insight is needed into the concept of empowerment, and the environment's role in the empowerment process. We performed an integrative literature review (PubMed, CINAHL, PsychINFO), including studies that addressed empowerment for people living with dementia in their title or abstract. Using qualitative data analysis software ATLAS.ti, we applied open codes to describe all relevant aspects of included articles. Common themes and categories were identified using inductive reasoning and constant comparison. Sixty-nine articles were included. We identified four themes: (1) description of the state of being empowered, (2) the process of empowerment, (3) contribution of the environment to the empowerment process, and (4) effects on other variables. We combined these results with the conceptual framework of our previous qualitative study on the definition of empowerment for people living with dementia based on stakeholders' perspectives. Subsequently, the combined information of both studies was visualized in a revised conceptual framework. This literature review provides more details as to the role of the environment for empowerment of people living with dementia and suggests that empowerment can be considered a dynamic process, taking place through interaction between the person living with dementia and their environment. Our revised conceptual framework of empowerment can serve as a basis for future studies on empowerment for people living with dementia, and to support (in)formal caregivers in the empowerment process.


Comparison of the efficiency of chitinous and ligneous substrates in metal and sulfate removal from mining-influenced water.
Mining-influenced water (MIW) remediation is challenging, not only due to its acidity and high metal content, but also due to its presence in remotely located mine sites with difficult surrounding environments. An alternative to common remediation technologies, is the use of sulfate-reducing bacteria (SRB) to achieve simultaneous sulfate reduction and metal removal in on-site anaerobic passive systems. In these systems, the organic carbon source (substrate) selection is critical to obtaining the desired effluent water quality and a reasonable treated volume. In this study, we evaluated the use of two different substrates: a chitinous product obtained from crushed crab shells, and a more traditional ligneous substrate. We put the substrates, both with and without water pretreatment consisting of aeration and pH adjustment, in anaerobic experimental columns. The treatment with the chitinous substrate was more effective in removing metals (Al, Cu, Fe, Cd, Mn, Zn) and sulfate for a longer period (458 days) than the ligneous substrate (78 days) before suffering Zn breakthrough. The reactors fed with pretreated water had longer operational periods and lower metals and sulfate concentrations in the effluent than those with untreated influent water. Zn was consistently removed to levels <0.3 mg/L for 513 days in the chitinous substrate columns, while levels <0.3 mg/L were maintained for only 140 days in the ligneous substrate pretreated column. The highest sulfate removal rates achieved in this study were in the range of 5-6 mol/m3/d for the chitinous substrate and 1-2 mol/m3/d for the ligneous substrate. Overall, the chitinous substrate proved to be more efficient in the removal of all the aforementioned metals and for sulfate when compared to the ligneous substrate. This could be the determinant when selecting a substrate for passive systems treating acidic MIW, particularly when Zn and Mn removal is necessary.


Developmental pharmacology and toxicology of anti-HIV therapeutic agents: dideoxynucleosides.
As the incidence of human immunodeficiency virus (HIV) infection has increased in women over the past decade, the need for safe, effective therapy during pregnancy has increased concomitantly. Although dideoxynucleosides such as 3'-deoxy-3'-azidothymidine (AZT), 2',3'-dideoxyinosine (ddI), 2',3'-dideoxycytidine (ddC), and 2',3'-didehydro-3'-deoxythymidine have been approved for use in the general population, the administration, efficacy, and toxicity of these compounds during pregnancy and development are now being investigated. Initial human studies suggest that maternal use of AZT during pregnancy is well tolerated by both mother and child and provides a promising degree of protection from vertical HIV transmission to the infant. In vitro and animal models have greatly increased our understanding of the distribution and toxicity resulting from fetal dideoxynucleoside exposure. AZT, ddI, and ddC rapidly cross the placenta by simple diffusion but with different rates of transfer. In vivo data confirm the differential transfer of these compounds with AZT fetal exposure approximately twice that of ddI or ddC. Active phosphorylated metabolites have been detected in placental tissue after in vitro perfusion with AZT. The active triphosphate has not been detected in placental perfusion studies or in the fetal rhesus monkey 3 h after maternal exposure to ddI or ddC. Although in vitro and in vivo laboratory animal studies suggest the potential for toxicity with preimplantation exposure, the risk for teratogenic events after postimplantational exposure appears to be low at therapeutically effective concentrations of these dideoxynucleosides.


Development of HPLC fingerprint for species differentiation and quality assessment of Rhizoma Smilacis Glabrae.
Rhizoma Smilacis Glabrae (RSG) is a commonly used herbal material in functional food and Traditional Chinese Medicine. A HPLC chromatographic fingerprint was developed for its quality control and species differentiation. Nine peaks were found in the chromatogram of RSG and all these peaks were identified by diode array detection and electrospray ionization-MS/MS: 5-O-caffeoylshikimic acid, taxifolin, engeletin, isoengeletin, trans-resveratrol, astilbin and its three stereoisomers. Six of these constituents were consistently found in 18 batches of samples. The standard fingerprint of RSG was generated by mean simulation of all tested samples. Using the standard fingerprint, RSG could be easily differentiated from Rhizoma Smilacis Chinae and Rhizoma Heterosmilacis, the two species that can be confused with RSG.


Quality of life issues in men undergoing androgen deprivation therapy: a review.
Androgen deprivation therapy (ADT) has been an essential treatment option for treating prostate cancer (PCa). The role for hormonal treatment initially was restricted to men with metastatic and inoperable, locally advanced disease. Now it has been extended to neoadjuvant or adjuvant therapy for surgery and radiotherapy, for biochemical relapse after surgery or radiation, and even as primary therapy for non-metastatic disease. Fifty percent of PCa patients treated will receive ADT at some point. There is growing concern about the adverse effects and costs associated with more widespread ADT use. The adverse effects on quality of life (QoL), including physical, social and psychological well-being when men are androgen-deprived, may be considerable. This review examines the QoL issues in the following areas: body feminisation, sexual changes, relationship changes, cognitive and affective symptoms, fatigue, sleep disturbance, depression and physical effects. Further suggestions for therapeutic approaches to reduce these alterations are suggested.


Platform for high-throughput antibody selection using synthetically-designed antibody libraries.
Synthetic humanized antibody libraries are frequently generated by random incorporation of changes at multiple positions in the antibody hypervariable regions. Although these libraries have very large theoretical diversities (>10(20)), the practical diversity that can be achieved by transformation of Escherichia coli is limited to about 10(10). To constrain the practical diversity to sequences that more closely mimic the diversity of natural human antibodies, we generated a scFv phage library using entirely pre-defined complementarity determining regions (CDR). We have used this library to select for novel antibodies against four human protein targets and demonstrate that identification of enriched sequences at each of the six CDRs in early selection rounds can be used to reconstruct a consensus antibody with selectivity for the target.


Diagnostic significance of S100A2 and S100A6 levels in sera of patients with non-small cell lung cancer.
Biochemical markers play a significant role in the diagnosis of lung cancer. Recent studies have demonstrated a link involving S100 Calcium Binding Proteins (S100A2, S100A6) and non-small cell lung cancer (NSCLC), but the expediency of their serum levels in NSCLC has not been established. In this study, we evaluate the potential of serum S100A2 and S100A6 levels as diagnostic markers for NSCLC. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the levels of S100A2 and S100A6 in 141 NSCLC patients and 150 healthy subjects. Serum levels of the two proteins in patients with NSCLC were higher compared to healthy controls (P = 0.0002 for S100A2 and P < 0.0001 for S100A6). Moreover, the levels of S100A2 and S100A6 were higher in the sera of stage I/II NSCLC patients compared to healthy controls with P = 0.01 and <0.0001, respectively. Receiver operating characteristic (ROC) analysis showed that S100A2 could distinguish NSCLC patients from healthy controls (AUC = 0.646), and S100A6 could also identify NSCLC (AUC = 0.668). Meanwhile, these two proteins showed notable capabilities for distinguishing stage I/II NSCLC from healthy controls (AUC = 0.708 for S100A2 and AUC = 0.702 for S100A6). Our results indicate that serum levels of S100A2 and S100A6 are significantly elevated in early stage NSCLC and may have the potential for NSCLC biomarker. Further studies with large sample population would help validate our findings.


Herbivores at the highest risk of extinction among mammals, birds, and reptiles.
As a result of their extensive home ranges and slow population growth rates, predators have often been perceived to suffer higher risks of extinction than other trophic groups. Our study challenges this extinction-risk paradigm by quantitatively comparing patterns of extinction risk across different trophic groups of mammals, birds, and reptiles. We found that trophic level and body size were significant factors that influenced extinction risk in all taxa. At multiple spatial and temporal scales, herbivores, especially herbivorous reptiles and large-bodied herbivores, consistently have the highest proportions of threatened species. This observed elevated extinction risk for herbivores is ecologically consequential, given the important roles that herbivores are known to play in controlling ecosystem function.


Covered exstrophy: a rare variant.
A case of covered exstrophy without sequestration of a bowel segment is reported. A 4-year-old female presented with dribbling of urine. Treatment to date has been simple excision of the covered membrane with functional closure of the bladder and bilateral posterior iliac osteotomies, with reconstruction of the bladder neck and genitalia to be performed at a later date. The embryogenesis of this rare variant, a review of the reported cases, and management options are discussed. Keyword Covered exstrophy. Exstrophy. Bladder variants


A comparison of the effects of kainic acid on somatostatin, substance P and dopamine in the rabbit retina.
Groups of adult, male Dutch belted rabbits received intravitreal injections of varying doses (30-240 nmol) of the excitatory neurotoxin kainic acid (KA) into one eye and saline vehicle into the other. One week later a segment of each retina was examined histologically and the remainder was assayed for somatostatin-like immunoreactivity (SLI), substance P-like immunoreactivity (SPLI), dopamine (DA) and protein. Histologically, KA at doses of 120 and 240 nmol produced destruction of the inner layers of the retina, with preservation of the photoreceptors. This damage is correlated with a dose-related depletion of retinal protein content. At KA doses of 120 and 240 nmol, both SPLI and DA content were reduced to 5-10% of control values. Although KA significantly reduced the retinal content of SLI even at a dose of 30 nmol, the greatest mean depletion of SLI observed at any dose was 50%. This failure of KA to reduce retinal SLI content by more than 50% at doses of KA which produce severe histologic damage to the neural retina and dramatic depletions of SPLI and DA content demonstrates that the SLI-containing structures of the rabbit retina are partially resistant to the neurotoxic action of KA. We hypothesize that SLI in the rabbit retina is contained in two pharmacologic types of cells in about equal abundance; one type is sensitive to and one type resistant to KA. In contrast, substance P- and dopamine-containing retinal neurons are uniformly sensitive to destruction by KA.


Nab-paclitaxel plus S-1 versus oxaliplatin plus S-1 as first-line treatment in advanced gastric cancer: results of a multicenter, randomized, phase III trial (GAPSO study).
This study aimed to investigate the superiority of nab-paclitaxel plus S-1 (AS) over oxaliplatin plus S-1 (SOX) in patients with advanced gastric cancer (AGC). In this multicenter, randomized, phase III superiority trial, eligible patients with unresectable, locally advanced gastric adenocarcinoma were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 260 mg/m2 on day 1 or 130 mg/m2 on days 1 and 8; oral S-1 40-60 mg twice daily for 14 days) or SOX (130 mg/m2 oxaliplatin on day 1; oral S-1 40-60 mg twice daily for 14 days) every 3 weeks for up to six cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival, objective response rate, and safety. Owing to slow enrolment, an unplanned interim analysis was performed, resulting in the early termination of the study on 31 December 2021 (data cutoff). Between March 2019 and March 2021, 97 patients (AS, n = 48; SOX, n = 49) were treated and evaluated for efficacy and safety of AS and SOX. As of the data cutoff, the median follow-up was 23.13 months [95% confidence interval (CI), 13.39-32.87]. The median PFS was 9.03 months (95% CI, 6.50-11.56) in the AS group and 5.07 months (95% CI, 4.33-5.81) in the SOX group, demonstrating a better PFS tendency following AS treatment than SOX treatment (hazard ratio = 0.59; 95% CI, 0.37-0.94; p = 0.03). The most common grade 3 or worse adverse events were anemia, neutropenia, and leukopenia in both groups, with a higher incidence of thrombocytopenia in the SOX group. Although this study was terminated early, the results demonstrated a better PFS tendency in patients with AGC who were treated with AS than in those treated with SOX, with controllable toxicities. Clinical Trials.gov identifiers: NCT03801668. Registered January 11, 2019.


Motor Recovery After Subcortical Stroke Depends on Modulation of Extant Motor Networks.
Stroke is the leading cause of long-term disability. Functional imaging studies report widespread changes in movement-related cortical networks after stroke. Whether these are a result of stroke-specific cognitive processes or reflect modulation of existing movement-related networks is unknown. Understanding this distinction is critical in establishing more effective restorative therapies after stroke. Using multivariate analysis (tensor-independent component analysis - TICA), we map the neural networks involved during motor imagery (MI) and executed movement (EM) in subcortical stroke patients and age-matched controls. Twenty subcortical stroke patients and 17 age-matched controls were recruited. They were screened for their ability to carry out MI (Chaotic MI Assessment). The fMRI task was a right-hand finger-thumb opposition sequence (auditory-paced 1 Hz; 2, 3, 4, 5, 2…). Two separate runs were acquired (MI and rest and EM and rest; block design). There was no distinction between groups or tasks until the last stage of analysis, which allowed TICA to identify independent components (ICs) that were common or distinct to each group or task with no prior assumptions. TICA defined 28 ICs. ICs representing artifacts were excluded. ICs were only included if the subject scores were significant (for either EM or MI). Seven ICs remained that involved the primary and secondary motor networks. All ICs were shared between the stroke and age-matched controls. Five ICs were common to both tasks and three were exclusive to EM. Two ICs were related to motor recovery and one with time since stroke onset, but all were shared with age-matched controls. No IC was exclusive to stroke patients. We report that the cortical networks in stroke patients that relate to recovery of motor function represent modulation of existing cortical networks present in age-matched controls. The absence of cortical networks specific to stroke patients suggests that motor adaptation and other potential confounders (e.g., effort and additional muscle use) are not responsible for the changes in the cortical networks reported after stroke. This highlights that recovery of motor function after subcortical stroke involves preexisting cortical networks that could help identify more effective restorative therapies.


Dermatologic findings associated with human immunodeficiency virus infection.
Both human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) are associated with an increased prevalence of several dermatologic diseases. We studied healthy homosexual men with negative reactivity to HIV antibody, homosexual men without AIDS but with positive reactivity to HIV antibody, and homosexual men with AIDS to compare the prevalence of dermatologic disease in these groups. We found that five cutaneous disorders were increased in persons with HIV infection. Oral hairy leukoplakia was increased both in seropositive subjects without AIDS and in subjects with AIDS. Condylomata acuminata and seborrheic dermatitis were slightly increased in seropositive non-AIDS subjects and significantly increased in the AIDS group. Molluscum contagiosum and oral candidiasis were increased only in the AIDS group.


Proteus Syndrome, a rare case with an unusual presentation: Case report.
Proteus Syndrome is a very rare syndrome, where only 200 cases has been reported so far. We were presented with a 45 year male with features of chronic Intestinal Obstruction. On Examination he had a giant right middle finger (Fig. 1), giant left forearm, with amputated left hand, and massive abdominal distension with tenderness in upper abdomen. Proteus Syndrome (PS) is a very rare syndrome, diagnosis of which is based on Biescker's criteria, either one finding from Criteria A, or two from B, or three from C. Confirmation of the disease is by finding genetic variation in the AKT1 gene. In addition to the presence to some of the criteria in our patient, he also had numerous intestinal lipomatosis, involving almost most of his small intestine. This in addition to high riding caecum and a narrow long mesentery which contributed to the development of small Bowel volvulus. PS should be suspected whenever we encounter patients with macrodactyly and this should alert us to the possibility of other congenital anomalies.


YAP promotes AP-1 expression in tubular epithelial cells in the kidney.
Chronic kidney disease (CKD) is a major health problem. Kidney fibrosis is a hallmark and final common pathway of CKD. The Hippo/yes-associated protein (YAP) pathway regulates organ size, inflammation, and tumorigenesis. Our previous study demonstrated tubular YAP activation by tubule-specific double knockout of mammalian STE20-like protein kinase 1/2 (Mst1/2) induced CKD in mice, but the underlying mechanisms remain to be fully elucidated. Activator protein (AP)-1 activation was found to promote tubular atrophy and tubulointerstitial fibrosis. Therefore, we studied whether YAP regulates AP-1 expression in the kidney. We found that expression of various AP-1 components was induced in kidneys subjected to unilateral ureteric obstruction and in Mst1/2 double knockout kidneys, and these inductions were blocked by deletion of Yap in tubular cells, with Fosl1 being most affected compared with other AP-1 genes. Inhibition of Yap also most highly suppressed Fosl1 expression among AP-1 genes in HK-2 and IMCD3 renal tubular cells. YAP bound to the Fosl1 promoter and promoted Fosl1 promoter-luciferase activity. Our results suggest that YAP controls AP-1 expression and that Fosl1 is the primary target of YAP in renal tubular cells.NEW & NOTEWORTHY Yes-associated protein (YAP) activation leads to tubular injury, renal inflammation, and fibrosis, but the underlying mechanisms are not fully understood. We now provide genetic evidence that YAP promotes activator protein-1 expression and that Fosl1 is the primary target of YAP in renal tubular cells.


Isolated electrothermal capsulorrhaphy in overhand athletes.
The purpose of this study was to determine the efficacy of arthroscopic electrothermal capsulorrhaphy for the treatment of instability in overhand athletes. Electrothermal capsulorrhaphy without labral repair was used to treat 20 symptomatic overhand athletes (15 baseball, 3 softball, and 2 volleyball). Nineteen patients were evaluated at a mean of 23 months. Overall Rowe results were 10 excellent, 4 good, 2 fair, and 3 poor, with a mean score of 82. The overall mean American Shoulder and Elbow Surgeons score was 85.7 (mean pain score, 42.2; mean score for activities of daily living, 43.5). Two failures (ten percent) required open shoulder stabilization. Ten athletes returned to their prior level of sport, three returned to a lower level, and six were unable to return to their sport. These preliminary results indicate that treatment of the overhand athlete with isolated electrothermal capsulorrhaphy is favorable but does not reproduce the success of open surgery. Overall recurrence and failure rates were high. Instability in overhand athletes may require something other than isolated electrothermal capsulorrhaphy to address laxity.


The East Baltimore Lift: a simple and effective method for reduction of posterior hip dislocations.
A supine technique for reducing posterior dislocations of the hip is presented. We believe this technique provides more controlled traction than do other maneuvers and have found it to be a safe and effective method to reduce the posteriorly dislocated hip.


Erythema multiforme following the infusion of hydroxyethyl starch.
Approximately 18 hours after attempted leukocytapheresis, erythema multiforme developed in a normal 28-year-old woman. About 50 milliliters of 6 percent hydroxyethyl starch (HES) had been infused before the procedure was stopped because of difficulty with access to the veins of her other arm. Although she had donated platelets several times, this was her first leukocytapheresis and first exposure to HES. Preapheresis steroids had not been given.


Phylogenomic resolution of Imparidentia (Mollusca: Bivalvia) diversification through mitochondrial genomes.
Despite significant advances in the phylogenomics of bivalves over the past decade, the higher-level phylogeny of Imparidentia (a superorder of Heterodonta) remains elusive. Here, a total of five new mitochondrial sequences (Chama asperella, Chama limbula, Chama dunkeri, Barnea manilensis and Ctena divergens) was added to provide resolution in nodes that required additional study. Although the monophyly of Lucinida remains less clear, the results revealed the overall backbone of the Imparidentia tree and the monophyly of Imparidentia. Likewise, most relationships among the five major Imparidentia lineages-Lucinida, Cardiida, Adapedonta, Myida and Venerida-were addressed with a well-supported topology. Basal relationships of Imparidentia recovered Lucinidae as the sister group to all remaining imparidentian taxa. Thyasiridae is a sister group to other imparidentian bivalves (except Lucinidae species) which is split into Cardiida, Adapedonta and the divergent clade of Neoheterodontei. Neoheterodontei was comprised of Venerida and Myida, the former of which now also contains Chamidae as the sister group to all the remaining venerid taxa. Moreover, molecular divergence times were inferred by calibrating nine nodes in the Imparidentia tree of life by extinct taxa. The origin of these major clades ranged from Ordovician to Permian with the diversification through the Palaeozoic to Mesozoic. Overall, the results obtained in this study demonstrate a better-resolved Imparidentia phylogeny based on mitochondrial genomes. The online version contains supplementary material available at 10.1007/s42995-023-00178-x.


Myocarditis Secondary to COVID-19 mRNA Vaccine: A Case Report.
Vaccine-induced myocarditis has been acknowledged in the past as a rare complication after vaccine administration including influenza and smallpox. Over the past year, there has been an increased number of myopericarditis cases reported by The Center for Disease Control and Prevention (CDC) following the administration of the BNT162b2 and mRNA-1273 vaccines. Most of these cases were among healthy young male adolescents. We report a case of myocarditis in a young male adolescent who presented with chest pain 2 weeks following the first dose of the mRNA COVID-19 vaccine. In the context of the COVID-19 pandemic, we believe it's crucial for healthcare providers to recognize and consider myocarditis as a differential diagnosis in young otherwise healthy individuals who present with chest pain and cardiac symptoms.


Umbilical cord blood culture in neonatal early-onset sepsis: a systematic review and meta-analysis.
Peripheral blood culture (PBC) is considered the gold standard for diagnosis of neonatal early-onset sepsis (EOS), but its diagnostic value can be questioned. We aimed to systematically asses the diagnostic test accuracy (DTA) of umbilical cord blood culture (UCBC) for EOS. A systematic literature search was performed in PubMed, Embase, Web of Science, and the Cochrane Library. Studies performing UCBC for the diagnosis of EOS were included. A total of 1908 articles were screened of which 17 were included. Incidences of positive PBC and UCBC were low in all studies. There was a large heterogeneity in the consistency between positive PBC and UCBC outcomes. PBC had a pooled sensitivity of 20.4% (95% CI 0.0-40.9) and specificity of 100.0% (95% CI 100.0-100.0) compared to 42.6% (95% CI 12.7-72.4%) and 97.8% (95% CI 93.1-100.0) of UCBC for clinical EOS, defined as clinical sepsis regardless of PBC outcomes. This systematic review shows that, compared to PBC, UCBC has higher sensitivity and comparable specificity for clinical EOS and might be considered as diagnostic test for EOS. Due to the limited number of studies, low incidences of EOS cases, and the imperfect reference standards for EOS, results should be interpreted cautiously. This is the first systematic review and meta-analysis investigating the diagnostic test accuracy of umbilical cord blood culture for neonatal early-onset sepsis. Peripheral blood culture is considered the gold standard for diagnosis of neonatal early-onset sepsis, but its value for this specific diagnosis can be questioned. Umbilical cord blood culture has higher sensitivity and comparable specificity for diagnosis of neonatal early-onset sepsis compared to peripheral blood culture, circumventing the risk for iatrogenic anemia and consequently might be used as a diagnostic tool for early-onset sepsis. Quality of evidence was regarded as low due to imperfect diagnostic methods of neonatal early-onset sepsis.


Molecular cloning of human von Ebner's gland protein, a member of the lipocalin superfamily highly expressed in lingual salivary glands.
Von Ebner's glands (VEG) are small lingual salivary glands. Their ducts open into trenches of circumvallate and foliate papillae, thus influencing the milieu where the interaction between taste receptor cells and sapid molecules takes place. The major secretions of human VEG is a protein with a molecular mass of 18 kDa. The human VEG protein crossreacts with antibodies raised against the rat VEG protein, indicating sequence similarity between the rat and human VEG proteins. This was subsequently confirmed by N-terminal protein sequencing. A cDNA clone, isolated from a human VEG library, contained an insert of 735 bp including an open reading frame that encodes the human VEG protein of 176 amino acids. Comparison of the human and rat VEG proteins revealed an overall identity of 60%. Immunocytochemistry, in situ hybridization and in vitro translation studies demonstrated the human VEG protein to be highly and exclusively expressed in VEG. The VEG proteins are members of the lipocalin protein superfamily and, together with the rat odorant binding protein II, they constitute a new subfamily. Sequence similarity to proteins such as the retinol binding protein and the odorant binding protein which are lipophilic ligand carriers, suggests a possible function for the human VEG protein in taste perception.


RU486-inducible retrovirus-mediated caspase-3 overexpression is cytotoxic to bcl-xL-expressing myeloma cells in vitro and in vivo.
The antiapoptotic protein bcl-x(L) is upregulated in a variety of solid tumors and in primary hematologic malignancies such as multiple myeloma. Activated caspase-3 cleaves proteins essential for cell survival, including bcl-x(L). To explore the potential of caspase-3 as a cytotoxic and immunostimulatory molecule in the treatment of malignancy, an RU486-inducible caspase-3 retrovirus was constructed, validated, and used to transduce first 3T3 and subsequently murine myeloma B9BM1 cells (creating the cell line B9BM-C3). After induction, apoptotic cell death of 3T3 and B9BM-C3 cells began by 4 h and was complete by 48 h postinduction, while nontransduced cells remained viable. Annexin V staining demonstrated 43, 76, and 98% apoptotic cell death at 12, 18, and 24 h postinduction. Activation of caspase-3 was evident in induced cells and cell death could be inhibited by the addition of a caspase-3-specific inhibitor. Overexpression of the myeloma-associated oncogene FGFR3, which upregulates bcl-x(L), delayed but did not prevent caspase-3-mediated killing. B9BM-C3 cells formed tumors after subcutaneous injection in mice. Early treatment with RU486 eradicated tumors; however, rechallenge of treated mice failed to demonstrate evidence of immunoprotection. These results indicate that therapeutic attempts to induce caspase-3 in malignant cells may prove useful in the treatment of bcl-x(L)-expressing tumors.


Non-genomic stimulation of tyrosine phosphorylation cascades by 1,25(OH)(2)D(3) by VDR-dependent and -independent mechanisms in muscle cells.
Studies with different cell types have shown that modulation of various of the fast as well as long-term responses to 1,25(OH)(2)D(3) depends on the activation of tyrosine kinase pathways. Recent investigations of our laboratory have demonstrated that 1,25(OH)(2)D(3) rapidly stimulates in muscle cells tyrosine phosphorylation of PLC-gamma and the growth-related proteins MAPK and c-myc. We have now obtained evidence using antisense technology indicating that VDR-dependent activation of Src mediates the fast stimulation of tyrosine phosphorylation of c-myc elicited by the hormone. This non-genomic action of 1,25(OH)(2)D(3) requires tyrosine phosphorylation of the VDR. Immunoprecipitation under native conditions coupled to Western blot analysis revealed 1,25(OH)(2)D(3)-dependent formation of complexes between Src and the VDR and c-myc. However, the activation of MAPK by the hormone was only partially mediated by the VDR and required in addition increased PKC and intracellular Ca(2+). Following its phosphorylation, MAPK translocates into the nucleus where it regulates c-myc transcription. Altogether these results indicate that tyrosine phosphorylation plays a role in the stimulation of muscle cell growth by 1,25(OH)(2)D(3). Data were also obtained involving tyrosine kinases and the VDR in hormone regulation of the Ca(2+) messenger system by mediating the stimulation of store-operated calcium (SOC; TRP) channels. Congruent with this action, 1,25(OH)(2)D(3) induces a rapid translocation of the VDR to the plasma cell membrane which can be blocked by tyrosine kinase inhibitors. Of mechanistic relevance, an association between the VDR and TRP proteins with the participation of the scaffold protein INAD was shown.


A comparative assay of epidemiological markers for Acinetobacter strains isolated in a hospital.
A comparative assay for epidemiological evaluation of three different Acinetobacter typing procedures, i.e. biotyping, phage-typing, and the analysis of the bacterial envelope protein profiles, was carried out using sixty-four multiresistant Acinetobacter strains isolated from clinical specimens. The antibiotic susceptibility of the strains was also considered. After geno-species identification, biotyping allowed the recognition of a relatively large and long-lasting presence, at an Intensive Therapy Unit, of two A. baumannii biotypes. Phage-typing and the analysis of the susceptibility to antibiotics allowed for the differentiation of strains belonging to different geno-species and biotypes, and in some cases also to the same biotypes. On the contrary, the analysis by polyacrylamide gel electrophoresis of the cell-envelope proteins failed to show any diversity not only within, but also between some of the biotypes of A. baumannii, the most prevalent species of the genus in the hospital environment.


Establishing a human health risk assessment methodology for metal species and its application of Cr6+ in groundwater environments.
The species of heavy metal is an important factor in determining human health risk. Quantifying the impacts on metal species can provide specific estimates of the heavy metal health risk to achieve more accurate risk. This paper was to develop a methodology to quantify and distinguish the contribution of metal species risk on human in site-specific groundwater. In this method, morphological simulation was used to obtain concentration and activity of metal species, for modifying the average daily dose from exposure pathways in human health assessment procedure. The carcinogenic and non-carcinogenic risks of Cr6+ morphologies in groundwater were examined for children and adults. The results demonstrated that the health risks of Cr6+ were depended on its species, and affected by pH and Ca2+ dose in groundwater. The new method provided a reference for policy decision on the prevention and treatment of metal element pollution.


Remission of Rheumatoid Arthritis and Primary Biliary Cholangitis After Treatment With Tocilizumab.
Rheumatoid arthritis (RA) is characterized by synovitis of multiple joints which if untreated progresses to joint destruction. Primary biliary cholangitis (PBC) is an autoimmune and progressive disease of the liver of unknown origin. About 1.8-5.6% of individuals with PBC have RA and patients with RA are at higher risk of developing PBC compared to the general population. We report a case of a 76-year-old man, with a history of PBC, and a recent RA diagnosis, in which tocilizumab therapy was effective in the control of RA and PBC, and a literature review was performed. This case, along with only one case published in literature in which tocilizumab was used in the treatment of RA and PBC, suggests that tocilizumab may be effective and safe in the treatment of RA in patients with PBC. Inhibition of IL-6 may also be effective in PBC treatment.


Berberine-induced growth inhibition of epithelial ovarian carcinoma cell lines.
The aim of this study is to analyze the impact of berberine on the two human epithelial ovarian carcinoma cell lines OVCAR-3 and SKOV-3 in relation to the potential usefulness of berberine in the treatment of epithelial ovarian cancer. Under adherent culture conditions, the cell lines were treated with berberine and analyzed for changes in cell growth. The cell cycle duration and degree of apoptosis were evaluated by means of propidium iodide staining and Annexin V staining. After the berberine treatment, the two cell lines showed a dose-dependent reduction in the growth rate. In the cell cycle analysis, the OVCAR-3 and SKOV-3 cells showed an increased DNA content of 5% in the G2/M phase and 7% in the S phase, respectively. Additionally, the results confirm the cell cycle arrest by immunoblotting and the up-regulation of p27; however, in the apoptosis analysis, neither cell line showed an increase in apoptosis after the berberine treatment. Berberine treatment can inhibit proliferation through a cell cycle arrest in OVCAR-3 and SKOV-3 cells. Thus, berberine may be a novel anticancer drug for the treatment of ovarian cancer.


Prophylactic CMV therapy does not improve three-yr patient and graft survival compared to preemptive therapy.
Despite increasing evidence in favor of prophylactic valganciclovir treatment in kidney transplant recipients for the prevention of cytomegalovirus (CMV) infection, the impact of preemptive vs. prophylactic treatment on long-term clinical outcomes is unclear. In this retrospective study, 187 kidney transplant recipients with serologic intermediate-risk constellation (recipient CMV IgG positive) received either preemptive or prophylactic treatment with valganciclovir. Patient survival (primary endpoint), graft survival, viremia rates, and other CMV-related outcomes were analyzed. Prophylactic therapy reduced the rates for CMV viremia during the first year (hazard ratio: 0.48, 95% confidence interval [CI] 0.30-0.75; p < 0.001). There was a trend for higher three-yr patient mortality in the prophylactic group (hazard ratio: 5.08, 95% CI 0.62-41.3; p = 0.091), and the rate of graft loss was not reduced (hazard ratio: 0.93, 95% CI 0.32-2.68; p = 0.894). Estimated glomerular filtration rate over three yr was on average 6.8 mL/min/1.73 m(2) lower in the prophylactic group (95% CI -11.68 to -1.81; p = 0.007) using a multivariate random effects model but showed more improvement over time. Prophylactic valganciclovir treatment reduced the rate of CMV infections during the first year post-transplant but no effects of prophylactic treatment on patient and graft survival or kidney function over three yr were observed.


Postoperative management following massive hepatectomy in a patient with Dubin-Johnson syndrome: report of a case.
We report herein the case of a 46-year-old man with Dubin-Johnson syndrome (DJS) who was referred to our hospital to undergo a right hepatic lobectomy for hepatocellular carcinoma. His complicated postoperative conjugated hyperbilirubinemia was successfully treated by hemopurification based on the increased level of serum hepatocyte growth factor (HGF). It is considered that hemopurification based on the early postoperative HGF levels has beneficial effects for patients with DJS; however, the specific role of hemopurification in the conjugated hyperbilirubinemia that develops postoperatively in these patients has not been determined.


Uterine artery pulsatility index: a predictor of methotrexate resistance in gestational trophoblastic neoplasia.
Neo-angiogenesis is a hallmark of cancer. The aim of this study was to test the hypothesis, in a prospective patient cohort, that in low-risk gestational trophoblastic neoplasia (LR-GTN) the uterine artery pulsatility index (UAPI), a measure of tumour vascularity, can predict resistance to methotrexate chemotherapy (MTX-R). 286 LR-GTN patients (Charing Cross Hospital (CXH) score 0-8, or FIGO score 0-6) were treated with methotrexate between January 2008 and June 2011 at CXH. During staging investigations, patients underwent a Doppler ultrasound to assess the UAPI. 239 patients were assessable for both UAPI and MTX-R. The median UAPI was lower (higher vascularity) in MTX-R compared with MTX-sensitive patients (0.8 vs 1.4, P<0.0001). In multivariate logistic regression, UAPI≤1 predicted MTX-R, independent of both CXH and FIGO scores. The risk of MTX-R in patients with a FIGO score of 6 and UAPI≤1 was 100% vs 20% in patients with UAPI>1 (χ(2) P<0.0001). UAPI represents an independently validated clinically useful predictor of MTX-R in LR-GTN. Further, consideration of whether to incorporate UAPI into the FIGO scoring system is now warranted so that patients with a score of 6 and a UAPI ≤1 might be upstaged and offered combination chemotherapy rather than MTX.


[Whole brain radiation therapy plus temozolomide in the treatment of brain metastases from non small cell lung cancer: a meta-analysis].
To explore the efficacy and safety of whole brain radiation therapy (WBRT) plus temozolomide (TMZ) versus WBRT alone in the treatment of brain metastases from non-small cell lung cancer (NSCLC) through a meta-analysis. All previously published and some unpublished studies were comprehensively searched from the databases of MEDLINE, EMBASE, Cochrane Library and CBM, etc. The meta-analysis included all randomized controlled trials (RCTs) to compare WBRT plus TMZ with WBRT alone in treatment of brain metastases from NSCLC. The primary meta-analysis was based upon objective remission (OR) and toxicity and the second overall survival (OS). Four RCTs identified by two reviewers were included. There was significant improvement for the WBRT + TMZ group in OR rate (RR = 1.55, P = 0.003); but without significant improvement in OS (P = 0.69). Meanwhile, WHO grade III/IV hematologic toxicity of myelosuppression increased in the WBRT + TMZ group (RR = 2.47, P = 0.008), but without significant difference in gastrointestinal toxicity (P = 0.14). For the treatment of brain metastases from NSCLC, the combined therapy of WBRT plus TMZ improves OR, but without significant improvement in OS. And the incidence of myelosuppression is elevated. Future large-scale, high-quality and prospective phase III RCTs are needed to confirm the clinical efficacy and safety of WBRT plus TMZ.


Modelling mitral valvular dynamics-current trend and future directions.
Dysfunction of mitral valve causes morbidity and premature mortality and remains a leading medical problem worldwide. Computational modelling aims to understand the biomechanics of human mitral valve and could lead to the development of new treatment, prevention and diagnosis of mitral valve diseases. Compared with the aortic valve, the mitral valve has been much less studied owing to its highly complex structure and strong interaction with the blood flow and the ventricles. However, the interest in mitral valve modelling is growing, and the sophistication level is increasing with the advanced development of computational technology and imaging tools. This review summarises the state-of-the-art modelling of the mitral valve, including static and dynamics models, models with fluid-structure interaction, and models with the left ventricle interaction. Challenges and future directions are also discussed.


The effects of crossbow impacts onto a common automotive vehicle side window-a preliminary study.
In recent times, the number of criminal incidents involving crossbows in the UK has increased with many incidents resulting in either injuries or fatalities. Whilst the effects of crossbow bolts on the body are well understood, there is a limited understanding on how these projectiles interact with the wider environment. One area of particular interest is the interaction between common vehicle side windows and bolts. In this study, the penetrability of two distinct bolts using an off-the-shelve crossbow against a common automotive side window was explored, where velocity loss up to 25 m/s post impact was recorded. All windows failed through radial glass fracture at a rate up to 1600 m/s, whilst bolt damage varied from tip holder decoupling, shaft damage, and traumatic fletching removal. No distinct relationship between bolt type, velocity, and window damage was identified.


Nutrition Policy and Healthy China 2030 Building.
Nutrition and health care are the most efficient and cost-effective ways to promote growth and prevent diseases. The dramatic decrease in the prevalences of stunting and malnutrition in China is the result of rapid economic development and nutrition efforts. The improvement in the Chinese populations' overall health status is consistent with the United Nation Sustainable Development Goal of "ending hunger, achieving food security and improving nutrition." Recent healthy policies, such as "Outline of the Healthy China 2030 Plan" and "Healthy China Action Plan (2019-2030)," pivot the shift from medical care to nutrition and health promotion, which sets a series of actions and goals that point out direction to China's nutrition policy improvement in the next decade. This paper systematically summarizes the China's nutrition policy environment and governance, implementation and actions of a series of food and nutrition policies, as well as available professional development and public education relevant to the field of nutrition. The challenges and prospects of nutrition actions are also addressed to pave a path for future policy-making and better nutrition improvements to successfully achieve Healthy China 2030.


Diethylstilbestrol, genetics, teratogenesis, and tumor spectrum in humans.
Diethylstilbestrol (DES) is the first example of transplacental carcinogenesis in humans, as evidenced by an excess of clear cell adenocarcinoma of the vagina and cervix in exposed women. We hypothesize that: 1) in utero DES exposure will be responsible for a broader spectrum of cancer with variable age of onset as a function of latency effects in exposed humans of both sexes; 2) teratogenicity of DES will be more far-reaching than currently recognized and will harbor cancer implications in the face of known associations between teratogenesis and carcinogenesis; and 3) genetic heterogeneity will be a critical etiologic discriminant in DES associated cancer. This hypothesis embraces a prodigious body of data at the infrahuman level, as well as extant pharmacogenetic and ecogenetic observations in humans which signify heritable variations in response to environmental carcinogenic exposures. This hypothesis has important implications for drug testing with appropriate preventive strategies. Herein, particular restraints with monitoring through governmental legal channels must be employed. Past experience has clearly indicated negligence in shouldering this responsibility by both the pharmaceutical industry and government regulatory bodies.


Which patient and treatment factors are related to successful cardiovascular risk score reduction in general practice? Results from a randomized controlled trial.
Cardiovascular disease is a leading cause of death. It is important to identify patient and treatment factors that are related to successful cardiovascular risk reduction in general practice. This study investigates which patient and treatment factors are related to changes in cardiovascular risk estimation, expressed as the Systematic Coronary Risk Evaluation (SCORE) 10 year risk of cardiovascular mortality. 179 general practice patients with mild-moderately elevated cardiovascular risk followed a one-year programme which included structured lifestyle and medication treatment by practice nurses, with or without additional self-monitoring. From the patient and treatment data collected as part of the "Self-monitoring and Prevention of RIsk factors by Nurse practitioners in the region of Groningen" randomized controlled trial (SPRING-RCT), the contribution of patient and treatment factors to the change in SCORE was analysed with univariate and multivariate analyses. In multivariate analyses with multiple patient and treatment factors, only SCORE at baseline, and addition of or dose change in lipid lowering or antihypertensive medications over the course of the study were significantly related to change in SCORE. Our analyses support the targeting of treatment at individuals with a high SCORE at presentation. Lipid lowering medication was added or changed in only 12% of participants, but nevertheless was significantly related to ΔSCORE in this study population. Due to the effect of medication in this practice-based project, the possible additional effect of the home monitoring devices, especially for individuals with no indication for medication, may have been overshadowed. trialregister.nl NTR2188.


Magnesium-dependent sphingomyelinase of infantile brain. Effect of detergents and a heat-stable factor.
The properties of the Mg2+-dependent sphingomyelinase, whose pH optimum is between 7 and 8, were investigated using post-mortem infantile brain. The enzyme could be extracted with 0.2% Triton X-100 and remained soluble when centrifuged at 170,000 X g. Subsequent removal of the detergent with SM2-Biobeads resulted in resedimentation of the enzyme at 80,000 X g. A detergent was needed for assaying enzymatic activity; either Triton X-100 or bile salts could be used. With increasing concentrations of detergent, the rates of hydrolysis of sphinomyelin increased, reached an optimum and then decreased, suggesting inhibition of the enzyme. The concentrations of detergent which resulted in optimal reaction rates were directly related to the protein concentration of the enzymatic preparation. A heat-stable factor which counteracts inhibition by the above detergents is present in brain as well as several other tissues. A lipid extract of the enzymatic preparation, or several purified lipids could not mimic the effect of the heat-stable factor. The interrelationship between enzyme, detergent and the heat-stable factor was investigated.


Kite Measurement Technique for Enhanced Accuracy and Technical Proficiency of Graft Preparation in Segmental Labral Reconstruction of the Hip.
Preserving labral integrity has become a guiding principle in hip preservation surgery given the recent understanding of the importance of the acetabular labral suction seal. When labral tissue is deficient, a labral reconstruction may be indicated to re-create the suction seal and improve hip biomechanics. One of the main challenges of segmental labral reconstruction techniques is obtaining an accurate measurement of the defect because incorrect sizing of the graft could result in incomplete restoration of the labral seal or an oversized graft that requires amputation. In this report, we present a kite measurement technique that allows for easy, accurate measurement of the segmental defect during segmental labral reconstruction.


Serum zonulin levels are increased in Alzheimer's disease but not in vascular dementia.
Zonulin is involved in the integrity and functioning of both intestinal-epithelial barrier and blood-brain barrier (BBB) by regulating tight junction molecular assembly. Since changes in microbiota and BBB may play a role in neurodegenerative disorders, we aimed to determine whether serum zonulin levels change in older patients affected by different types of dementia or mild cognitive impairment (MCI). We evaluated serum zonulin levels in patients with late-onset AD (LOAD), vascular dementia (VAD), MIXED (AD + VAD) dementia, amnestic MCI, and in healthy controls. Compared with controls, serum zonulin increased in LOAD, MIXED dementia, and aMCI but not in VAD, independent of potential confounders (ANCOVA p = 0.01; LOAD vs controls, p = 0.01; MIXED vs. controls, p = 0.003; aMCI vs. controls, p = 0.04). Notably, aMCI converting to dementia showed significantly higher levels of zonulin compared with stable aMCI (p = 0.04). Serum zonulin inversely correlated with the standardized Mini-Mental State Examination (MMSE) score (p < 0.05), regardless of potential confounders. We found increased serum zonulin levels in patients with aMCI, LOAD and MIXED dementia, but not in VAD; moreover, zonulin levels were higher in aMCI converting to AD compared with stable ones. Our findings suggest that a dysregulation of intestinal-epithelial barrier and/or BBB may be an early specific event in AD-related neurodegeneration.


Phosphorylation inhibits the activity of μ-calpain at different incubation temperatures and Ca2+ concentrations in vitro.
This study aimed to investigate the effects of phosphorylation on the activity of μ-calpain and its sensitivity to temperature and Ca2+. For temperature sensitivity analysis, sarcoplasmic protein was treated with alkaline phosphatase (AP) and phosphatase inhibitor (PI) at 4, 25 and 37°C. The results showed that the degradation degree of μ-calpain in the AP group was significantly higher after incubation for 12h. For calcium sensitivity analysis, samples treated with AP and PI were incubated at 0.01, 0.05, 0.1 and 1mM Ca2+. The results showed that the degradation rate of μ-calpain was maximum in the AP group and minimum in the PI group at 0.01, 0.05 and 0.1mM Ca2+. The differences between the three groups reduced as concentration increased. These data demonstrate that phosphorylation plays a negative role in regulating μ-calpain activity. This study clarifies the regulatory mechanism of μ-calpain activation in vitro and/or in postmortem muscle.


Soluble osteopontin inhibits apoptosis of adherent endothelial cells deprived of growth factors.
Osteopontin (OPN) is primarily an extracellular glycosylated phosphoprotein capable of stimulating cell migration and cell attachment, predominantly to mineralized surfaces. Found in moderate levels in plasma, it acts as a cytokine able to modify gene expression via integrins and certain CD44 isoforms. In this work we show that soluble OPN inhibits apoptosis of adherent human umbilical vein endothelial cells incubated in medium lacking critical growth factors and cytokines. In a dose-dependent manner OPN reduced the formation of apoptotic bodies and suppressed DNA fragmentation. OPN also caused an increase in Bcl-X(L) mRNA levels, suppressed the apparent dispersion of Bcl-X(L) throughout the cytoplasm, and slightly enhanced IkappaB-alpha protein degradation. These data suggest that a function of OPN in homeostatic processes is to facilitate the survival of stressed endothelial cells, possibly by occupying unligated integrins and suppressing integrin-mediated death.


Identification and functional analysis of a novel missense mutation in GJA8, p.Ala69Thr.
To explore the molecular genetic cause of a four-generation autosomal dominant congenital cataract family in China. Targeted region sequencing was performed to screen for the potential mutation, and Sanger sequencing was used to confirm the mutation. The homology model was constructed to identify the protein structural change, PolyPhen-2 and Provean were used to predict the mutation impact. Functional and cellular analysis of the wild and mutant GJA8 were performed in DF-1 cells by western blotting, dye uptake assay, immunofluorescence, Annexin V-FITC staining. A novel heterozygous mutation (c.205G > A; p.Ala69Thr) was identified within GJA8, which cosegregated with congenital cataract phenotype in this family. Bioinformatics analysis showed the mutation was located in a highly conserved region, and the mutation was predicted to be pathogenic. Function analysis indicated that the mutation inhibited GJA8 hemichannel activity, reduced cell tolerance to oxidative stress, changed the protein distribution pattern and inhibited the cell growth. We have identified a novel missense mutation in GJA8 (c.205G > A, p.Ala69Thr) in a four-generation Chinese family and our results will further broaden the gene mutation spectrum of GJA8.


Metabolite Modulation in Human Plasma in the Early Phase of Acclimatization to Hypobaric Hypoxia.
The exposure of healthy subjects to high altitude represents a model to explore the pathophysiology of diseases related to tissue hypoxia. We explored a plasma metabolomics approach to detect alterations induced by the exposure of subjects to high altitude. Plasma samples were collected from 60 subjects both on plain and at high altitude (5300 m). Metabolite profiling was performed by gas chromatography-mass spectrometry (GC-MS) and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS) in conjunction with univariate and multivariate statistical analyses. ELISA assays were further employed to measure the levels of several relevant enzymes together with perturbed metabolic pathways. The results showed that hypobaric hypoxia caused significant and comprehensive metabolic changes, as represented by significant changes of 44 metabolites and 4 relevant enzymes. Using MetaboAnalyst 3.0, it was found that several key metabolic pathways were acutely perturbed. In addition, 5 differentially expressed metabolites in pre-exposure samples from the acute mountain sickness-susceptible (AMS-S) group compared with those from the AMS-resistant (AMS-R) group are identified, which warrant further validation as potential predictive biomarkers for AMS-S individuals. These results provide new insights for further understanding the pathophysiological mechanism of early acclimatization to hypobaric hypoxia and other diseases correlated to tissue hypoxia.


Interactions of a designed peptide with lipopolysaccharide: Bound conformation and anti-endotoxic activity.
Designed peptides that would selectively interact with lipopolysaccharide (LPS) or endotoxin and fold into specific conformations could serve as important scaffolds toward the development of antisepsis compounds. Here, we describe solution structure of a designed amphipathic peptide, H(2)N-YVKLWRMIKFIR-CONH(2) (YW12D) in complex with endotoxin as determined by transferred nuclear Overhauser effect spectroscopy. The conformation of the isolated peptide is highly flexible, but undergoes a dramatic structural stabilization in the presence of LPS. Structure calculations reveal that the peptide presents two amphipathic surfaces in its bound state to LPS whereby each surface is characterized by two positive charges and a number of aromatic and/or aliphatic residues. ITC data suggests that peptide interacts with two molecules of lipid A. In activity assays, YW12D exhibits neutralization of LPS toxicity with very little hemolysis of red blood cells. Structural and functional properties of YW12D would be applicable in designing low molecular weight non-toxic antisepsis molecules.


Application of optimal multichannel filtering to simulated nerve signals.
The optimal linear filters derived in the preceding paper can be thoroughly evaluated using computer simulations, based on the properties of mammalian sensory and motor nerve fibres. Using reasonable values for action potential waveforms, conduction velocity and electrode noise, good separation of motor and sensory signals can be obtained. The performance of the filters is degraded by 1) increasing the electrode noise, 2) introducing dispersion in the conduction velocities, or 3) variation in the waveform of the action potentials from that used in designing the filters. However, the variations needed to seriously degrade performance are quite large compared to those which are likely to be present in mammalian nerves. Use of these filters to distinguish different classes of sensory (or motor) signals based on conduction velocity is discussed.


Metabolism of estradiol by uterine peroxidase: nature of the water-soluble products.
The nature of the water-soluble products formed by incubating labelled estradiol with uterine peroxidase in the presence of H2O2 and tyrosine was examined by two-dimensional thin-layer chromatography and high voltage electrophoresis. It was shown that the steroid and amino acid were associated in a 1:2 or 1:3 ratio and evidence was provided by 3H-exchange for the interaction of tyrosine with ring A of estradiol at C-2 and C-4. The possible role of estrogen-induced peroxidase in the uterus in vivo is discussed.


Cortico-limbic connectivity in MAOA-L carriers is vulnerable to acute tryptophan depletion.
A gene-environment interaction between expression genotypes of the monoamine oxidase A (MAOA) and adverse childhood experience increases the risk of antisocial behavior. However, the neural underpinnings of this interaction remain uninvestigated. A cortico-limbic circuit involving the prefrontal cortex (PFC) and the amygdala is central to the suppression of aggressive impulses and is modulated by serotonin (5-HT). MAOA genotypes may modulate the vulnerability of this circuit and increase the risk for emotion regulation deficits after specific life events. Acute tryptophan depletion (ATD) challenges 5-HT regulation and may identify vulnerable neuronal circuits, contributing to the gene-environment interaction. Functional magnetic resonance imaging measured the resting-state state activity in 64 healthy males in a double-blind, placebo-controlled study. Cortical maps of amygdala correlation identified the impact of ATD and its interaction with low- (MAOA-L) and high-expression variants (MAOA-H) of MAOA on cortico-limbic connectivity. Across all Regions of Interest (ROIs) exhibiting an ATD effect on cortico-limbic connectivity, MAOA-L carriers were more susceptible to ATD than MAOA-H carriers. In particular, the MAOA-L group exhibited a larger reduction of amygdala connectivity with the right prefrontal cortex and a larger increase of amygdala connectivity with the insula and dorsal PCC. MAOA-L carriers were more susceptable to a central 5-HT challenge in cortico-limbic networks. Such vulnerability of the cortical serotonergic system may contribute to the emergence of antisocial behavior after systemic challenges, observed as gene-environment interaction. Hum Brain Mapp 38:1622-1635, 2017. © 2016 Wiley Periodicals, Inc.


The nature of the carbohydrate-peptide linkage region in glycoproteins from the cellulosomes of Clostridium thermocellum and Bacteroides cellulosolvens.
The cellulase complexes of two cellulolytic bacteria, Clostridium thermocellum and Bacteroides cellulosolvens, were subjected to extensive Pronase digestion. Glycopeptide fractions were isolated by gel permeation and fast protein liquid chromatography and analyzed by monosaccharide analysis, amino acid analysis, methylation analysis, and 1H NMR spectroscopy. Alkaline borohydride-induced deglycosylation/amino acid conversion and periodate oxidation studies on the glycopeptide fraction of the C. thermocellum cellulosome demonstrated that the earlier established collection of carbohydrate moieties with 3-O-Me-D-GlcpNAc-alpha (1-->2)-[D-Galp-alpha (1-->3)]-D-Galf-alpha (1-->2)-D-Gal (where 3-O-Me-D-GlcpNAc is 3-O-methyl-N-acetylglucopyranosamine, Galp is galactopyranose, and Galf is galactofuranose) as the major component, is O-linked to threonine via galactopyranose. Using the same approach for the glycopeptide fraction of the cellulase complex of B. cellulosolvens, it was found that the reported collection of carbohydrate moieties with D-Galf-alpha (1-->3)-D-GlcpNAc-alpha (1-->2)-D-Galf-alpha (1-->2)-[D-Galf-beta (1-->3)]-D-Gal as the major component, is O-linked mainly to threonine and partly to serine via galactopyranose. In both species, the hydroxyamino-acid-bound galactopyranose residue has probably an alpha-configuration. The carbohydrate chains appear as clusters located in highly Thr/Pro-rich peptide regions of the glycoproteins. The results are consistent with the notion that the glycosylation sites are localized in linker sequences which connect the various binding domains of the noncatalytic S1 subunit of the cellulosome.


[Ontogenetic features of the accumulation and restoration of thiamine of the digestive system organs in white rats].
Accumulation and renewal of thiamine in tissues of the uneven-aged rats have been investigated. The activity of thiamine-metabolizing and thiamine-retaining systems is shown to decrease in tissues of the digestive system with aging; the same refers to the intensity of enterohepatic recirculation of that vitamin. These phenomena underlie the revealed retardation of the thiamine renewal in organs of the digestive system.


Uterovaginal prolapse in a primigravida presenting in active first stage of labor: a case report.
Uterovaginal prolapse is the descent of the uterus and vagina down the birth canal toward the introitus. The occurrence of uterovaginal prolapse in a primigravida is very rare. It can cause preterm labor, fetal demise, spontaneous abortion, postpartum hemorrhage, maternal urinary complications, sepsis, and death. This case report presents the rare occurrence of uterovaginal prolapse in a primigravida woman with no major risk factors identified for prolapse, who presented in active first stage of labor and delivered vaginally. A 30-year-old Oromo primigravida woman who did not remember her last normal menstrual period but claimed amenorrhea of 9 months duration presented with the urge to bear down of 12 hours duration and passage of liquor of 8 hours duration. She was referred from the local health center to Jimma Medical Center with a diagnosis of prolonged labor. At presentation, she was in active first stage of labor with cervix 5-6 cm and fetal heartbeat was negative. She was followed for the progress of labor, and 4 hours after admission to the labor ward, she delivered a freshly dead male neonate weighing 3000 g. Her postpartum period was uneventful, and she was discharged on her third postpartum day and referred after 6 weeks to the outpatient department. Uterovaginal prolapse occurring in primigravida and during labor at first recognition is very rare, with congenital weakness being a possible underlying pathology. Management of uterovaginal prolapse during labor should be individualized on the basis of fetal condition and the severity of prolapse. For a patient with pelvic organ prolapse in labor, expectant management is a good option when there is no severe edema resulting in obstructed labor, as in our case, where the patient delivered vaginally and the prolapse resolved postpartum.


Prospects of three-dimensional high resolution electron microscopy of non-periodic structures.
In the first part of the paper the general features of three-dimensional electron microscopy of non-periodic structures at high resolution are discussed. Such an analysis requires series of 20 or more exposures of mechanically moved specimens. It is fundamentally important that the integral radiation dose, however, need not be increased--three-dimensional analysis yields extra information without additional radiation loading. It is demonstrated that the constraints characteristic for atomic resolution can in future facilitate many difficulties like restricted tilting range (conical tilting), inaccuracies in the refinement of the origin determination etc. Data collection up to atomic resolution is possible with existing image reconstruction methods if the chromatic spread of the cathodes can be partially corrected. The relatively great radiation induced changes of "stable" specimens will require additional averaging in the experiment (quasi-simultaneous registration). The advantage of a time dependent analysis of radiation sensitive structures--especially the possibility of using redundancies in the analysis (trace structure analysis)--is discussed. The experimental part (studies of radiation damage and three-dimensional work on carbon foils) presents examples of such analyses. The main experimental difficulty consists in the collection of many exposures with no extra load of the specimen in the intervals between exposures.


Infantile asphyxia due to aberrant uvula--an anatomic misadventure.
A case of unexpected death of an infant with an abnormally elongated uvula is presented. The child, born prematurely, was recovering from protracted treatment in hospital, including surgical interventions and periods of ventilation support necessitating recurrent intubations and anesthesia. She was discharged home in good general health, affected by episodes of cough, and was found dead in her crib a week later. The proximity of the aberrant uvula to the vocal cords may have caused intermittent laryngospasm, with subsequent symptoms of cough and airway obstruction, ending in a fatal outcome. Recurrent airway irritation may have contributed to uvular hypertrophy, due to inflammatory and reactive changes. It is pertinent for the pathologist to thoroughly examine the structures of the pharynx, and the uvula in particular, in any case of pediatric death suspected to result from asphyxia or sudden infant death syndrome (SIDS).


[Outpatient thoracic surgery: Evolution of the indications, current applications and limits].
The objectives of outpatient surgery are to reduce the risks connected to hospitalization, to improve postoperative recovery and to decrease the health costs. Few studies have been performed in the field of thoracic surgery and there remains great scope for progress in outpatient lung surgery. The purpose of this article is to present a revue of the current situation and the prospects for the development of out patient thoracic surgery.


The FEN1 L209P mutation interferes with long-patch base excision repair and induces cellular transformation.
Flap endonuclease-1 (FEN1) is a multifunctional, structure-specific nuclease that has a critical role in maintaining human genome stability. FEN1 mutations have been detected in human cancer specimens and have been suggested to cause genomic instability and cancer predisposition. However, the exact relationship between FEN1 deficiency and cancer susceptibility remains unclear. In the current work, we report a novel colorectal cancer-associated FEN1 mutation, L209P. This mutant protein lacks the FEN, exonuclease (EXO) and gap endonuclease (GEN) activities of FEN1 but retains DNA-binding affinity. The L209P FEN1 variant interferes with the function of the wild-type FEN1 enzyme in a dominant-negative manner and impairs long-patch base excision repair in vitro and in vivo. Expression of L209P FEN1 sensitizes cells to DNA damage, resulting in endogenous genomic instability and cellular transformation, as well as tumor growth in a mouse xenograft model. These data indicate that human cancer-associated genetic alterations in the FEN1 gene can contribute substantially to cancer development.