Filamentous members of cluster III Defluviicoccus have the in situ phenotype expected of a glycogen-accumulating organism in activated sludge.
The in situ ecophysiology of alphaproteobacterial filamentous Cluster III Defluviicoccus present in enhanced biological phosphorus removal (EBPR)-activated sludge systems was evaluated using FISH-MAR and histochemical staining methods. These organisms, sharing the Nostocoida limicola morphotype, are known to be responsible for serious episodes of activated sludge bulking. The data presented here also demonstrate an ability to assimilate short-chain fatty acids and synthesize poly-β-hydroxyalkanoates (PHA) anaerobically, and then utilize this stored PHA under aerobic conditions, but with no corresponding synthesis of polyphosphate. These features are consistent with an in situ phenotype of glycogen-accumulating organisms (GAO), populations thought to lower the efficiency of EBPR systems by outcompeting polyphosphate-accumulating organisms (PAO) for substrates in their anaerobic feed phase. Survey data indicate that these GAO are as commonly seen as the known PAO in full-scale EBPR-activated sludge systems, which suggest that they might play important roles there, and therefore should not be viewed just as laboratory curiosities.


Acute Kidney Injury Risk and Contrast Volume in Intact Versus Ruptured Endovascular Aneurysm Repair in the Vascular Quality Initiative.
Renal impairment after repair of ruptured abdominal aortic aneurysm has been associated with post-operative mortality. Acute kidney injury (AKI) risk specifically related to contrast administration in endovascular aneurysm repair (EVAR) for intact vs ruptured aneurysms has not been previously described. It was our objective to evaluate the risk of AKI and the association with contrast administration in EVAR for ruptured (rEVAR) and intact (iEVAR) aneurysm repair in the Vascular Quality Initiative (VQI). Adult patients less than 90 years old undergoing EVAR in the VQI without prior abdominal aortic surgery or who were not actively on dialysis preoperatively were included. Patients immediately converted to an open repair were excluded. Patients were grouped by repair urgency, and patient and operative characteristics and outcomes compared. Univariable and multivariable analyses were performed to identify factors associated with the primary outcome of AKI. Survival was evaluated by Kaplan-Meier analysis. Of 38,775 EVAR patients identified, 86.5% underwent elective surgery for an intact aneurysm, 8.4% had urgent surgery for a symptomatic, intact aneurysm, and 5.1% had emergent repair for a ruptured aneurysm. Significant risk factors for AKI included contrast volume, a preoperative eGFR <30 mL/min, procedure urgency, COPD, congestive heart failure (CHF), and total procedure time. The factor most associated with AKI was aneurysm rupture prior to repair (OR 8.6, CI 7.2-10.3, P <.01). The association of contrast volume with the outcome was the least strong with a 4% increase in risk per 25 mL of contrast (OR 1.04, 95% CI 1.01-1.07). With the development of AKI, postoperative survival was reduced regardless of indication. Of all factors assessed, aneurysm rupture was the most and contrast volume the least associated with AKI after EVAR. Further studies should evaluate methods of preventing post-EVAR AKI.


Clinical impairment measures and reading performance in a large age-related macular degeneration group.
To investigate the relationship between clinical impairment measures and reading performance in a large population with age-related macular degeneration. The following clinical measures were evaluated on 243 patients with age-related macular degeneration: better eye distance visual acuity (ETDRS chart); threshold near word reading acuity (Bailey-Lovie Word Reading chart); maximum reading speed and critical print size (MNREAD chart); letter contrast sensitivity (Pelli-Robson); and kinetic perimetry (Bjerrum screen) to determine the nearest non-scotomatous point to fovea (NNPF; in degrees) and the central scotoma area (mm2). Distance acuity correlated well to threshold near word acuity (r = 0.71), but word acuity was usually poorer. Critical print size was strongly related (p < 0.001) to near visual acuity (r2 = 0.31 and beta = 0.47) and was poorer than threshold near word visual acuity by a mean difference of -0.41 (range, -1.10 to 0.34), which represents a mean acuity reserve of 2.5:1. On single regression, distance (p < 0.0001, r2 = 0.35, and beta = -102.37) and near acuities (p < 0.0001, r2 = 0.52, beta = -126.53), critical print size (p = 0.0001, r2 = 19, and beta = 0.002), contrast sensitivity (p < 0.0001, r2 = 19, and beta = 79.47), scotoma size (p = 0.006, r2 = 12, and beta = -0.04), and NNPF (p = 0.001, r2 = 12, and beta = -4.39) were all highly significantly related to reading speed although these predicted only a low percentage of variance. Best prediction of reading speed was obtained on multiple regression, where NNPF and near word acuity explained 60% of the variance (p < 0.0001). Optimal prediction of reading speed with clinical parameters appears to be based on the combination of near word acuity and scotoma area, explaining 60% of the variance. Other factors not measured in this study are likely to account for the rest of the prediction.


The role of endoplasmic reticulum stress in maintaining and targeting multiple myeloma: a double-edged sword of adaptation and apoptosis.
Increased cellular protein production places stress on the endoplasmic reticulum (ER), because many of the nascent proteins pass through the ER for folding and trafficking. Accumulation of misfolded proteins in the ER triggers the activation of three well-known pathways including IRE1 (inositol requiring kinase 1), ATF6 (activating transcription factor 6), and PERK (double stranded RNA-activated protein kinase-like ER kinase). The activity of each sensor modulates the overall ER strategy for managing protein quality control as cellular needs change due to growth, differentiation, infection, transformation, and host of other possible physiological states. Here we review the role of ER stress in multiple myeloma (MM), an incurable plasma cell neoplasm. MM is closely linked to dysregulated unfolded protein response in the ER due to the heightened production of immunoglobulin and the metabolic demands of malignant uncontrolled proliferation. Together, these forces may mean that myeloma cells have an "Achilles heel" which can be exploited as a treatment target: their ER stress response must be constitutively active at a remarkably high level to survive their unique metabolic needs. Therefore, inhibition of the ER stress response is likely to injure the cells, as is any further demand on an already over-worked system. Evidence for this vulnerability is summarized here, along with an overview of how each of the three ER stress sensors has been implicated in myeloma pathogenesis and treatment.


Perfluorooctane sulfonic acid and organohalogen pollutants in liver of three freshwater fish species in Flanders (Belgium): relationships with biochemical and organismal effects.
A perfluorooctane sulfonic acid (PFOS) assessment was conducted on gibel carp (Carassius auratus gibelio), carp (Cyprinus carpio), and eel (Anguilla anguilla) in Flanders (Belgium). The liver PFOS concentrations in fish from the Ieperlee canal (Boezinge, 250-9031 ng/g wet weight, respectively) and the Blokkersdijk pond (Antwerp, 633-1822 ng/g wet weight) were higher than at the Zuun basin (Sint-Pieters-Leeuw, 11.2-162 ng/g wet weight) and among the highest in feral fish worldwide. Eel from the Oude Maas pond (Dilsen-Stokkem) and Watersportbaan basin (Ghent) had PFOS concentrations ranging between 212 and 857 ng/g wet weight. The hepatic PFOS concentration was significantly and positively related with the serum alanine aminotransferase activity, and negatively with the serum protein content in eel and carp. The hepatic PFOS concentration in carp correlated significantly and negatively with the serum electrolyte concentrations whereas a significant positive relation was found with the hematocrit in eel. Although 13 organochlorine pesticides, 22 polychlorinated biphenyl (PCB) congeners and 7 polybrominated diphenyl ethers (PBDEs) were also measured in the liver tissue, only PCB 28, PCB 74, gamma-hexachlorocyclohexane (gamma-HCH) and hexachlorobenzene (HCB) were suggested to contribute to the observed serological alterations in eel.


Calcium Signaling Regulates Autophagy and Apoptosis.
Calcium (Ca2+) functions as a second messenger that is critical in regulating fundamental physiological functions such as cell growth/development, cell survival, neuronal development and/or the maintenance of cellular functions. The coordination among various proteins/pumps/Ca2+ channels and Ca2+ storage in various organelles is critical in maintaining cytosolic Ca2+ levels that provide the spatial resolution needed for cellular homeostasis. An important regulatory aspect of Ca2+ homeostasis is a store operated Ca2+ entry (SOCE) mechanism that is activated by the depletion of Ca2+ from internal ER stores and has gained much attention for influencing functions in both excitable and non-excitable cells. Ca2+ has been shown to regulate opposing functions such as autophagy, that promote cell survival; on the other hand, Ca2+ also regulates programmed cell death processes such as apoptosis. The functional significance of the TRP/Orai channels has been elaborately studied; however, information on how they can modulate opposing functions and modulate function in excitable and non-excitable cells is limited. Importantly, perturbations in SOCE have been implicated in a spectrum of pathological neurodegenerative conditions. The critical role of autophagy machinery in the pathogenesis of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases, would presumably unveil avenues for plausible therapeutic interventions for these diseases. We thus review the role of SOCE-regulated Ca2+ signaling in modulating these diverse functions in stem cell, immune regulation and neuromodulation.


Identification of small molecule inhibitors of Interleukin-18.
Interleukin-18 (IL-18) is a pleiotropic pro-inflammatory cytokine belonging to the IL-1 superfamily. IL-18 plays an important role in host innate and adaptive immune defense but its aberrant activities are also associated with inflammatory diseases such as rheumatoid arthritis and Crohn's disease. IL-18 activity is modulated in vivo by its naturally occurring antagonist, IL-18 Binding Protein (IL-18BP). Recent crystal structures of human IL-18 (hIL-18) in complex with its antagonists or cognate receptor(s) have revealed a conserved binding interface on hIL-18. Through virtual screening of the National Cancer Institute Diversity Set II and in vitro competitive ELISA we have identified three compounds (NSC201631, NSC80734, and NSC61610) that disrupt hIL-18 binding to the ectromelia virus IL-18BP. Through cell-based bioassay, we show that NSC80734 inhibits IL-18-induced production of IFN-γ in a dose-dependent manner with an EC50 of ~250 nM. Our results and methodology presented here demonstrate the feasibility of developing small molecule inhibitors that specifically target the rather large interface of IL-18 that is involved in extensive protein-protein interactions with both IL-18BP and its cognate receptor(s). Our data therefore provide the basis for an approach by which small molecules can be identified that modulate IL-18 activity.


Design, Synthesis, Anticancer Evaluation, and Molecular Docking Studies of Oxazole-Incorporated Naphthyridine Derivatives.
A novel series of oxazole incorporated naphthyridine (21 a-j) derivatives were designed and, synthesized followed by screening of their anticancer activity profiles against human breast cancer (MCF-7), human lung cancer (A549) and human prostate (PC3 & DU-145) cancer cell lines by employing MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay using etoposide as the positive control. Of these compounds, N-(6-chloro-3-(4-(3,4,5-trimethoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine with 3,4,5-trimethoxy substituent on the aryl moiety attached to oxazole ring showed potent anticancer activity against PC3, A549, MCF-7, and DU-145 cell lines with IC50 values of 0.13±0.095 μM; 0.10±0.084 μM; 0.18±0.087 μM and 0.15±0.076 μM respectively. Apart from this, compounds N-(6-chloro-3-(4-(3,5-dimethoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine, N-(6-chloro-3-(4-(4-methoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine, and N-(6-chloro-3-(4-(3,5-dimethylphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine also showed better anticancer activities against four cancer cell lines screened for. These activities were also validated through the molecular docking simulations, which further indicated demonstration of better interaction energy and profile by these compounds.


Enterohemorrhagic E. coli requires N-WASP for efficient type III translocation but not for EspFU-mediated actin pedestal formation.
Upon infection of mammalian cells, enterohemorrhagic E. coli (EHEC) O157:H7 utilizes a type III secretion system to translocate the effectors Tir and EspF(U) (aka TccP) that trigger the formation of F-actin-rich 'pedestals' beneath bound bacteria. EspF(U) is localized to the plasma membrane by Tir and binds the nucleation-promoting factor N-WASP, which in turn activates the Arp2/3 actin assembly complex. Although N-WASP has been shown to be required for EHEC pedestal formation, the precise steps in the process that it influences have not been determined. We found that N-WASP and actin assembly promote EHEC-mediated translocation of Tir and EspF(U) into mammalian host cells. When we utilized the related pathogen enteropathogenic E. coli to enhance type III translocation of EHEC Tir and EspF(U), we found surprisingly that actin pedestals were generated on N-WASP-deficient cells. Similar to pedestal formation on wild type cells, Tir and EspF(U) were the only bacterial effectors required for pedestal formation, and the EspF(U) sequences required to interact with N-WASP were found to also be essential to stimulate this alternate actin assembly pathway. In the absence of N-WASP, the Arp2/3 complex was both recruited to sites of bacterial attachment and required for actin assembly. Our results indicate that actin assembly facilitates type III translocation, and reveal that EspF(U), presumably by recruiting an alternate host factor that can signal to the Arp2/3 complex, exhibits remarkable versatility in its strategies for stimulating actin polymerization.


[Clinical characteristics, diagnosis and treatment of digestive tract leakage after orthotopic liver transplantation].
To investigate the clinical characteristics, diagnosis and treatment of digestive tract leakage after orthotopic liver transplantation (OLT). Sixty-one recipients had digestive tract leakage in early stage after OLT among 1173 cases from January 2000 to December 2010. There were 55 male and 6 female patients, aging from 36 to 61 years, with a median of 45 years. Digestive tract leakage included bile leakage (46 cases), gastric leakage (5 cases), duodenal leakage (1 case), jejunal leakage (4 cases), ileal leakage (1 case) and colon transversum leakage (4 cases). Ten of recipients with gastrointestinal leakage had 1 to 3 times of abdominal surgery before OLT. Abdominal drainage was used in 28 cases with bile leakage, and additionally, endoscopic retrograde cholangiopancreatography, endoscopic nasobiliary drainage and stenting were performed for 8 of them, and surgical neoplasty for another 18 patients with bile leakage. Simple surgical neoplasty of perforation was performed for 13 patients with gastrointestinal leakage, and diverticulectomy and neoplasty for 1 case with duodenal leakage, and partial jejunostomy for one severe jejunal leakage. Nutritional support was administered for all of cases. The incidence rate of digestive tract leakage in early stage after OLT was 5.20% (61/1173). Intra-operative iatrogenic injury of gastrointestinal tract was occurred in 6 cases with gastrointestinal leakage. After treatment, 11 cases died of multiple organ failure resulted from severe infection, with mortality of 18.0% (11/61), including 4 cases with bile leakage, with the mortality of 8.6% (4/46), and 7 cases with gastrointestinal tract leakage, with the mortality of 46.6% (7/15). The remanent 50 cases through comprehensive treatment with a span of 1 to 3 months recovered and discharged healthily. No digestive tract leakage reoccurred in the follow-up of 6 to 84 months. The morbidity of digestive tract leakage in early stage after OLT is low, but its mortality is high, especially for gastrointestinal tract leakage. High dose corticosteroids therapy, history of abdominal operation and intra-operative iatrogenic injury may be high risk factor. Comprehensive treatment is crucial for improving prognosis.


Small bowel adenocarcinoma presenting with refractory iron deficiency anemia - case report and review of literature.
Cancers of the small bowel are relatively rare and account for approximately 1-2% of all gastrointestinal neoplasms. The most common histologic subtype - adenocarcinoma - constitutes 40% of all cases. These cancers generally present with vague abdominal discomfort and are often diagnosed at a late stage and carry a poor prognosis. The treatment of choice of early-stage small bowel adenocarcinoma is surgical resection. No standard treatment protocol has been defined for unresectable or metastatic disease. Here, we report a case of a 56-year-old woman who presented with unexplained iron deficiency anemia. Extensive initial studies with serial CT scans of the abdomen, esophagogastroduodenoscopy, small bowel capsule endoscopy and colonoscopy were noncontributory. She was later found to have a metastatic small bowel adenocarcinoma and treated with palliative chemotherapy. She achieved a modest response to the treatment. Interestingly, in our case, the sole presentation was unexplained iron deficiency anemia. Physician's awareness regarding the possibility of small bowel cancer especially in the setting of iron deficiency and its workup has been emphasized. This enhances the chance of early detection and hence better survival.


The risk of racial bias while tracking influenza-related content on social media using machine learning.
Machine learning is used to understand and track influenza-related content on social media. Because these systems are used at scale, they have the potential to adversely impact the people they are built to help. In this study, we explore the biases of different machine learning methods for the specific task of detecting influenza-related content. We compare the performance of each model on tweets written in Standard American English (SAE) vs African American English (AAE). Two influenza-related datasets are used to train 3 text classification models (support vector machine, convolutional neural network, bidirectional long short-term memory) with different feature sets. The datasets match real-world scenarios in which there is a large imbalance between SAE and AAE examples. The number of AAE examples for each class ranges from 2% to 5% in both datasets. We also evaluate each model's performance using a balanced dataset via undersampling. We find that all of the tested machine learning methods are biased on both datasets. The difference in false positive rates between SAE and AAE examples ranges from 0.01 to 0.35. The difference in the false negative rates ranges from 0.01 to 0.23. We also find that the neural network methods generally has more unfair results than the linear support vector machine on the chosen datasets. The models that result in the most unfair predictions may vary from dataset to dataset. Practitioners should be aware of the potential harms related to applying machine learning to health-related social media data. At a minimum, we recommend evaluating fairness along with traditional evaluation metrics.


Logistic quantile regression for bounded outcomes.
When research interest lies in continuous outcome variables that take on values within a known range (e.g. a visual analog scale for pain within 0 and 100 mm), the traditional statistical methods, such as least-squares regression, mixed-effects models, and even classic nonparametric methods such as the Wilcoxon's test, may prove inadequate. Frequency distributions of bounded outcomes are often unimodal, U-shaped, and J-shaped. To the best of our knowledge, in the biomedical and epidemiological literature bounded outcomes have seldom been analyzed by appropriate methods that, for one, correctly constrain inference to lie within the feasible range of values. In many respects, continuous bounded outcomes can be likened to probabilities or propensities. Yet, what has long been heeded when modeling the probability of binary outcomes with the widespread use of logistic and probit regression, so far appears to have been overlooked with continuous bounded outcomes with consequences at times disastrous. Logistic quantile regression constitutes an effective method to fill this gap.


Evaluation of somatic cell count thresholds to detect subclinical mastitis in Gyr cows.
The objectives of this study were (1) to determine the sensitivity (Se) and specificity (Sp) of somatic cell count (SCC) thresholds to identify subclinical mastitis in Gyr cows caused by major and minor pathogens; (2) to study the effects of month of sampling, rear or front mammary quarters, herd, intramammary infection (IMI), and bacterial species on SCC at quarter level; and (3) to describe the prevalence of IMI in Gyr cows in commercial dairy herds. In total, 221 lactating Gyr cows from 3 commercial dairy farms were selected. Milk samples were collected from individual quarters once a month for 1 yr from all lactating cows for SCC and bacteriological analysis. Mammary quarters were considered the experimental units and the SCC results were log(10)-transformed. Four SCC thresholds (100, 200, 300 and 400 × 10(3) cells/mL) were used to determine Se and Sp to identify infected mammary quarters. The overall prevalence of IMI in quarter milk samples of Gyr cows was 49.8%, and the prevalence of minor pathogens was higher (31.9%) than that of major pathogens (17.8%). Quarter samples with microbial isolation presented higher SCC compared with negative samples. Sensitivity and Sp of selected SCC thresholds varied according to the group of pathogen (major and minor) involved in the IMI definition. Sensitivity increased and Sp decreased when mammary quarters with only major pathogens isolation were considered positive. The use of a single SCC analysis to classify quarters as uninfected or infected in Gyr cows may not be a useful test for this breed because Se and Sp of SCC at the studied thresholds were low. The occurrence of IMI and the bacterial species are the main factors responsible for SCC variation in mammary quarters of Gyr cows. Milk samples with major pathogens isolation elicited higher SCC than those with minor pathogens.


Role of rostaglandins in reproduction.
From the preceding analysis of prostaglandin research in the reproductive field, it is clear that there have been three major discoveries: a) prostaglandins cause contractions of the human uterus during pregnancy; b) prostaglandins are luteolytic in many subprimate species, but not in humans; and c) prostaglandin levels in the blood and amniotic fluid are elevated during labor in many species, including humans. These important findings have led to major advances in clinical medicine and animal husbandry and to a further understanding of some of the events in the reproductive cycle.


Silymarin ameliorates cisplatin-induced hepatotoxicity in rats: histopathological and ultrastructural studies.
The benefit of silymarin, a plant extract with strong antioxidant activity against hepatotoxicity induced by cisplatin in rats was investigated in this study. Cisplatin is one of the most effective chemotherapeutic drugs, yet it alone does not achieve a satisfactory therapeutic outcome and at high doses it can produce undesirable side effects. Five equal-sized groups (18 rats each) of male Sprague Dawley rats [control, vehicle; cisplatin; silymarin 2 h after cisplatin injection; and silymarin 2 h before cisplatin injection] were used. Histopathological and ultrastructural observation of livers were carried out using light and electron microscopy. Results documented that cisplatin produced behavioral, external features animal changes, as well as hazard pathological picture changes in liver where most hepatocytes appeared diminutive with vacuolated cytoplasm, sinusoids dilated and organelle disorganized. These results revealed that cisplatin may be toxic and terminates in complex liver damage. Administrations of silymarin 2 h after cisplatin, significantly increase the body weight returning it to normal, yet it failed in complete protection against the pathological alteration caused by cisplatin. Pretreatment with silymarin 2 h before cisplatin significantly decreased the pathological changes induced by cisplatin and appeared highly protective. These results suggested that silymarin possess protective effects against cisplatin hepatotoxic action in animal models. Since, no significant toxicity of silymarin is reported in human studies, this plant extract can be used as a dietary supplement by patients taking anticancerous medications and might serve as a novel combination agent with cisplatin since it plays a significant role in reducing its toxicity.


Use of risk-adjusted CUSUM and RSPRT charts for monitoring in medical contexts.
In this paper we discuss the use of charts derived from the sequential probability ratio test (SPRT): the cumulative sum (CUSUM) chart, RSPRT (resetting SPRT), and FIR (fast initial response) CUSUM. The theoretical development of the methods is described and some considerations one might address when designing a chart, explored, including the approximation of average run lengths (ARLs), the importance of detecting improvements in a process as well as detecting deterioration and estimation of the process parameter following a signal. Two examples are used to demonstrate the practical issues of quality control in the medical setting, the first a running example and the second a fully worked example at the end of the paper. The first example relates to 30-day mortality for patients of a single cardiac surgeon over the period 1994-1998, the second to patient deaths in the practice of a single GP, Harold Shipman. The charts' performances relative to each other are shown to be sensitive to the definition of the 'out of control' state of the process being monitored. In light of this, it is stressed that a suitable means by which to compare charts is chosen in any specific application.


Expression of beta-N-acetylgalactosaminylated N-linked sugar chains is associated with functional differentiation of bovine mammary gland.
During lactation the mammary gland synthesizes a large amount of glycoproteins including those composing milk fat globule membrane (MFGM). Our previous study showed that N-linked sugar chains with GalNAc beta1-->4GlcNAc structure appears to increase in bovine MFGM glycoproteins during early lactation [Ujita et al. (1993) FEBS Lett. 332, 119-122]. Western blot analysis of membrane glycoproteins from lactating and post-lactating bovine mammary glands using Wistaria floribunda agglutinin (WFA), which binds oligosaccharides terminating with beta-N-acetylgalactosamine, and Ricinus communis agglutinin-I (RCA-I), which binds oligosaccharides preferentially terminating with beta-1,4-galactose, showed that the number and reactivity of protein bands to WFA but not to RCA-I decrease drastically in the post-lactating mammary sample. Establishment of primary cultured epithelial cells from lactating bovine mammary gland and their culture on collagen-coated dishes in the presence of a mixture of lactogenic hormones revealed that N-linked sugar chains with GalNAc beta1-->4GlcNAc structure are expressed in the functionally differentiated cells without altering the apparent beta-galactosylation of the oligosaccharides. These results strongly suggest that the expression of GalNAc beta1-->4GlcNAc structure on N-linked sugar chains is associated with the mammary gland differentiation.


Commissioning. When push comes to shove.
A study of four HAs in three regions found that they had little influence on encouraging trusts to implement the recommendations of the Changing Childbirth report over the period 1993-98. Where changes had been introduced this was often through the influence of an opinion leader in the trust, such as directors of midwifery. The results suggest healthcare professionals providing services have substantial influence over the fate of strategic change initiatives.


The suppression of ox-LDL-induced inflammatory response and apoptosis of HUVEC by lncRNA XIAT knockdown via regulating miR-30c-5p/PTEN axis.
Exposure of oxidized low-density lipoprotein (ox-LDL) could cause dysfunction of HUVEC, thus leading to atherosclerosis development, which is a common inflammatory vascular disease. Long noncoding RNA X-inactive specific transcript (XIST) has been reported to be implicated in atherosclerosis. However, the mechanism by which this lncRNA participates in the progression of atherosclerosis is poorly defined. HUVEC challenged by ox-LDL were used as a cellular model of atherosclerosis. Cell viability, apoptosis, LDH release, and inflammatory cytokines secretion were detected by MTT, flow cytometry, and ELISA assays. The expression levels of XIST, microRNA (miR)-30c-5p, and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) were measured by quantitative Real Time-Polymerase Chain Reaction and Western blot. The target interaction between XIST and miR-30c-5p or miR-30c-5p and PTEN was validated by the Luciferase reporter assay and RNA immunoprecipitation. Treatment of ox-LDL induced cell apoptosis and inflammatory cytokines release in HUVEC. XIST expression was enhanced in HUVEC treated by ox-LDL, and its knockdown decreased cell apoptosis and inflammatory response in ox-LDL-treated cells. MiR-30c-5p was a target of XIST and its overexpression suppressed cell apoptosis and inflammatory response induced by ox-LDL, which was weakened by the introduction of XIST. PTEN was a target of miR-30c-5p, and its interference led to great inhibition of cell apoptosis and inflammatory response induced by ox-LDL in HUVEC, while this effect was attenuated by miR-30c-5p deficiency or XIST overexpression. XIST knockdown suppresses inflammatory response and apoptosis of HUVEC stimulated by ox-LDL by increasing miR-30c-5p and decreasing PTEN.


Problematic drug use and drug use disorders in EU countries and Norway: an overview of the epidemiology.
To estimate the prevalence of drug use disorders in the European Union and Norway. Based on a systematic literature search and an expert survey, publications after 1990 on prevalence of drug use disorders (DUD, defined as drug dependence and drug abuse or harmful use) in EU countries and Norway were reviewed. The search included both direct estimations based on general population surveys using the DSM-IIIR, DSM-IV, or ICD-10 definitions of DUD; and indirect estimates based on other epidemiological methods, such as multiplier procedures based on treatment or legal data and capture-recapture techniques. The indirect methods did not use diagnostic criteria, but criteria based on duration and pattern of use, labelled as problematic drug use as a meaningful approximation. The majority of DUD as estimated from direct methods using general population surveys were cannabis use disorders, usually not included in indirect estimates. The prevalence of thus defined disorders can be as high as 3%. For disorders other than cannabis use disorders (i.e. opioid, cocaine and amphetamine use disorders), indirect estimates of prevalence were consistently higher than those based on direct estimates, and ranged between 0.3% and 0.9% in European Union countries and Norway. Men have higher prevalence rates of DUD than women, but the difference was much less pronounced in general population surveys. Younger age (18-25 years) is the age group with the highest estimates. General population surveys typically result in a serious underestimation of the prevalence of DUD other than cannabis use disorders, because many people with DUD are not reached by these surveys (hidden populations). Based on the more valid indirect estimates, it is concluded that problem drug use constitutes a relatively high burden of disease and social problems in Europe.


Proposing a novel technique to exclude the left ventricle with an assist device: insights from 4-dimensional flow magnetic resonance imaging.
Left ventricular assist device (LVAD) implantation has become an effective treatment for end-stage heart failure patients. However, LVAD support disrupts the natural intracavitary blood flow path through the heart, introducing flow patterns potentially associated with thrombosis especially around the inflow cannula. We present initial insights into in vitro 4D flow magnetic resonance imaging (MRI)-based analysis of flow patterns and an enzyme-activated milk test in a porcine left ventricular (LV) model during LVAD support, in a standard implant technique and in combination with a novel cone-shaped LV sparing prosthesis. 4D MRI of an LVAD-supported ex vivo porcine heart failure model was performed in a mock circulatory loop with an LVAD flow of 4.5 l/min. Two separate sets of hearts with an MR-compatible LVAD inflow cannula were used: one with a standard inflow via the pulmonary veins into the LV, one sparing the LV with the cone-shaped prosthesis sutured to the mitral annulus and the LVAD inflow cannula sparing the LV cavity. In correlation, an enzyme-activated milk test was performed to reveal locations of disturbed flows. Data were analysed visually and by performing a case-by-case analysis of flow patterns and enzyme activation locations. Using 4D flow MRI, the standard implant technique showed markedly altered flow patterns with flow velocity reduction in the LV cavity especially around the inflow conduit. The average flow velocity in the LV cavity was 12.8 ± 2.9 m/s. In contrast, the LV-sparing technique with a cone-shaped prosthesis showed faster and more organized flow of 36.3 ± 7.2 m/s on average to the LVAD inflow cannula. Compared with the standard technique, no recirculating blood flow components were detected. The enzyme-activated milk test confirmed the location and extent of helical and vertical flow patterns. For the first time, intracardiac flows in an LVAD setting have been shown in vitro based on a mock porcine ex vivo heart failure model by applying 4D flow MRI. Differences in flow characteristics of the same model using a prosthesis sparing the LV cavity are encouraging to further investigate their potential to reduce potential LVAD-associated side-effects, such as intracavitary clotting and its sequelae.


Complete map and identification of the phosphorylation site of bovine lens major intrinsic protein.
To determine the complete primary structure, including posttranslational modifications, of bovine lens major intrinsic protein (MIP) using a recently developed combination of liquid chromatography and mass spectrometry. The MIP was isolated from bovine lenses by sucrose gradient centrifugation and was cleaved with cyanogen bromide (CNBr). A high-performance liquid chromatographic system, developed for hydrophobic protein analysis, was used to separate the cleavage fragments. Matrix-assisted laser desorption ionization and electrospray tandem mass spectrometry were employed to obtain molecular weight and sequence data from bovine MIP CNBr fragments, directly or after subsequent digestion with trypsin. The complete sequence of bovine MIP was mapped by molecular weight measurements of CNBr fragments, confirming the reported DNA sequence. The C-terminal peptide (177 to 263) was fully sequenced and the major site of phosphorylation was determined to be at serine 235 rather than at the previously reported serine 243. The level of phosphorylation in the native protein was determined to be 25%. No other posttranslational derivatizations were observed with the exception of the previously detected deamidation of asparagine 246. These results represent the first complete MIP sequence map at the amino acid level and identify the single major phosphorylation site at serine 235.


Mate preference for a phenotypically plastic trait is learned, and may facilitate preference-phenotype matching.
Fixed, genetically determined, mate preferences for species whose adult phenotype varies with rearing environment may be maladaptive, as the phenotype that is most fit in the parental environment may be absent in the offspring environment. Mate preference in species with polyphenisms (environmentally dependent alternative phenotypes) should therefore either not focus on polyphenic traits, be polyphenic themselves, or learned each generation. Here, we test these alternative hypotheses by first describing a female-limited seasonal polyphenism in a sexually dimorphic trait in the butterfly Bicyclus anynana, dorsal hindwing spot number (DHSN), and then testing whether male and female mate preferences for this trait exist, and whether they are seasonally polyphenic, or learned. Neither naïve males nor naïve females in either seasonal form exhibited mating preferences for DHSN. However, males, but not females, noticed DHSN variation and learned mate preferences for DHSN. These results suggest that individuals may accommodate environmentally dependent variation in morphological traits via learned mate preferences in each generation, and that learned mate preference plasticity can be sexually dimorphic.


In vivo MRI assessment of the human locus coeruleus along its rostrocaudal extent in young and older adults.
The locus coeruleus (LC), a major origin of noradrenergic projections in the central nervous system (CNS), may serve a critical role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). As such, there is considerable interest to develop magnetic resonance imaging (MRI) techniques to assess the integrity of the LC in vivo. The high neuromelanin content of the LC serves as an endogenous contrast for MRI but existing protocols suffer from low spatial resolution along the rostrocaudal axis of the LC rendering it difficult to differentiate its integrity in caudal and rostral portions. This study presents a novel approach to investigate the human LC in vivo using T1-weighted Fast Low Angle Shot (FLASH) MRI at 3 T (T). Using high-resolution isotropic imaging to minimise the effect of low spatial resolution in the slice direction, this study aimed to characterise the rostrocaudal distribution of LC signal intensity attributed to neuromelanin from 25 young (22-30) and 57 older (61-80) adults. We found a significant age-related increase in maximum but not median signal intensity, indicating age-related differences were not homogenous. Instead, they were confined to the rostral third of the LC with relative sparing of the caudal portion. The findings presented demonstrate in vivo T1-weighted FLASH imaging may be used to characterise signal intensity changes across the entire rostrocaudal length of the LC (a corresponding standardised LC map is available for download), which may help to identify how the human LC is differentially affected in aging and neurodegenerative disease.


A rare cause of acute urinary retention in women: meatal condyloma accuminata, a case report.
Acute urinary retention in women is a rarely seen phenomenon due to pharmacological, neuromuscular, anatomical, functional and infectious causes. Human papillomaviruses causing condyloma acuminata is one of the rarely reported viral infectious cause of acute urinary retention in case reports. A 45-year-old woman with acute urinary retention was found to have a round solid lesion on external urethral meatus. Histopathological examination revealed as condyloma acuminata. Urethral condyloma can be treated by local excision as an effective method for early improvement of voiding function. Even if the genital condyloma can be locally excised, patients should be referred to the gynecologists for cervical cancer screening.


The presence of in-house attending trauma surgeons does not improve management or outcome of critically injured patients.
The presence of a surgeon at the initial assessment and care of the trauma patient has been the focal point of trauma center designation. However, for Level I verification, the American College of Surgeons Committee on Trauma currently does not require the presence of an attending trauma surgeon in the hospital (IH), provided senior surgical residents are immediately available. Likewise, the state of Missouri does not mandate an IH presence of the attending trauma surgeon but requires senior (postgraduate year 4 or 5) level surgical residents to immediately respond, with a 20-minute response time mandated for the attending surgeon if IH or out of the hospital (OH). Nevertheless, some claim that IH coverage by attending surgeons provides better care for seriously injured patients. This retrospective study assessed patient care parameters over the past 10 years on critically injured patients to detect any difference in outcome whether the surgeon was IH or OH at the time of the trauma team activation (cardiopulmonary instability, Glasgow Coma Scale [GCS] score < 9, penetrating truncal injury). Patients were subcategorized into blunt/penetrating, shock (systolic blood pressure < 90 mm Hg) on arrival, GCS score < 9, Injury Severity Score (ISS) > 15, or ISS > 25. Response was examined from 8 am to 6 pm weekdays (IH) or 6 pm to 8 am weekdays and all weekends (OH). Patient care parameters examined were mortality, complications, time in the emergency department, time to the operating room, time to computed tomographic scanning, intensive care unit length of stay (LOS), and hospital LOS. For all patients (n = 766), there was no significant difference in any parameters except intensive care unit LOS (IH, 4.90 +/- 7.96 days; OH, 3.58 +/- 7.69 days; p < 0.05). For blunt trauma (n = 369), emergency department time was shorter (99.71 +/- 88.26 minutes vs. 126.51 +/- 96.68 minutes, p < 0.01) and hospital LOS was shorter (8.04 +/- 1.02 days vs. 11.08 +/- 1.15 days, p < 0.05) for OH response. For penetrating trauma (n = 377), shock (n = 187), GCS score < 9 (n = 248), ISS > 15 (n = 363), and ISS > 25 (n = 230), there were no statistically significant differences in any patient care parameter between IH and OH response. For those in most need of urgent operation-penetrating injuries and shock-there were no differences in time to operating room or mortality for OH or IH response. As long as initial assessment and care is provided by senior level IH surgical residents and as long as the attending surgeon responds in a defined period of time (if OH) to guide critical decision-making, the IH presence of an attending surgeon has not been shown in this retrospective study to improve care of the critically injured patient.


Responses of primate locus coeruleus and subcoeruleus neurons to stimulation at reinforcing brain sites and to natural reinforcers.
In alert rhesus monkeys the activity of 64-neurons was recorded in the locus coeruleus and subcoeruleus region, collectively referred to as coeruleus (C) neurons. C neurons were identified physiologically by antidromic activation from electrodes in the medial forebrain bundle (MFB) and medial septal nucleus which sustained intracranial self-stimulation (ICSS) behavior, and/or anatomically by their proximity to microlesions at unit recording sites. The following results were obtained: (1) the current intensity that supported the highest rate of MFB and septal ICSS was similar to the current intensity for evoking antidromic responses in C neurons; (2) stimulation in the vicinity of the dopaminergic neurons of nucleus A10 did not activate C neurons; (3) C neurons were antidromically activated by ipsilateral and contralateral MFB shocks; (4) the C axons had slow estimated conduction velocities (1-5 m/sec), and a mean neural refractory period of 0.8 msec; (5) the behaviorally determined refractory period for MFB ICSS was also approximately 0.8 msec; and (6) mean firing rates while the monkey sat quietly were 15 +/- 2 Hz (S.D.) for subcoeruleus cells and 5 +/- 3 Hz for locus coeruleus cells, and activity of most cells changed negligibly during operant responding for apple-sauce reinforcement. These results suggest that the reinforcing effects of ICSS may be mediated by activation of coeruleus cells, but that these cells do not appear to be strongly involved in operant responding for natural reinforcers.


Transformation optics with photonic band gap media.
We introduce a class of optical media based on adiabatically modulated, dielectric-only, and potentially extremely low-loss, photonic crystals (PC). The media we describe represent a generalization of the eikonal limit of transformation optics (TO). The basis of the concept is the possibility to fit some equal frequency surfaces of certain PCs with elliptic surfaces, allowing them to mimic the dispersion relation of light in anisotropic effective media. PC cloaks and other TO devices operating at visible wavelengths can be constructed from optically transparent substances such as glasses, whose attenuation coefficient can be as small as 10 dB/km, suggesting the TO design methodology can be applied to the development of optical devices not limited by the losses inherent to metal-based, passive metamaterials.


Dynamics of resilience in forced migration: a 1-year follow-up study of longitudinal associations with mental health in a conflict-affected, ethnic Muslim population.
The concept of 'resilience' is of increasing interest in studies of mental health in populations facing adversity. However, lack of longitudinal data on the dynamics of resilience and non-usage of resilience-specific measurements have prevented a better understanding of resilience-mental health interactions. Hence, the present study was conducted to investigate the stability of levels of resilience and its associations with sociodemographic and mental health exposures in a conflict-affected internal-migrant population in Sri Lanka. A prospective follow-up study of 1 year. Puttalam district of North Western province in postconflict Sri Lanka (baseline in 2011, follow-up in 2012). An ethnic Muslim population internally displaced 20 years ago (in 1990) from Northern Sri Lanka, aged 18 or above and currently in the process of return migration. It was hypothesised that levels of resilience would be associated with mental health outcomes. Resilience was measured on both occasions using the 14-item Resilience Scale (RS-14), social support by the Multidimensional Social Support Scale and Lubben Social Network Scale and common mental disorders by the Patient Health Questionnaire (PHQ). Of 450 participants interviewed at baseline in 2011, 338 (75.1%) were re-interviewed in 2012 after a 1-year follow-up. The mean resilience scores measured by RS-14 were 80.2 (95% CI 78.6 to 81.9) at baseline and 84.9 (83.5 to 86.3) at follow-up. At both time points, lower resilience was independently associated with food insecurity, lower social support availability and social isolation. At both time points, there were significant associations with common mental disorders (CMDs) in unadjusted analyses, but they only showed independence at baseline. The CMD prevalence, maintenance and incidence at follow-up was 8.3%, 28.2% and 2.2%, respectively. In this displaced population facing a potential reduction in adversity, resilience was more strongly and robustly associated with economic and social factors than with the presence of mental disorder.


Comparison of Clinicopathological Characteristics in the Patients with Cardiac Cancer with or without Esophagogastric Junctional Invasion: A Single-Center Retrospective Cohort Study.
Background. This study addresses clinicopathological differences between patients with gastric cardia and subcardial cancer with and without esophagogastric junctional invasion. Methods. We performed a single-center, retrospective cohort study. We studied patients who underwent curative surgery for gastric cardia and subcardial cancers. Tumors centered in the proximal 5 cm of the stomach were classed into two types, according to whether they did (Ge) or did not (G) invade the esophagogastric junction. Results. A total of 80 patients were studied; 19 (73.1%) of 26 Ge tumors and 16 (29.6%) of 54 G tumors had lymph nodes metastases. Incidence of nodal metastasis in pT1 tumors was significantly higher in the Ge tumor group. No nodal metastasis in cervical lymph nodes was recognized. Only two patients with Ge tumors had mediastinal lymph node metastases. Incidence of perigastric lymph node metastasis was significantly higher in those with Ge tumors. Ge tumors tended to be staged as progressive disease using the esophageal cancer staging manual rather than the gastric cancer staging manual. Conclusion. Because there are some differences in clinicopathological characteristics, it is thought to be adequate to distinguish type Ge from type G tumor.


Effect of Impella During Veno-Arterial Extracorporeal Membrane Oxygenation on Pulmonary Artery Flow as Assessed by End-Tidal Carbon Dioxide.
Peripheral veno-arterial extracorporeal membrane oxygenation (VA ECMO) exposes the patient to a pulmonary blood flow bypass and a left ventricle afterload increase. Impella, a catheter-mounted microaxial rotary pump, has been proposed for left ventricle (LV) unloading in combination with VA ECMO. In order to assess the effect of Impella on pulmonary flow and LV preload, we checked Doppler pulmonary artery velocity-time integral (pVTI) and LV diastolic diameter (LVED) by transesophageal echocardiography and end-tidal carbon dioxide (EtCO2) during a step-by-step increase in Impella flow (Impella ramp test). From 134 patients on VA ECMO retrieved from our database, 27 (20%) have benefited secondary Impella implantation, out of which 11 patients had available EtCO2, pVTI, and LVED measurements at various levels of Impella speeds. We observed a proportional increases in pVTI and EtCO2 and decrease in LVED (p ≤ 0.001) during Impella flow increase. There was a significant correlation between EtCO2 and pVTI (Pearson correlation coefficient 0.64; p = 0.006). The study shows that Impella improves pulmonary flow, an effect that can be easily measured by EtCO2 monitoring, and ensures LV discharge, allowing adapting Impella flow adequately to patient's individual needs.


Chapter 20: Atopic dermatitis.
Atopic dermatitis (AD), also known as atopic eczema, is a chronic relapsing inflammatory dermatosis characterized by pruritus, xerosis, and a close association with IgE-mediated sensitization to aeroallergens and foods. More than 60% of children with AD are at risk to develop allergic rhinitis or asthma (the atopic march). The distribution of lesions varies by age. Infants tend to have lesions on the cheeks and scalp, and very young children typically have involvement over the extremities cheeks, forehead, and neck. Rash in the diaper area of infants is rarely AD. Lesions in older children and adults are usually located in flexural areas, such as the antecubital and popliteal fossae, along with the head and neck. Acute lesions of AD begin as erythematous papules and serous exudates. Secondary lesions include excoriations and crusted erosions due to scratching. Subacute lesions appear as erythematous scaling papules and plaques. If the itch and rash progress uncontrolled, chronic lichenified AD develops featuring accentuated skin markings with hyperpigmentation. Trigger avoidance, skin hydration, and topical steroids are the first steps for improvement. In acute lesions of AD, the Th2 cells produce IL-4, IL-13, and IL-31, which may potentiate barrier dysfunction and contribute to pruritus. In chronic lesions, the Th1 cells predominate and secrete interferon gamma and IL-12. Barrier dysfunction from filaggrin predisposes patients to AD. Skin superinfection, particularly with Staphylococcus aureus, is common, and cultures of affected lesions help guide therapy. Eczema herpeticum from herpes simplex virus can be life-threatening in AD patients.


The use of Landsat to monitor Deep Water Dumpsite 106.
Since the early 1970's, remote sensing has been used to study ocean dumping at some of the hearshore ocean dump sites off the coast of the United States, but little remote sensing had been done over the deep water ocean disposal sites. This report summarizes what has been learned from the remote sensing of ocean dumping by the Landsat satellites at Deep Water Dumpsite 106. Of the three major types of waste material discharged at Deep Water Dumpsite 106, only the titanium pigment process acid waste has been sighted. From early in 1977 to May 1979, 11 acid dumps were observed by Landsat. All five of the dumps sighted in 1977 occurred within warm core Gulf Stream eddies and the plumes moved clockwise within the eddies. Four of those dumps were seen to be located northeast of the original dump location while the fifth one was sighted south of the original dump location. The six remaining observed dumps, discharged in the absence of an eddy, were seen to be located generally south of the original dumping locations. The average speed of the dump movement was 0.68 kt with a range from 0.17 to 1.17 kts. Plume dispersion showed a tendency toward greater dispersion as the plume got older with the widest plume cross section measured on the order of 2100 m.


Principles of rheumatoid arthritis control.
One percent of the UK population suffers from rheumatoid arthritis (RA), with a female to male ratio of 3:1. The disease has a major influence on employment and disability rates. About 15% are classified as having serious illness, which prognostically is equivalent to 3-vessel coronary artery disease. Overall life expectancy for those with RA is reduced on average by 5 years. Financial costs are enormous. Per-patient, each year, direct and indirect costs total about 7000 pounds sterling. Costs escalate with disease severity. In a specialist rheumatology clinic, about 12% of new referrals have RA, and these patients account for more than 40% of the followup workload. The approach to management is changing, with emphasis on earlier, more aggressive intervention. This is acknowledged to improve outcome. For the severe disease, management has been revolutionized by the introduction of biologic agents. RA is managed by a multidisciplinary team, and there are active patient support groups. Advances in knowledge about genetic and immunological mechanisms of disease hold promise for further progress. Never was there a greater need for a successful alliance to deliver effective, high quality services involving government, professionals, patients, and their advocates.


Neuro-Ophthalmologic Variability in Presentation of Genetically Confirmed Wolfram Syndrome: A Case Series and Review.
Wolfram syndrome is a neurodegenerative disorder caused by pathogenic variants in the genes WFS1 or CISD2. Clinically, the classic phenotype is composed of optic atrophy, diabetes mellitus type 1, diabetes insipidus, and deafness. Wolfram syndrome, however, is phenotypically heterogenous with variable clinical manifestations and age of onset. We describe four cases of genetically confirmed Wolfram syndrome with variable presentations, including acute-on-chronic vision loss, dyschromatopsia, and tonic pupils. All patients had optic atrophy, only three had diabetes, and none exhibited the classic Wolfram phenotype. MRI revealed a varying degree of the classical features associated with the syndrome, including optic nerve, cerebellar, and brainstem atrophy. The cohort's genotype and presentation supported the reported phenotype-genotype correlations for Wolfram, where missense variants lead to milder, later-onset presentation of the Wolfram syndrome spectrum. When early onset optic atrophy and/or diabetes mellitus are present in a patient, a diagnosis of Wolfram syndrome should be considered, as early diagnosis is crucial for the appropriate referrals and management of the associated conditions. Nevertheless, the condition should also be considered in otherwise unexplained, later-onset optic atrophy, given the phenotypic spectrum.


The nature of the lamprey visual pigment.
From the retina of the land-locked population of the sea lamprey, Petromyzon marinus, a photolabile pigment was extracted which was identified spectrophotometrically as a member of the rhodopsin group of pigments. Using the absorption spectrum of a relatively pure solution and analysis by means of difference spectra, the peak of this pigment was placed at about 497 mmicro. The method of selective bleaching by light of different wave lengths revealed no significant amounts of any other pigment in the extracts. A similar pigment was also detected in retinal extracts of the Pacific Coast lamprey, Entospenus tridentatus. These results are significant for two reasons: (a) the lamprey is shown to be an example of an animal which spawns in fresh water but which is characterized by the presence of rhodopsin, rather than porphyropsin, in the retina; (b) the primitive phylogenetic position of the lamprey suggests that rhodopsin was the visual pigment of the original vertebrates.


Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever.
46% of sera from 30 children with rheumatic chorea showed IgG antibody reacting with neuronal cytoplasm of human caudate and subthalamic nuclei. The antibody was also detected in 14% of 50 children with active rheumatic carditis. 55 normal control sera, as well as 148 sera from a broad variety of other disease states showed a low prevalence (1.8-4.0%) of positive reactions. In rheumatic chorea the presence of anti-neuronal antibody appeared to correlate with severity and duration of clinical attacks. Antibody reacting with neuronal cytoplasm was completely removed by absorption with Group A streptococcal membranes or with isolated human neurons from caudate nucleus. Partial absorption of antibody was also recorded using Group A cell wall preparations but not with Group A carbohydrate. No absorption of positive reactions was seen with streptococcal Group D membranes or cell walls. In rheumatic chorea, anti-neuronal antibody appeared to represent cross-reaction with antigens shared by Group A streptococcal membranes.


Redesigning enzymes by site-directed mutagenesis.
The systematic alteration of protein structure has now become possible with genetic engineering. Recent developments in techniques for the chemical synthesis of DNA fragments and in recombinant DNA technology have enabled the facile modification of proteins by highly specific mutagenesis of their genes. Enzymes with novel properties may be produced in large quantities from the mutant genes. Kinetic analysis of the mutant enzymes can be combined with high-resolution structural data from protein X-ray crystallography to provide direct measurements on the relationships between structure and function. In particular, the strength and nature of enzyme-substrate interactions and their roles in catalysis and specificity may be studied. The tyrosyl-tRNA synthetase from Bacillus stearothermophilus is being systematically analysed by site-directed mutagenesis. A fine-structure analysis is revealing the subtle roles of hydrogen bonding in catalysis and specificity. Modification of the residues that hydrogen-bond with ATP and tyrosine shows how the energetics must be analysed in terms of an exchange reaction with solvent water. Based on this idea, and structural data, an enzyme of vastly improved enzyme-substrate affinity has been engineered. There thus appear to be real prospects of engineering proteins of new specificities, activities and structural properties. Direct information is also being gathered on the nature of enzyme catalysis. For example, the catalysis of formation of Tyr-AMP from Tyr and ATP does not appear to use the classical mechanisms of acid-base or covalent catalysis. Instead, there just appears to be a binding site that stabilizes the high-energy pentacoordinate intermediate in the reaction.


Molecular Chromophore-DNA Architectures With Fullerenes: Optical Properties and Solar Cells.
Supramolecular chemistry allows the construction of complex molecular architectures and the design of collective photophysical properties. DNA is an attractive template to build such supramolecular architectures due to its helical structure, the defined distances between the bases and the canonical base pairing that results in precise control of the chromophore position. The tailored properties of DNA-templated supramolecules eventually allow their implementation into optoelectronic applications. For the generation of free charge carriers from photo-generated excitons, fullerenes can be utilized. We synthesized two fullerene derivates, one of which binds by electrostatic interactions to single-stranded DNA, while the other contains two 2'-deoxyuridine moieties and assembles specifically along oligo-2'-deoxyadenosines (dA20) as DNA template. The DNA-directed assembly of both fullerenes in aqueous solution was investigated by UV/Vis absorbance and circular dichroism (CD) spectroscopy. The specific interactions with DNA make fullerenes with the 2'-deoxyuridine moieties a significantly better component for supramolecular DNA architectures. We studied the fluorescence quenching of both fullerenes with a DNA chromophore assembly. To investigate one of the key properties for optoelectronic applications, that is the supramolecular structure of the DNA-based assemblies in the solid phase, we characterized the CD of supramolecular chromophore-DNA architectures in thin films. Remarkably, the helical chirality of the chromophore assemblies that is induced by the DNA template is conserved even in the solid state. Upon implementation into organic solar cells, the external quantum efficiency measurements showed charge carrier generation on all three chromophore components of the DNA assemblies. The fullerenes with the 2'-deoxyuridine moieties enhance the quantum efficiency of the conversion process significantly, demonstrating the potential of DNA as structural element for ordering chromophores into functional π-systems, which may be employed in future organic solar cells.


The viral capping enzyme nsP1: a novel target for the inhibition of chikungunya virus infection.
The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a novel class of small molecules ([1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones) with potent in vitro activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections.


Schwalbe line's cells: a new cell type in the trabecular meshwork of Macaca mulatta.
In the eye of Macaca mulatta, at the anterior end of the trabecular meshwork, just beneath the ridge known as Schwalbe line in gonioscopy, cells are present that contain secretory inclusions. These cells have been termed Schwalbe line's cells. They form a discontinuous cord, oriented circumferentially at the corneal periphery, deep to the endothelial lining of the anterior chamber. They are characterized by a prominent Golgi apparatus and by two types of secretory granules: round bodies, up to 0.6 micron in diameter and containing moderately dense material, and larger inclusions, up to 1 micron in diameter and consisting of stacks of osmiophilic lamellae. Membrane whorls and fragments are also commonly found in the spaces between the cells and possibly arise from exocytosis of the lamellar bodies. Schwalbe line's cells have been observed in young as well as in old animals. They are joined to one another by gap junctions and puncta adhaerentia. Because their cytoplasmic inclusions bear a striking morphological resemblance to the multilamellar bodies or cytosomes of the type II alveolar epithelial cells of the lung, the hypothesis is advanced that Schwalbe line's cells produce a phospholipid material that is released in the aqueous humor and thus facilitates its movement through the tissues of the sclerocorneal angle.


[Isoelectric focusing of invertebrate actins].
A method combining advantages of both, charge electrophoresis and isoelectric focusing (IEF) was developed for analysing actins of different tissues. This method was used in investigations of actins from invertebrate muscle sources. Each type of actin has one isoform, pI of which is close to that of the smooth muscle beta-isoactin. Actins from different tissues of the mollusc Spisula s. were identical according to the IEF data.


Up-regulation of neuropeptide Y-Y2 receptors in an animal model of temporal lobe epilepsy.
Receptor autoradiography with the Y2 receptor ligand 125I-peptide YY3-36 and in situ hybridization were applied to investigate changes in neuropeptide tyrosine-Y2 receptor expression after kainic acid-induced recurrent seizures in the rat hippocampus. In the strata oriens and radiatum of CA1 to CA3, which are densely innervated by Y2 receptor-bearing Schaffer collateral terminals, a transient 2-fold increase in Y2 receptor affinity was observed after 4-12 hr, with a later slow decline. No change was seen in Y2 mRNA expression in CA2/CA3 pyramidal cells, from which Schaffer collaterals originate. Conversely, in granule cells of the dentate gyrus, markedly elevated Y2 mRNA concentrations were observed (by 740% in the dorsal hippocampus) 24-48 hr after kainate injection. At the same time, a marked and lasting (up to 6 months) increase in the number of Y2 receptor sites (by 800%) was seen in the dentate hilus, which is innervated densely by mossy fibers. The early increase in Y2 receptor affinity in Schaffer collaterals was accompanied by a 60% decrease in the EC50 of peptide YY3-36 in inhibiting K(+)-stimulated glutamate release in hippocampal slices from kainic acid-treated rats. Our data indicate transient up-regulation of presynaptic Y2 receptors in Schaffer collaterals by a change in affinity and a permanent de novo synthesis of presynaptic Y2 receptors in granule cells/mossy fibers. These changes may cause augmented presynaptic inhibition of glutamate release from different hippocampal sites and, in conjunction with increased concentrations of neuropeptide tyrosine in mossy fibers, may represent an endogenous reactive anticonvulsant mechanism.


Prevalence and Prognosis of Hypothyroidism in Patients With Chronic Thromboembolic Pulmonary Hypertension: An Updated Review With Description of Case Series.
Hypothyroidism has been shown to have several effects on organs, including derangements in the coagulation system, impairing endothelial function, but data on the importance of hypothyroidism in the pathogenesis and development of chronic thromboembolic pulmonary hypertension (CTEPH) are limited. This report presents an updated review of the prevalence and prognosis of hypothyroidism in patients diagnosed with CTEPH, including a detailed retrospective description of the series. The descriptive case series included 34 adult patients diagnosed with CTEPH, of whom 11 patients were diagnosed with hypothyroidism. The prevalence of hypothyroidism in CTEPH was found to be 32.35%. All patients with hypothyroidism had NYHA functional Class II-III. Hemodynamic values obtained through right heart catheterization (RHC) showed that patients with hypothyroidism had significantly higher mean pulmonary arterial pressures (mPAP), with a mean of 56.91 mm Hg vs 43.93 mm Hg (p = 0.026), and the PVR in dynes/sec/cm5 was 932 vs 541 (p = 0.027). Significant differences in PVR were found in wood units (WU) 11.91 vs 7.11 (p = 0.042). The mean level of brain natriuretic peptide (BNP) between both groups was 797.3 pg/mL for patients with hypothyroidism vs 262.02 pg/mL in patients with euthyroidism (p = .032). Hypothyroidism may significantly affect patients' clinical and hemodynamic outcomes in patients with CTEPH. Hypothyroidism as a risk factor in the evaluation and treatment of these patients is vital to optimize outcomes in CTEPH; further research is warranted whether hypothyroidism therapies could alter such outcomes.


A kinetic chain approach for shoulder rehabilitation.
To introduce an approach to shoulder rehabilitation that integrates the kinetic chain throughout the rehabilitation program while providing the theoretical rationale for this program. The focus of a typical rehabilitation program is to identify and treat the involved structures. However, in activities of sport and daily life, the body does not operate in isolated segments but rather works as a dynamic unit. Recently, rehabilitation programs have emphasized closed kinetic chain exercises, core-stabilization exercises, and functional programs. These components are implemented as distinct entities and are used toward the end of the rehabilitation program. Kinetic chain shoulder rehabilitation incorporates the kinetic link biomechanical model and proximal-to-distal motor-activation patterns with proprioceptive neuromuscular facilitation and closed kinetic chain exercise techniques. This approach focuses on movement patterns rather than isolated muscle exercises. Patterns sequentially use the leg, trunk, and scapular musculature to activate weakened shoulder musculature, gain active range of motion, and increase strength. The paradigm of kinetic chain shoulder rehabilitation suggests that functional movement patterns and closed kinetic chain exercises should be incorporated throughout the rehabilitation process. The exercises in this approach are consistent with biomechanical models, apply biomechanical and motor control theory, and work toward sport specificity. The exercises are designed to stimulate weakened tissue by motion and force production in the adjacent kinetic link segments.


Profiling whole-tissue metabolic reprogramming during cutaneous poxvirus infection and clearance.
Human poxvirus infections have caused significant public health burdens both historically and recently during the unprecedented global Mpox virus outbreak. Although vaccinia virus (VACV) infection of mice is a commonly used model to explore the anti-poxvirus immune response, little is known about the metabolic changes that occur in vivo during infection. We hypothesized that the metabolome of VACV-infected skin would reflect the increased energetic requirements of both virus-infected cells and immune cells recruited to sites of infection. Therefore, we profiled whole VACV-infected skin using untargeted mass spectrometry to define the metabolome during infection, complementing these experiments with flow cytometry and transcriptomics. We identified specific metabolites, including nucleotides, itaconic acid, and glutamine, that were differentially expressed during VACV infection. Together, this study offers insight into both virus-specific and immune-mediated metabolic pathways that could contribute to the clearance of cutaneous poxvirus infection.


Soybean oligosaccharides combined with probiotics reduce faecal odour compound content by improving intestinal microbiota in pigs.
As a potential prebiotic, soybean oligosaccharides (SBOS) can improve animal health by modulating gut microbiota. The aim of this study was to investigate the different effects of supplementing SBOS and supplementing SBOS plus probiotic on the growth and health of pigs. Three groups of growing pigs (n = 12) were fed with basal diet (Control), basal diet + 0.5% SBOS (SBOS), or basal diet +0.5% SBOS + 0.1% compound probiotics (SOP) for 42 days. Results showed that SBOS and SOP treatments had positive effects on the pigs in the experiment, and the latter was more effective. Compared with the control pigs, the average daily gain of SBOS group and SOP group slightly increased, SOP significantly increased the serum levels of growth hormone and thyroid hormone T3. Importantly, serum concentrations of immunoglobulin (IgA, IgG and IgM), total antioxidant capacity and superoxide dismutase in both treatments were increased significantly, SOP group most. Moreover, the faecal odour compounds of pigs, especially skatole, were significantly reduced by the treatments. Additionally, SOP significantly increased the diversity and richness of the faecal microbiota, both the treatments increased genera of norank_f_Muribaculaceae and Ruminococcaceae but reduced Lactobacillus. Correlation analysis indicated that Lactobacillus was significantly positively correlated with odour compounds, while Ruminococcaceae was the opposite. Conclusively, synbiotics combined with SBOS and probiotics had stronger promotion effects on the growth and health of pigs.


The homeodomain protein CePHOX2/CEH-17 controls antero-posterior axonal growth in C. elegans.
An essential aspect of a neuron's identity is the pattern of its axonal projections. In C. elegans, axons extend either longitudinally or circumferentially in response to distinct molecular cues, some of which have been identified. It is currently unclear, however, how the differential capacity to respond to these cues is transcriptionally implemented in distinct neuronal subtypes. Here, we characterise a C. elegans paired-like homeobox gene, CePhox2/ceh-17, expressed in five head neurons, ALA and the 4 SIAs, all of which project axons towards the tail along the lateral and sublateral cords. Abrogation of ceh-17 function, while leaving intact many phenotypic traits of these neurons, disrupts their antero-posterior axonal elongation beyond the mid-body region. Conversely, ectopic expression of ceh-17 in the mechanoreceptors, several of which are known to pioneer their tract, leads to exaggerated longitudinal axonal outgrowth. Thus, ceh-17 is a novel gene involved in fasciculation-independent longitudinal axonal navigation.


Complex patterns of gene expression in human T cells during in vivo aging.
Human aging is associated with complex alterations that contribute to remodelling of physiological processes and ultimately manifests in loss of tissue/organ function. Peripheral blood T cells do not escape this phenomenon and undergo profound remodelling with aging. Thus, investigating the effects of aging on T cells transcriptomics and identifying the underlying regulatory mechanisms can be of extreme importance to understand the aging process in the Immune System (IS). To this aim, we performed an analysis of gene expression data of T cells collected from peripheral blood of 25 healthy human donors of different age from 25 to more than 95 years, in order to characterize changes that occur throughout the entire adult lifespan. By means of microarray analysis, we observed large groups of genes exhibiting non-monotonic expression patterns over time: such behaviour, that could not be observed in typical "two-group" experiments (e.g. young vs. old people) highlights similarities in gene expression profiles of young and "successfully aged" individuals. Genes whose expression profiles change during lifespan were grouped into three main patterns (eigenmodes) to which different biological functions were significantly associated. The analysis of KEGG pathways to which these genes belong indicated that the biological processes altered in T cell aging are not only those typically associated with immune cells (Jak-STAT signalling, T cell receptor signalling, cytokine-cytokine receptor interactions, etc.) but also some not specific of immune cells, such as long-term depression, PPAR and mTOR signalling, glucose and glutathione metabolism, suggesting that T cell aging may be representative of a more generalised aging phenomenon. Thus, the T cell may represent a useful cellular model to study organismal aging. We further searched for over-represented transcription factor binding sites (TFBSs) in the promoter regions of genes clustered by similarity of their age-related patterns to evidence possible co-regulation. A comparison between over-representation of TFBSs and the time course of the corresponding transcription factor (TF) expression levels revealed that a restricted group of TFs may play a central role in driving aging-specific changes in gene expression of T cells.


A parallel semisynthetic approach for structure-activity relationship studies of peptide YY.
The gut hormone peptide YY (PYY) is postprandially secreted from enteroendocrine L cells and is involved in the regulation of energy homeostasis. The N-terminal truncated version PYY(3-36) decreases food intake and has potential as an anti-obesity agent. The anorectic effect of PYY(3-36) is mediated through Y₂ receptors in the hypothalamus, vagus, and brainstem regions, and it is well known that the C-terminal tetrapeptide sequence of PYY(3-36) is crucial for Y2 receptor activation. The aim of this work was to develop a semisynthetic methodology for the generation of a library of C-terminally modified PYY(3-36) analogues. By using an intein-based expression system, PYY(3-29) was generated as a C-terminal peptide α-thioester. Heptapeptides bearing an N-terminal cysteine and modifications at one of the four C-terminal positions were synthesized in a 96-well plate by parallel solid-phase synthesis. In the plate format, an array of [Ala30]PYY(3-36) analogues were generated by ligation, desulfurization, and subsequent solid-phase extraction. The generated analogues, in which either Arg33, Gln34, Arg35, or Tyr36 had been substituted with proteinogenic or non-proteinogenic amino acids, were tested in a functional Y₂ receptor assay. Generally, substitutions of Tyr36 were better tolerated than modifications of Arg33, Gln34, and Arg35. Two analogues showed significantly improved Y₂ receptor selectivity; therefore, these results could be used to design new drug candidates for the treatment of obesity.


History of migraine and the risk of spontaneous cervical artery dissection.
The pathophysiology of spontaneous cervical artery dissection (sCAD) is largely unknown. An association with migraine has been suggested, but not definitively proven. In the setting of a hospital-based prospective case-control study we assessed personal and family history of migraine in 72 patients with sCAD, 72 patients with cerebral infarct unrelated to a CAD (non-CAD) and 72 control subjects. Personal history of migraine was significantly associated to sCAD compared to non-CAD (59.7% vs. 30.6%; OR 3.14; 95% CI 1.41-7.01) and controls (18.1%; OR 7.41; 95% CI 3.11-17.64). As opposed to migraine with aura, migraine without aura was significantly more frequent among sCAD than among non-CAD (56.9% vs. 25.0%; OR 3.91; 95% CI 1.71-8.90) and controls (12.5%; OR 9.84; 95% CI 3.85-25.16). Similar results were observed when the frequencies of family history of migraine were compared. These findings are consistent with the hypothesis that migraine may represent a predisposing condition for sCAD.


Vision specific quality of life of pediatric contact lens wearers.
Several studies have shown that children are capable of wearing and caring for contact lenses, but it is not known whether the benefits outweigh the risks associated with contact lens wear. The purpose of this article is to compare the vision-related quality of life benefits of children randomized to wear spectacles or contact lenses for 3 years using the Pediatric Refractive Error Profile. The Pediatric Refractive Error Profile was administered to 484 children who wore glasses at baseline. The children were then randomly assigned to wear contact lenses (n = 247) or spectacles (n = 237) for 3 years. The survey was administered at the baseline examination, at 1 month, and every 6 months for 3 years. During 3 years, the overall quality of life improved 14.2 +/- 18.1 units for contact lens wearers and 2.1 +/- 14.6 units for spectacle wearers (p < 0.001). In all scales except the visual performance scales (Distance Vision, Near Vision, and Overall Vision), the quality of life improved more for older subjects than younger subjects. The three scales with the largest improvement in quality of life for contact lens wearers were Activities, Appearance, and Satisfaction with Correction. Myopic children younger than 12 years of age report better vision-related quality of life when they are fit with contact lenses than when they wear glasses. Older children, children who participate in recreational activities, children who are motivated to wear contact lenses, and children who do not like their appearance in glasses will benefit most.


Involvement of dsRNA virus in the protein composition and growth kinetics of host Trichomonas vaginalis.
Trichomonas vaginalis harbors a double-stranded (ds)-RNA virus, and the presence of virus is related to upregulated expression and phenotypic variation of a prominent immunogen (Khoshnan A, Alderete JF (1994) J Virol 68: 4035-4038). To further test the influence of virus on T. vaginalis, virus-infected (V+) isolates were compared to virus-free (V-), agar-cloned progeny trichomonads derived from the parental isolates for accumulation of total proteins and cysteine proteinases. Comparative high resolution two dimensional (2D)-SDS-PAGE was performed of trichomonads grown in a chemostat under identical conditions. At least 47 proteins were identified as specifically expressed by representative V+ isolate 347, and approximately 41 spots were specific to the corresponding V- progeny, showing an association between virus and the presence and absence of parasite proteins. Qualitatively and quantitatively dissimilar cysteine proteinase patterns were detected from numerous V+ isolates and the V- progeny. A 2D analysis for isolate 347 showed the appearance of unique proteinase activities for parental parasites and presence of at least one proteinase in the V- progeny. Finally, the V+ T. vaginalis isolate 347, but not the V- isolate 347 progeny nor other V+ isolates, underwent fluctuations in density during chemostat growth allowing for purification of virus particles from the V+ isolate 347 supernatants during decreased parasite density.


Phenotypic and transcriptional analysis of the antimicrobial effect of lactic acid bacteria on carbapenem-resistant Acinetobacter baumannii: Lacticaseibacillus rhamnosus CRL 2244 an alternative strategy to overcome resistance?"
Carbapenem-resistant Acinetobacter baumannii (CRAB) is a recognized nosocomial pathogen with limited antibiotic treatment options. Lactic acid bacteria (LAB) constitute a promising therapeutic alternative. Here we studied the antibacterial properties of a collection of LAB strains using phenotypic and transcriptomic analysis against A. baumannii clinical strains. One strain, Lacticaseibacillus rhamnosus CRL 2244, demonstrated a potent inhibitory capacity on A. baumannii with a significant killing activity. Scanning electron microscopy images showed changes in the morphology of A. baumannii with an increased formation of outer membrane vesicles. Significant changes in the expression levels of a wide variety of genes were also observed. Interestingly, most of the modified genes were involved in a metabolic pathway known to be associated with the survival of A. baumannii . The paa operon, Hut system, and fatty acid degradation were some of the pathways that were induced. The analysis reveals the impact of Lcb. rhamnosus CRL 2244 on A. baumannii response, resulting in bacterial stress and subsequent cell death. These findings highlight the antibacterial properties of Lcb. rhamnosus CRL 2244 and its potential as an alternative or complementary strategy for treating infections. Further exploration and development of LAB as a treatment option could provide valuable alternatives for combating CRAB infections.


Recombinant EPF/chaperonin 10 promotes the survival of O4-positive pro-oligodendrocytes prepared from neonatal rat brain.
Chaperonin 10 (cpn 10) is a small heat-shock protein that is usually intracellular. Early pregnancy factor (EPF), a biologically active protein that was first described in the serum of pregnant mammals, is homologous to cpn 10. EPF/cpn 10 has been reported to have effects on immunomodulation and cell survival and to inhibit activation of toll-like receptors by lipopolysaccharide. We found that recombinant EPF/cpn 10 was able to suppress experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, which is a disease causing inflammation and demyelination of the brain and spinal cord. This beneficial effect could be due to anti-inflammatory and/or cell survival properties of EPF/cpn 10. We aimed to assess the effects of cpn 10 on cells of the oligodendrocyte lineage because oligodendrocytes are the brain cells that produce myelin and that are depleted in multiple sclerosis. Two forms of recombinant EPF/cpn 10 were prepared in the pGEX expression system and in the baculovirus expression system. Purified O4(+) pro-oligodendrocytes were prepared from the brains of day-old Wistar rats and isolated by cell sorting with flow cytometry. Single cells were dispensed into micro-well plates and tested for survival in the presence of a range of concentrations of the two forms of cpn 10. We also studied the effects of bFGF, PDGF, IGF-1 and insulin as controls. With cpn 10 present, there was enhanced survival of O4(+) cells.


Cyclical "flipping" of morphology in block copolymer thin films.
We studied the kinetics of nanopattern evolution in (polystyrene-b-polyethylene oxide) diblock copolymer thin films. Using scanning force microscopy, a highly unexpected cylindrical flipping of morphology from normal to parallel to the film plane was detected during solvent annealing of the film (with average thickness of 30 nm) at high vapor pressure. Using an in situ time-resolved light scattering device combined with an environmental cell enabled us to obtain kinetic information at different vapor pressures. The data indicated that there is a threshold value for the vapor pressure necessary for the structural transition. We propose a swelling and deswelling mechanism for the orientation flipping of the morphology. The cyclic transition occurs faster in thick films (177 nm) where the mass uptake and solvent volume fraction is smaller and therefore the driving force for phase separation is higher. We induced a stronger segregation by confining the chains in graphoepitaxially patterned substrates. As expected, the cyclic transition occurred at higher rate. Our work is another step forward to understanding the structure evolution and also controlling the alignment of block copolymer nanocylinders independently of thickness and external fields.


PI3K-mTOR-S6K Signaling Mediates Neuronal Viability via Collapsin Response Mediator Protein-2 Expression.
Collapsin response mediator protein (CRMP)-2 and the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway are associated with common physiological functions such as neuronal polarity, axonal outgrowth and synaptic strength, as well as various brain disorders including epilepsy. But, their regulatory and functional links are unclear. Alterations in CRMP-2 expression that lead to its functional changes are implicated in brain disorders such as epilepsy. Here, we investigate whether changes in CRMP-2 expression, possibly regulated by mTOR-related signaling, correlates with neuronal growth and viability. Inhibition of mTOR and/or phosphoinositol-3-kinase (PI3K) led to deceased p-S6K, and p-S6 signals also reduced CRMP-2 expression. These changes corresponded to inhibition of neuronal viability and proliferation in cultured hippocampal HT-22 cells under both basal serum-free and serum- or insulin-induced mTOR pathway-activated conditions. CRMP-2 expression tended to be increased by mTOR activation, indicated by an increase in p-S6/S6 level, in pentylentetrazole (PTZ)-induced epileptic rat hippocampal tissues was also significantly reduced by mTOR inhibition. Knockdown of CRMP-2 by si-RNA reduced the neuronal viability without changes in mTOR signaling, and overexpression of CRMP-2 recovered the glutamate-induced neurotoxicity and decrease of mTOR signaling in HT-22 cells. In conclusion, CRMP-2 protein expression controlled by the PI3K-mTOR-S6K signaling axis exerts its important functional roles in neuronal growth and survival.


[Clinical-psychological analysis of the development of movement, perceptual, intellectual and speech functions in children with cerebral palsy].
105 children with cerebral paralysis at the age under 3 years were examined. CNS damages in children of early age with disneuroontogenesis may be divided into 4 degrees of severity. This enables to estimate objectively both the patients' state and the results of their therapy in the groups with the same degree of severity of CNS damage. High efficiency of the complex method of metameric stimulation of the development of static-motor and psychospeech functions allows to recommend this method for treatment of children with cerebral paralysis. Application of this method in children of early age with disorders of neurologic development in some cases prevents neurologic disability.


[V. V. Strel'tsov: founder of the Institute and father of our country's aerospace medicine].
The paper gives an account of the scientific-and-practical activity of the prominent Soviet physiologist V. V. Streltsov, Head of the Fourth Sector, Research Sanitary Institute, and the initiator of the Aviation Medicine Institute. He was a brilliant experimenter, innovator, organizer of unique researches who developed the physiological aspects of high altitude, speedy, night and instrumental blind flights, the problems of stratospheric aviation. He made the first experimental ascent in the altitude chamber. He was one of the first aviation physicians who made a parachute jump. He was the first inflight medical investigator who tested the on-board oxygen equipment in group cross-country flight on the closed route Moscow-Kharkov-Moscow.


Total parenteral nutrition in infants and children.
The current literature on pediatric parenteral alimentation, including some of its newer modifications, was reviewed. In light of this review, a 1-year experience with 20 patients on the pediatric surgical service of the Mayo Clinic who received total parenteral nutrition for a variety of life-threatening problems is reported. Our data confirm that premature infants, infants with intractable diarrhea, and both infants and adolescents with surgical problems precluding enteral feeding can be given sufficient parenteral kilocalories to regain lost weight and continue to grow, and that this can be done with a minimal rate of complications.


Point: chemosensitivity assays have a role in the management of recurrent ovarian cancer.
In this era of personalized medicine, patients with recurrent ovarian cancer deserve better than the 25% response rate that is associated with drugs selected based on clinical information alone. In the past decade, marked laboratory improvements have enabled chemosensitivity assay testing to yield a 0.70 correlation with response, and to accurately predict progression-free and overall survival. Compelling retrospective data supporting the use of this technology cannot be ignored while waiting for a cooperative group to test whether chemosensitivity assay should be used to direct salvage therapy.


Ischaemic heart disease: clinical improvement with metabolic approach.
The term myocardial ischemia describes a condition which exists when fractional uptake of oxygen in the heart is not sufficient to maintain the rate of cellular oxidation. This leads to extremely complex situations which have extensively in recent years. A large amount of experimental research has been directed to establish the precise sequence of biochemical events leading to myocyte necrosis as such knowledge could lead to rational treatments designed to delay myocardial cell death. At the present time there is no simple answer to the question of what determines cell death and no recovery on reperfusion. Problems arise because: 1) ischemic-damage is not homogeneous and many factors may combine to cause cell death; 2) severity of biochemical changes and development of necrosis are usually associated (both the processes being dependent on the duration of ischemia) and it is impossible to establish a causal relationship; 3) the inevitability of necrosis can only be assessed by reperfusion of the ischaemic myocardium. Restoration of flow, however, might result in numerous further negative consequences, thus directly influencing the degree of recovery. From the clinical point of view, we have recently learnt that there are several potential manifestations and outcomes associated with myocardial ischaemia and reperfusion. Without doubt ventricular dysfunction (either systolic or diastolic) of the ischaemic zone is the most reliable clinical sign of ischemia, since ECG changes and symptoms are often absent. The ischaemia-induced ventricular dysfunction, at least initially, is reversible, as early reperfusion of the myocardium results in restoration of normal metabolism and contraction. In the ischaemic zone, recovery of contraction might occur instantaneously or, more frequently, with a considerable delay, thus yielding the condition recently recognised as the stunned myocardium. On the other hand, when ischemia is severe and prolonged, cell death might occur. Reperfusion at this stage is associated with the released of intracellular enzymes, disruption of cell membranes, influx of calcium, persistent reduction of contractility, and eventual necrosis of at least a portion of the tissue. This entity has been called reperfusion damage by those who believe that much of the injury is the consequence of events occurring at the moment of reperfusion rather than a result of changes occurring during the period of ischaemia. The existence of reperfusion damage, however, it has been questioned, and has been argued that, with the exception of induction of arrhythmias, it is difficult to be certain that reperfusion causes further injury. The existence of such an entity has clinical relevance, as it would imply the possibility of improving recovery with specific interventions applied at the time of reperfusion. In 1985 Rahimtoola described another possible out-come of myocardial ischemia. He demonstrated that late reperfusion (after months or even years) of an ischaemic area showing ventricular wall-motion abnormalities might restore normal metabolism and function. He was the first to introduce the term hibernating myocardium, referring to ischemic myocardium in which the myocytes remain viable but in which contraction is chronically depressed. Our data on metabolic changes occurring during ischemia followed by reperfusion which were obtained either in the isolated and perfused rabbit hearts or in CAD patient undergoing intracoronary thrombolysis or aortocoronary bypass grafting will be reviewed.


Cdk5-mediated oligodendrocyte myelin breakdown and neuroinflammation: Implications for the link between Type 2 Diabetes and Alzheimer's disease.
Oligodendrocytes, crucial myelinating glia in the central nervous system, play a vital role in maintaining axonal integrity and facilitating efficient nerve impulse conduction. The degradation of myelin in oligodendrocytes has been implicated in Alzheimer's disease (AD) and cognitive dysfunction. Interestingly, individuals with Type 2 Diabetes (T2D) have a significantly higher likelihood of developing cognitive impairment, possibly due to insulin resistance and glucose toxicity within the central nervous system (CNS). However, the precise relationship between these two disorders remains elusive. Our study proposes a potential link between T2D and AD, involving Cdk5-mediated breakdown of oligodendrocyte myelin and neuroinflammation. In the context of T2D, glucose toxicity in oligodendrocytes leads to heightened Cdk5 kinase activity and cPLA2 hyperactivation, resulting in chronic inflammation and myelin deterioration. This myelin breakdown in oligodendrocytes is thought to contribute to the development of AD and cognitive dysfunction. Notably, the administration of a Cdk5 inhibitor (TFP5) effectively alleviates neuroinflammation and myelin degradation. Moreover, our findings demonstrate heightened activity of Cdk5, cPLA2, and phospho-cPLA2 levels in the brain of a mouse model with Type 2 Diabetes (T2D). Hence, our findings suggest that targeting Cdk5 could be a promising therapeutic strategy to counteract AD pathogenesis in T2D-related conditions.


A System Dynamics Model of Serum Prostate-Specific Antigen Screening for Prostate Cancer.
Since 2012, US guidelines have recommended against prostate-specific antigen (PSA) screening for prostate cancer. However, evidence of screening benefit from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening trial and the European Randomized Study of Screening for Prostate Cancer has been inconsistent, due partly to differences in noncompliance and contamination. Using system dynamics modeling, we replicated the PLCO trial and extrapolated follow-up to 20 years. We then simulated 3 scenarios correcting for contamination in the PLCO control arm using Surveillance, Epidemiology, and End Results (SEER) incidence and survival data collected prior to the PSA screening era (scenario 1), SEER data collected during the PLCO trial period (1993-2001) (scenario 2), and data from the European trial's control arm (1991-2005) (scenario 3). In all scenarios, noncompliance was corrected using incidence and survival rates for men with screen-detected cancer in the PLCO screening arm. Scenarios 1 and 3 showed a benefit of PSA screening, with relative risks of 0.62 (95% confidence interval: 0.53, 0.72) and 0.70 (95% confidence interval: 0.59, 0.83) for cancer-specific mortality after 20 years, respectively. In scenario 2, however, there was no benefit of screening. This simulation showed that after correcting for noncompliance and contamination, there is potential benefit of PSA screening in reducing prostate cancer mortality. It also demonstrates the utility of system dynamics modeling for synthesizing epidemiologic evidence to inform public policy.