Functional analysis of the Arabidopsis PAL gene family in plant growth, development, and response to environmental stress.
Phenylalanine ammonia-lyase (PAL) catalyzes the first step of the phenylpropanoid pathway, which produces precursors to a variety of important secondary metabolites. Arabidopsis (Arabidopsis thaliana) contains four PAL genes (PAL1-PAL4), but there has been no genetic analysis to assess the biological functions of the entire gene family. Here, we report the generation and analysis of combined mutations for the four Arabidopsis PAL genes. Contrary to a previous report, we found that three independent pal1 pal2 double mutants were fertile and generated yellow seeds due to the lack of condensed tannin pigments in the seed coat. The pal1 pal2 double mutants were also deficient in anthocyanin pigments in various plant tissues, which accumulate in wild-type plants under stress conditions. Thus, PAL1 and PAL2 have a redundant role in flavonoid biosynthesis. Furthermore, the pal1 pal2 double mutants were more sensitive to ultraviolet-B light but more tolerant to drought than wild-type plants. We have also generated two independent pal1 pal2 pal3 pal4 quadruple knockout mutants, which are stunted and sterile. The quadruple knockout mutants still contained about 10% of the wild-type PAL activity, which might result from one or more leaky pal mutant genes or from other unknown PAL genes. The quadruple mutants also accumulated substantially reduced levels of salicylic acid and displayed increased susceptibility to a virulent strain of the bacterial pathogen Pseudomonas syringae. These results provide further evidence for both distinct and overlapping roles of the Arabidopsis PAL genes in plant growth, development, and responses to environmental stresses.


Circular RNA CSNK1G1 promotes the progression of osteoarthritis by targeting the miR‑4428/FUT2 axis.
Osteoarthritis (OA) is a chronic disease that results in chronic arthralgia and functional disability of the affected joint. To date, there is no effective treatment available for this disease. Circular RNAs (circRNAs) are a type of intracellular stable RNA that can regulate the development and progression of OA. However, the function of circCSNK1G1 in OA has not yet been investigated. In the present study, it was found that circCSNK1G1 was upregulated in OA cartilage tissues. The upregulation of circCSNK1G1 was associated with extracellular matrix (ECM) degradation and chondrocyte apoptosis. Moreover, the expression of miR‑4428 was downregulated and that of fucosyltransferase 2 (FUT2) was upregulated in OA‑affected cartilage tissues. Dual‑luciferase reporter assay and RNA immunoprecipitation confirmed that miR‑4428 targeted FUT2 mRNA to inhibit FUT2 expression. circCSNK1G1 and FUT2 induced ECM degradation and chondrocyte apoptosis. The negative effects of circCSNK1G1 and FUT2 were reversed by miR‑4428. On the whole, the present study demonstrates that circCSNK1G1 promotes the development of OA by targeting the miR‑4428/FUT2 axis. Thus, the circCSNK1G1/miR‑4428/FUT2 axis may present a novel target for the treatment of OA in the clinical setting.


Deficiency of glucagon gene-derived peptides induces peripheral polyneuropathy in mice.
Although diabetic polyneuropathy (DPN) is the commonest diabetic complication, its pathology remains to be clarified. As previous papers have suggested the neuroprotective effects of glucagon-like peptide-1 in DPN, the current study investigated the physiological indispensability of glucagon gene-derived peptides (GCGDPs) including glucagon-like peptide-1 in the peripheral nervous system (PNS). Neurological functions and neuropathological changes of GCGDP deficient (gcg-/-) mice were examined. The gcg-/- mice showed tactile allodynia and thermal hyperalgesia at 12-18 weeks old, followed by tactile and thermal hypoalgesia at 36 weeks old. Nerve conduction studies revealed a decrease in sensory nerve conduction velocity at 36 weeks old. Pathological findings showed a decrease in intraepidermal nerve fiber densities. Electron microscopy revealed a decrease in circularity and an increase in g-ratio of myelinated fibers and a decrease of unmyelinated fibers in the sural nerves of the gcg-/- mice. Effects of glucagon on neurite outgrowth were examined using an ex vivo culture of dorsal root ganglia. A supraphysiological concentration of glucagon promoted neurite outgrowth. In conclusion, the mice with deficiency of GCGDPs developed peripheral neuropathy with age. Furthermore, glucagon might have neuroprotective effects on the PNS of mice. GCGDPs might be involved in the pathology of DPN.


Enzyme reactor design under thermal inactivation.
Temperature is a very relevant variable for any bioprocess. Temperature optimization of bioreactor operation is a key aspect for process economics. This is especially true for enzyme-catalyzed processes, because enzymes are complex, unstable catalysts whose technological potential relies on their operational stability. Enzyme reactor design is presented with a special emphasis on the effect of thermal inactivation. Enzyme thermal inactivation is a very complex process from a mechanistic point of view. However, for the purpose of enzyme reactor design, it has been oversimplified frequently, considering one-stage first-order kinetics of inactivation and data gathered under nonreactive conditions that poorly represent the actual conditions within the reactor. More complex mechanisms are frequent, especially in the case of immobilized enzymes, and most important is the effect of catalytic modulators (substrates and products) on enzyme stability under operation conditions. This review focuses primarily on reactor design and operation under modulated thermal inactivation. It also presents a scheme for bioreactor temperature optimization, based on validated temperature-explicit functions for all the kinetic and inactivation parameters involved. More conventional enzyme reactor design is presented merely as a background for the purpose of highlighting the need for a deeper insight into enzyme inactivation for proper bioreactor design.


The effect of 6-hydroxydopamine lesions on the release of amino acids in the direct and indirect pathways of the basal ganglia: a dual microdialysis probe analysis.
The loss of dopaminergic neurons of the substantia nigra in Parkinson's disease and in animal models of Parkinson's disease is associated with an imbalance in the activity of the so-called 'direct' and 'indirect' pathways of information flow through the basal ganglia. The aim of the present study was to determine whether the imbalance is reflected in changes in the release of GABA, aspartate and glutamate in the pathways using dual probe microdialysis in freely moving rats. Control and 6-hydroxydopamine-(6-OHDA)-lesioned rats were implanted with microdialysis probes in the neostriatum and substantia nigra or globus pallidus and the release of amino acids was analysed in the dialysates. Basal levels of amino acids were largely unaltered by the 6-OHDA lesion; however, the levels of GABA in the globus pallidus dialysates were significantly elevated in the lesioned rats, indicating an imbalance in favour of the indirect pathway. Administration of kainic acid to the neostriatum enhanced the release of GABA locally and in the distal probes in the substantia nigra and globus pallidus. In 6-OHDA-lesioned rats, stimulated release of GABA in the substantia nigra was abolished, indicating a reduction in transmission along the direct pathway. Thus, consistent with the direct-indirect pathway model of the basal ganglia, the 6-OHDA lesion results in an elevation of the basal release of GABA in the striatopallidal (indirect) pathway and a reduction in the evoked release of GABA in the striatonigral (direct) pathway. These imbalances may underlie, at least in part, the motor abnormalities of Parkinson's disease and in animal models of Parkinson's disease.


Butyrate increases the efficiency of translation of gamma-globin mRNA.
Fetal hemoglobin (Hb F) levels increase in most patients with sickle cell disease following intermittent butyrate therapy. Although the full effects of butyrate on Hb F levels usually require multiple treatment cycles, in some patients a peak level is achieved after a few days of butyrate therapy. Our investigation of the mechanism(s) responsible for this rapid induction of Hb F by butyrate showed that reticulocyte gamma-globin chain synthesis markedly increased within 24 hours of butyrate exposure, without concomitant changes in reticulocyte gamma-globin mRNA levels. This suggests that butyrate might induce Hb F by increasing the efficiency of translation of gamma-globin mRNA. This hypothesis was confirmed by ribosome loading studies that demonstrated enrichment of the polysomal fraction of reticulocytes with gamma-globin mRNA following butyrate exposure. Thus, the induction of Hb F by butyrate may be mediated by translational effects in addition to its well-known effects on transcription of the gamma-globin genes.


Progress in metabolic engineering of Saccharomyces cerevisiae.
The traditional use of the yeast Saccharomyces cerevisiae in alcoholic fermentation has, over time, resulted in substantial accumulated knowledge concerning genetics, physiology, and biochemistry as well as genetic engineering and fermentation technologies. S. cerevisiae has become a platform organism for developing metabolic engineering strategies, methods, and tools. The current review discusses the relevance of several engineering strategies, such as rational and inverse metabolic engineering, evolutionary engineering, and global transcription machinery engineering, in yeast strain improvement. It also summarizes existing tools for fine-tuning and regulating enzyme activities and thus metabolic pathways. Recent examples of yeast metabolic engineering for food, beverage, and industrial biotechnology (bioethanol and bulk and fine chemicals) follow. S. cerevisiae currently enjoys increasing popularity as a production organism in industrial ("white") biotechnology due to its inherent tolerance of low pH values and high ethanol and inhibitor concentrations and its ability to grow anaerobically. Attention is paid to utilizing lignocellulosic biomass as a potential substrate.


Long form of thymic stromal lymphopoietin of keratinocytes is induced by protein allergens.
A growing body of evidence suggests that epicutaneous sensitization of protein allergens induces immediate-type hypersensitivity (IHS) following induction of Type 2 immune responses in animals and humans. Thymic stromal lymphopoietin (TSLP) derived from keratinocytes is a cytokine that can activate dendritic cells and has been implicated in development of inflammatory Type 2 helper T-cells. However, there is no direct evidence that allergens directly regulate TSLP expression in keratinocytes. This study aimed to evaluate the response of TSLP to protein allergens in cultured human keratinocytes and to identify appropriate endpoints for IHS. The transcription of long-form TSLP (loTSLP) was strongly induced by ovalbumin, wheat gluten (WG), acid-hydrolyzed WG (acid-HWG), and extracts from feces of Dermatophagoides pteronyssinus and D. farina, and trypsin, but not by rare allergens, human serum albumin (HSA), or extracts of mite bodies. In acid-HWG, loTSLP mRNA was significantly augmented by acid hydrolysis of WG for 0.5 h compared to WG. However, prolonged acid hydrolysis attenuated this induction similarly to that reported in previous animal studies. These results suggested that intense loTSLP transcriptional induction was a characteristic of a high-allergenic protein. Additionally, TSLP production was induced by exposure to ovalbumin, WG, and acid-HWG in combination with a trio of cytokines, i.e. interleukin (IL)-4, IL-13, and tumor necrosis factor (TNF)-α. However, no TSLP protein was detected following exposure to HSA, even in the presence of these cytokines. With acid-HWG, TSLP protein release was consistent with loTSLP transcription. Thus, intense loTSLP transcriptional induction and TSLP protein expression are each effective indicators that can be used for in vitro screening of IHS.


The heterogeneity of bound acetylcholine and synaptic vesicles.
Synaptic vesicles containing radioactive acetylcholine have been isolated from slices of Torpedo electric organ incubated with radioactive choline. The recently synthesized radioactive acetylcholine is preferentially removed from the vesicles by iso-osmotic gel filtration. There is therefore a small compartment of loosely bound recently synthesized acetylcholine within the monodisperse vesicle fraction. The specific radioactivity of this compartment correlates most closely with the ;free' acetylcholine of electric organ that is lost when the tissue is homogenized. Membrane-associated vesicles did not contain any particular enrichment of this compartment. On standing at 6 degrees C the loosely bound compartment stabilizes so that it survives iso-osmotic filtration. A study of this phenomenon revealed that it was proportional to the extent of the loss of tightly bound acetylcholine from the vesicles. Incubation with Ca(2+), at pH5.5, or partial hypo-osmotic shock, caused losses of tightly bound acetylcholine and proportional increases in the stabilization of loosely bound acetylcholine of vesicles. Incubation at 20 degrees C caused less loss of tightly bound, and less stabilization of loosely bound, acetylcholine. A theoretical treatment of these exchanges also shows that the random factors promoting loss of tightly bound acetylcholine are statistically correlated with those which cause stabilization of loosely bound acetylcholine. The reciprocal relationship between the exchanges is inconsistent with there being two distinct populations of vesicles, one containing recently synthesized, loosely bound acetylcholine and the other containing tightly bound acetylcholine. It is proposed that all the vesicles contain a core of tightly bound acetylcholine and a surface layer of loosely bound acetylcholine. The origin of the extravesicular acetylcholine and also of the acetylcholine released on stimulation is discussed in the light of these results.


VPS18 recruits VPS41 to the human HOPS complex via a RING-RING interaction.
Eukaryotic cells use conserved multisubunit membrane tethering complexes, including CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting), to control the fusion of endomembranes. These complexes have been extensively studied in yeast, but to date there have been far fewer studies of metazoan CORVET and HOPS. Both of these complexes comprise six subunits: a common four-subunit core and two unique subunits. Once assembled, these complexes function to recognise specific endosomal membrane markers and facilitate SNARE-mediated membrane fusion. CORVET promotes the homotypic fusion of early endosomes, while HOPS promotes the fusion of lysosomes to late endosomes and autophagosomes. Many of the subunits of both CORVET and HOPS contain putative C-terminal zinc-finger domains. Here, the contribution of these domains to the assembly of the human CORVET and HOPS complexes has been examined. Using biochemical techniques, we demonstrate that the zinc-containing RING (really interesting new gene) domains of human VPS18 and VPS41 interact directly to form a stable heterodimer. In cells, these RING domains are able to integrate into endogenous HOPS, showing that the VPS18 RING domain is required to recruit VPS41 to the core complex subunits. Importantly, this mechanism is not conserved throughout eukaryotes, as yeast Vps41 does not contain a C-terminal zinc-finger motif. The subunit analogous to VPS41 in human CORVET is VPS8, in which the RING domain has an additional C-terminal segment that is predicted to be disordered. Both the RING and disordered C-terminal domains are required for integration of VPS8 into endogenous CORVET complexes, suggesting that HOPS and CORVET recruit VPS41 and VPS8 via distinct molecular interactions.


Genomic Methylation Inhibits Expression of Hepatitis B Virus Envelope Protein in Transgenic Mice: A Non-Infectious Mouse Model to Study Silencing of HBV Surface Antigen Genes.
The Hepatitis B virus genome persists in the nucleus of virus infected hepatocytes where it serves as template for viral mRNA synthesis. Epigenetic modifications, including methylation of the CpG islands contribute to the regulation of viral gene expression. The present study investigates the effects of spontaneous age dependent loss of hepatitis B surface protein- (HBs) expression due to HBV-genome specific methylation as well as its proximate positive effects in HBs transgenic mice. Liver and serum of HBs transgenic mice aged 5-33 weeks were analyzed by Western blot, immunohistochemistry, serum analysis, PCR, and qRT-PCR. From the third month of age hepatic loss of HBs was observed in 20% of transgenic mice. The size of HBs-free area and the relative number of animals with these effects increased with age and struck about 55% of animals aged 33 weeks. Loss of HBs-expression was strongly correlated with amelioration of serum parameters ALT and AST. In addition lower HBs-expression went on with decreased ER-stress. The loss of surface protein expression started on transcriptional level and appeared to be regulated epigenetically by DNA methylation. The amount of the HBs-expression correlated negatively with methylation of HBV DNA in the mouse genome. Our data suggest that methylation of specific CpG sites controls gene expression even in HBs-transgenic mice with truncated HBV genome. More important, the loss of HBs expression and intracellular aggregation ameliorated cell stress and liver integrity. Thus, targeted modulation of HBs expression may offer new therapeutic approaches. Furthermore, HBs-transgenic mice depict a non-infectious mouse model to study one possible mechanism of HBs gene silencing by hypermethylation.


Application of chemometric methods to differential scanning calorimeter (DSC) to estimate nimodipine polymorphs from cosolvent system.
The focus of this study was to evaluate the applicability of chemometrics to differential scanning calorimetry data (DSC) to evaluate nimodipine polymorphs. Multivariate calibration models were built using DSC data from known mixtures of the nimodipine modification. The linear baseline correction treatment of data was used to reduce dispersion in thermograms. Principal component analysis of the treated and untreated data explained 96% and 89% of the data variability, respectively. Score and loading plots correlated variability between samples with change in proportion of nimodipine modifications. The R(2) for principal component regression (PCR) and partial lease square regression (PLS) were found to be 0.91 and 0.92. The root mean square of standard error of the treated samples for calibration and validation in PCR and PLS was found to be lower than the untreated sample. These models were applied to samples recrystallized from a cosolvent system, which indicated different proportion of modifications in the mixtures than those obtained by placing samples under different storage conditions. The model was able to predict the nimodipine modifications with known margin of error. Therefore, these models can be used as a quality control tool to expediently determine the nimodipine modification in an unknown mixture.


Effects of Adipose Plasma Transfusion Compared with Normal Plasma Transfusion on Adverse Transfusion Reactions, Important Functional Indicators, and Clinical Safety in Patients with Parenteral Nutrition: Based on a Retrospective Cohort Study.
Based on a retrospective cohort study, the study aims to investigate the effects of adipose plasma transfusion compared with normal plasma transfusion on adverse transfusion reactions, important functional indicators, and clinical safety in patients with parenteral nutrition (PN). One hundred and twenty inpatients who needed PN and plasma transfusion in Xianning Central Hospital from September 1, 2021, to March 31, 2022, were enrolled as the actual application verification cases. All the patients in the group noticed the informed consent form, and the normal plasma transfusion was set as the control group (n = 40), and the fat plasma transfusion was set as the study group. Mild adipose plasma transfusion was adopted in study group ① and moderate adipose plasma transfusion was used in study group ②, 40 cases in each group. The blood routine tests, blood lipids, blood coagulation, liver function tests, and the incidence of adverse reactions of blood transfusion were compared. The comparison results of platelet count, red blood cell count, hemoglobin, and hematocrit among the three groups are as follows: study group ②> study group ①> control group (P < 0.05).The levels of blood lipids in the three groups, triglyceride, total cholesterol, high density lipoprotein, and low density lipoprotein were compared in group ②>group ①>control group (P < 0.05).The liver function tests indexes of the three groups were compared: ALT, AST, LDH: study ②<study ①<control group; ALP: study ②>study ①>control group. Regarding the incidence of adverse transfusion reactions, the incidence of adverse transfusion reactions in the study group was lower than in the control group (P < 0.05). Compared with normal plasma transfusion, the inpatients who need PN and plasma transfusion can effectively use the scrapped mild and moderate fatty plasma and reduce the plasma scrap rate. In the meantime, it has little effect on the function of the important indexes of the patients, and the incidence of adverse reactions of blood transfusion is low and the safety is high. Infusion of adipose plasma can also improve the effective individual and rational utilization of blood products. Trial registration: This trial is registered with chiCTR220005918.


Chemical and physical characteristics of a phosphoprotein from human parotid saliva.
The isolation of a highly purified phosphoprotein, previously named protein A, from human parotid saliva is described. This protein has an unusually high amount of glycine, proline and dicarboxylic amino acids. Together these amino acids account for 80% of all residues. The protein contains 1.9mol of P/mol of protein, probably as phosphate in an ester linkage to serine, and about 0.5% carbohydrate, but no hexosamine. The N-terminal is blocked and the following C-terminal sequence is proposed: -Aal-Asp-Ser-Gln-Gly-Arg-Arg. The sioelectric point is 4.43. The molecular weight of the protein determined by ultracentrifugation is 9900 and from chemical analyses 11000. Circular-dichrosim and nuclea-magnetic-resonance spectra indicate the absence of polyproline and triple-helical-collagen-like structure for the protein. There is little restriction on the orientation of the single phenylalanine residue in the protein., but there is also an indication of conformational restraint in the protein.


Evidence for a role of kallikrein-P6nin system in patients with shock after blunt trauma.
Bradykinin (BK) is activated via plasma and/or tissue kallikrein-kinin (K-K) system pathways during hypotension after blunt trauma. The precise role of the K-K system in human subjects has not been defined. We developed a new method for measuring levels of BK in the blood and examined the role of the K-K system in patients with shock after trauma. Eight patients were entered into this study. We measured the levels of a high-molecular-weight kininogen (HMWK), a low-molecular-weight kininogen (LMWK), BK, and (1-5)-BK in the blood of patients in an unstable state (Pre) and a stable state (Post). At Pre, the blood BK level was significantly elevated, the HMWK and LMWK levels were significantly lower, and the (1-5)-BK level was significantly higher than the respective levels at Post. Our data suggest a significant role for the K-K system in the pathogenesis of shock after blunt trauma. This newly developed method for determination of the activation of the plasma K-K system appears to be useful for determining the severity of a trauma.


Pathology in Prostate Cancer: Limitations With Current Techniques.
Study of the pathology of prostate cancer is the clinical mainstay for evaluating the biology of the disease to predict prognosis and to recommend treatment options. Recent studies of whole-mount specimens are beginning to clarify the significance of tumor volume, grade, and multifocality. The studies are limited, however, by the constraints imposed by our inability to perform repeated studies over time.


A mixed-methods approach to understanding barriers and facilitators to healthy eating and exercise from five European countries: highlighting the roles of enjoyment, emotion and social engagement.
Healthy adults are consistently falling below national and international recommendations for physical activity and dietary intake across Europe. This study took a co-creative approach with adult samples from five European countries to qualitatively and quantitatively establish motivators, barriers and sustaining factors for positive health behaviour change. Stage 1 delivered a newly-designed online programme, creating a community who identified challenges, motivators and solutions to sustaining positive healthy eating and physical activity behaviours. Stage 2 administered an online survey (developed from Stage 1 findings) to a larger sample to quantify the relative importance of these motivators and barriers. Results from both stages indicated enjoyment, positive emotions, and reward as key motivators for both behaviours across all five countries. Barriers included habit-breaking difficulties, temptation and negative affective states. Those with a high BMI placed more importance on social pressure than those with healthy BMI. Participants' reports of motivators and barriers reflected relevant approaches from consumer science, behavioural economics, and psychology. Interventions supporting adults who are not chronically ill but would benefit from improved diet and/or physical activity should not focus exclusively on health as a motivating factor. Emphasis on enjoyable behaviours, social engagement and reward will likely improve engagement and sustained behaviour change.


Effects of selenium on apoptosis and abnormal amino acid metabolism induced by excess fatty acid in isolated rat hepatocytes.
Increased serum free fatty acid (FFA) occurs in subjects with non-alcoholic fatty liver disease (NAFLD) and also triggers oxidative stress, apoptosis, and insulin resistance. Selenium (Se) is an antioxidant agent. However, the effect of Se on NAFLD or diabetes is still unclear. We investigated the effect of Se on apoptosis and abnormal amino acid metabolism initiated by excess FFA in isolated rat hepatocytes. Primary hepatocytes from rats were isolated and exposed to excessive FFA (0.5 mM oleate/palmitic acid 2:1) and 0.1 μM Se. Se protected primary hepatocytes against oxidative stress and apoptosis induced by excess FFA, but did not play a role on abnormal amino acid metabolism and insulin resistance initiated by FFA in isolated rat hepatocytes. Although Se had the capability of preventing the apoptosis initiated by ROS, insulin resistance failed to be reversed in hepatocytes exposed to FFA. This failure may be attributed to the limitation of Se in regulating branched chain amino acids abundance. This indicates that apoptosis and insulin resistance might be involved in different pathways when isolated hepatocytes were exposed to FFA and Se.


A Nurse Practitioner service designed to address the health needs of children living in housing instability: A non-randomised, concurrent mixed methods study protocol.
In 2019-2020 we conducted a pilot study of a Nurse Practitioner clinic working with housing insecure children (0-18 years) that found high levels of developmental delay, missed immunizations and dental caries. This present non-randomized, concurrent mixed-methods study protocol explains the next phase of the research designed proving proof of concept for a Nurse Practitioner model of care for these vulnerable children. Focusing on identifying and understanding clinic admission processes, tracking referral pathways and uptake, and how many vulnerable children miss potential care and why. This will help us to understand and address gaps in health service delivery for this cohort. The study uses a concurrent mixed- method design where both qualitative and quantitative data are collected during the same period (between January 2021 and March 2022 as per the funding timeline). The concurrent mixed-method design will collect data from: A comprehensive assessment tool used by the Nurse Practitioner to evaluate the child accessing specialist homeless services, which assess their mental, physical and social health needs. Documentation about the child's referral needs and uptake by disadvantage families. Interviews with housing insecure families, and staff/managers of the specialist homeless service. A review of Nurse Practitioner case notes. Surveys of families with children accessing the Nurse Practitioner service. Addressing the childhood impacts of family homelessness is of global importance. Structural equation modelling, from the surveys and in-depth health assessments along with the thematic analysis of the interviews with parents and staff/managers provide an understanding of the relationships between referral uptake and variables such as education, homelessness and transport accessibility. Investigating the enablers and barriers to the usual health access and our extended referral uptake impacted by family homelessness enables a better understanding of the current health gaps. Just over one fifth of Australian children live with their families in some form of housing instability including homelessness. These children, aged from birth to 18 years, are often disconnected from health and similar social institutions, making them an underserviced population. Our research investigates a Nurse Practitioner services that helps reconnect children with services to help avoid poor long-term health outcomes.


[Prehospital care to multiple victims with simulated trauma].
To assess the quality of prehospital care agencies conducted in Vitória, capital of Espírito Santo State, Brazil. We conducted a retrospective study in the archives of the League of Academic Surgery and Trauma Care of Espírito Santo (Lacates) regarding 40 victims of a simulated crash between a bus and two cars. The patients were treated by four teams: Military Fire Department of Espírito Santo, Samu 192, County Guard and Civil Defense. The performance of these teams was evaluated by Lacates, through analysis of a check-list with pre-established guidelines for each victim. The Fire Department of Espírito Santo (CBMES), which extricated victims, outlined the danger zones and carried out the screening by the method START, acted correctly in 92.5% of cases. The Samu 192 victims, which attended victims by the mnemonic method (ABCDE) in medical outposts, acted correctly in 92.5% of cases in the category Airway; 97.5% in breathing, 92.5% in circulation, 90% in Neurological Assessment, and 50% in the Exhibition and Environmental Control. The analysis showed that the ABCDE care was correct in 42.5% of cases. The transport of patients was performed correctly in 95% of cases. The County Guard secured the patency of the avenues for transportation of patients and Civil Defense successfully coordinated the work of teams involved in the command post. The triage and transport of victims have been performed satisfactorily. However, more attention should be given to exposure and hypothermia protection of victims, since this item compromised treatment.


Walled-off pancreatic necrosis and other current concepts in the radiological assessment of acute pancreatitis.
Acute pancreatitis is an inflammatory condition caused by intracellular activation and extravasation of inappropriate proteolytic enzymes determining destruction of pancreatic parenchyma and peripancreatic tissues. This is a fairly common clinical condition with two main presentations, namely, endematous pancreatitis - a less severe presentation -, and necrotizing pancreatitis - the most severe presentation that affects a significant part of patients. The radiological evaluation, particularly by computed tomography, plays a fundamental role in the definition of the management of severe cases, especially regarding the characterization of local complications with implications in the prognosis and in the definition of the therapeutic approach. New concepts include the subdivision of necrotizing pancreatitis into the following presentations: pancreatic parenchymal necrosis with concomitant peripancreatic tissue necrosis, and necrosis restricted to peripancreatic tissues. Moreover, there was a systematization of the terms acute peripancreatic fluid collection, pseudocyst, post-necrotic pancreatic/peripancreatic fluid collections and walled-off pancreatic necrosis. The knowledge about such terms is extremely relevant to standardize the terminology utilized by specialists involved in the diagnosis and treatment of these patients.


Subword-based semantic retrieval of clinical and bibliographic documents.
The increasing amount of electronically available documents in bibliographic databases and the clinical documentation requires user-friendly techniques for content retrieval. A domain-specific approach on semantic text indexing for document retrieval is presented. It is based on a subword thesaurus and maps the content of texts in different European languages to a common interlingual representation, which supports the search across multilingual document collections. Three use cases are presented where the semantic retrieval method has been implemented: a bibliographic database, a department EHR system, and a consumer-oriented Web portal. It could be shown that a semantic indexing and retrieval approach, the performance of which had already been empirically assessed in prior studies, proved useful in different prototypical and routine scenarios and was well accepted by several user groups.


Development of prognosis in palliative care study (PiPS) predictor models to improve prognostication in advanced cancer: prospective cohort study.
To develop a novel prognostic indicator for use in patients with advanced cancer that is significantly better than clinicians' estimates of survival. Prospective multicentre observational cohort study. 18 palliative care services in the UK (including hospices, hospital support teams, and community teams). 1018 patients with locally advanced or metastatic cancer, no longer being treated for cancer, and recently referred to palliative care services. Performance of a composite model to predict whether patients were likely to survive for "days" (0-13 days), "weeks" (14-55 days), or "months+" (>55 days), compared with actual survival and clinicians' predictions. On multivariate analysis, 11 core variables (pulse rate, general health status, mental test score, performance status, presence of anorexia, presence of any site of metastatic disease, presence of liver metastases, C reactive protein, white blood count, platelet count, and urea) independently predicted both two week and two month survival. Four variables had prognostic significance only for two week survival (dyspnoea, dysphagia, bone metastases, and alanine transaminase), and eight variables had prognostic significance only for two month survival (primary breast cancer, male genital cancer, tiredness, loss of weight, lymphocyte count, neutrophil count, alkaline phosphatase, and albumin). Separate prognostic models were created for patients without (PiPS-A) or with (PiPS-B) blood results. The area under the curve for all models varied between 0.79 and 0.86. Absolute agreement between actual survival and PiPS predictions was 57.3% (after correction for over-optimism). The median survival across the PiPS-A categories was 5, 33, and 92 days and survival across PiPS-B categories was 7, 32, and 100.5 days. All models performed as well as, or better than, clinicians' estimates of survival. In patients with advanced cancer no longer being treated, a combination of clinical and laboratory variables can reliably predict two week and two month survival.


Innovating public participation methods: Technoscientization and reflexive engagement.
We reconstruct the innovation journey of 'citizen panels', as a family of participation methods, over four decades and across different sites of development and application. A process of aggregation leads from local practices of designing participatory procedures like the citizens jury, planning cell, or consensus conference in the 1970s and 1980s, to the disembedding and proliferation of procedural formats in the 1990s, and into the trans-local consolidation of participatory practices through laboratory-based expertise since about 2000. Our account highlights a central irony: anti-technocratic engagements with governance gave birth to efforts at establishing technoscientific control over questions of political procedure. But such efforts have been met with various forms of reflexive engagement that draw out implications and turn design questions back into matters of concern. An emerging informal assessment regime for technologies of participation as yet prevents closure on one dominant global design for democracy beyond the state.


[Fractures in the elderly--a challenge for prevention and health promotion--results from the KORA fracture study Augsburg].
Fractures of the appendicular bones are frequent and can cause a loss of the ability for independent living, depending on age and fracture localisation. They affect both sexes at different times and in different ways. The basic epidemiology for Germany of this injury resp. disease and knowledge regarding medium-term health-related consequences has been provided by work done in the context of the KORA Augsburg Fracture Study 1998, a follow-up of older participants of the third MONICA Augsburg survey S3 (1994/95) and through further research in the past years. Results of a validation study support the value of questionnaire-based patients recall of fractures and their location. It could be shown that age, gender, time since fracture and impaired walking have the greatest predictive value among a number of factors. Limitations of physical function are apparent especially during the first two years after a fragility fracture. After five years functional capacity of survivors equals the functional capacity of control persons of the same age. These population-representative and validated data support model-based cost-effective strategies of population-orientated disease prevention and health promotion. An age and gender-specific approach (gender mainstreaming) is mandatory.


Fluid resuscitation in sepsis: the great 30 mL per kg hoax.
Large volume fluid resuscitation is currently viewed as the cornerstone of the treatment of septic shock. The surviving sepsis campaign (SSC) guidelines provide a strong recommendation to rapidly administer a minimum of 30 mL/kg crystalloid solution intravenously in all patients with septic shock and those with elevated blood lactate levels. However, there is no credible evidence to support this recommendation. In fact, recent findings from experimental, observational and randomized clinical trials demonstrate improved outcomes with a more restrictive approach to fluid resuscitation. Accumulating evidence suggests that aggressive fluid resuscitation is harmful. Paradoxically, excess fluid administration may worsen shock. In this review, we critically evaluate the scientific evidence for a weight-based fluid resuscitation approach. Furthermore, the potential mechanisms and consequences of harm associated with fluid resuscitation are discussed. Finally, we recommend an individualized, conservative and physiologic guided approach to fluid resuscitation.


Defining the malignant potential of the giant pigmented nevus.
An unusual giant pigmented nevus, containing lymphocytic infiltrates and apparent muscle invasion, but without the presence of melanoma, is described in detail--including its related immunological parameters. The controversy concerning the malignant potential of giant pigmented nevi, and the paradoxes that are encountered clinically, are discussed.


Overexpression of Fas ligand (FasL) during malignant transformation in the large bowel and in Barrett's metaplasia of the esophagus.
Esophageal and colorectal adenocarcinomas overexpress Fas ligand (FasL), which can protect them from immune surveillance. The aim of this work was to determine whether FasL expression, and therefore FasL-dependent immune evasion, occurs early during malignant transformation in Barrett's metaplasia (BM) of the esophagus, and in the large intestine. Sections of formalin-fixed and paraffin-embedded tissue from esophageal and large bowel biopsies and resection specimens were immunostained for FasL using standard immunoperoxidase technique. The percentage of positive cells was correlated with the degree of dysplasia in BM and with the size and villous architecture of colorectal adenomas. In BM, FasL was detected in 55% of cases negative for dysplasia, and was associated with inflammation in almost all positive cases. By contrast, all cases of BM (100%) with low- or high-grade dysplasia were FasL-positive. In the large intestine, 25% of small adenomas were negative for FasL, and FasL overexpression was significantly more frequent in larger adenomas and in adenomas with tubulovillous or villous morphology. Our results suggest that (1) FasL overexpression is acquired early during malignant transformation of BM and the large bowel and (2) FasL overexpression occurs relatively earlier during malignant progression of BM than the large bowel, probably as a result of the preceding repeated inflammation.


The association between community crime and childhood asthma prevalence in Chicago.
Little attention has been given to exposure to crime as a possible socioenvironmental contributor to variability in urban childhood asthma prevalence. To determine the association of violent crime, property crime, and drug abuse violations with childhood asthma prevalence in Chicago. In 2003-2005, the Chicago Initiative to Raise Asthma Health Equity conducted an asthma screening survey of children in grades K to 8 attending Chicago public and Catholic schools. Crime data were obtained from the Chicago Police Department. In addition to simple regression analysis, multilevel logistic regression analysis was performed to estimate the effect of criminal activity on neighborhood asthma variance. Of the surveys returned, 45,371 (93%) were geocoded into 247 neighborhoods. Neighborhoods were divided into quartile groups by mean asthma prevalence (9%, 12%, 17%, and 22%). Criminal activity (annual incidence per 100,000 people) was significantly higher (P < .001) in neighborhoods with a high asthma prevalence, especially drug abuse violations, which increased more than 6-fold (461 vs 2,921), and violent crimes, which increased more than 3-fold (448 vs 1,566). After adjusting for community race/ethnicity, only violent crime continued to be significantly associated with the neighborhood asthma prevalence (odds ratio, 1.27; 95% confidence interval, 1.04-1.55, P < .05). When considered alongside sociodemographic and individual characteristics, violence continued to contribute significantly (P < .05), explaining 15% of neighborhood variation in childhood asthma. Evidence suggests an association between violent crime and childhood asthma prevalence in Chicago. A deeper understanding of the mechanisms that underlie this association may lend insight into potential interventions to address urban asthma.


Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo.
It is widely assumed that glatiramer acetate (GA), an approved agent for the immunomodulatory treatment of multiple sclerosis, acts primarily as an antigen for T lymphocytes. Recent studies, however, indicated that in vitro, GA directly inhibits dendritic cells, a rare but potent type of professional antigen-presenting cell (APC). To investigate whether these in vitro observations are relevant to the actions of GA in vivo, we studied the effects of GA on monocytes, the major type of circulating APC. In a first series of experiments, we investigated the effects of GA on monocyte reactivity in vitro. Monocytes were stimulated with ligands for Toll-like receptor (TLR)-2 (peptidoglycan and lipoteichoic acid), TLR-4 [lipopolysaccharide (LPS)] and TLR-5 (flagellin), as well as two proinflammatory cytokines (interferon-gamma and granulocyte-monocyte colony-stimulating factor). Monocyte activation was measured by induction of the surface markers signalling lymphocytic activation molecule (SLAM), CD25 and CD69 (detected by cytofluorometry), and by production of monocyte-derived tumour necrosis factor (TNF)-alpha (detected by enzyme-linked immunospot assay). GA had a broad inhibitory effect on all measures of monocyte reactivity, regardless of which stimulator was used. It is unlikely that this reflects a simple toxic effect, because monocyte viability and CD14 expression were unaffected. In a second series of experiments, we investigated the properties of monocytes cultured ex vivo from eight GA-treated multiple sclerosis patients, eight untreated multiple sclerosis patients and eight healthy subjects. We found that LPS-induced SLAM expression and TNF-alpha production were significantly reduced in monocytes from GA-treated patients compared with controls. These results demonstrate for the first time that GA inhibits monocyte reactivity in vitro and in vivo, significantly extending the current concept of the mechanism of action of GA.


Oral health and nutritional Status of Preschool-Aged Children in Maiduguri, North-East, Nigeria.
The most prevalent oral diseases, dental caries and periodontal disease, result in pain, discomfort, and loss of oral functions, often leading to poor nutrition. To assess the prevalence and relationship between oral health and nutritional status among children aged 2 to 5 years in Maiduguri, North-East Nigeria. A cross-sectional study that assessed caries experience, gingival status and nutritional status of children. Anthropometric measurements of weight-for-age and mid-upper arm circumference (MUAC) were used to assess nutritional status. Participants were randomly selected from three private schools. The MUAC was measured using a standardised tape rule. The weight-for-age by sex of the participants was extrapolated from the weight-for-age WHO chart. Oral health was assessed using the WHO Oral Health Survey Methods. Data were analysed using SPSS for Windows (version 23). Statistical significance was placed at 95% confidence and p ≤ 0.05. There were 239 participants with a male:female ratio of 1.2:1 (SE=0.03). Mean dmft was 0.72 (SE 0.09) and 63.2% had healthy gingiva (SE 0.04). The mean weight was 16.8kg (SE=0.15) and mean MUAC was 15.3 cm. Caries prevalence was associated with nutritional status and positively correlated (r=0.03, P=0.64). Gingival status was associated but inversely correlated with MUAC (r= -0.02, P= 0.76). Normal nutritional status was associated with no caries prevalence and healthy gingiva. Underweight was associated with caries prevalence. Adequate and healthy nutrition promotes good oral health in children.


Relationship between Serum Levels of Anti-Mullerian Hormone, Adiponectin and Oxidative Stress Markers in Patients with Polycystic Ovary Syndrome.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Anti-Mullerian hormone (AMH) is a valid indicator of ovarian function and is used for PCOS diagnosis. Some studies have shown that adipokines affect the synthesis of AMH, and therefore they are somehow related in function. The aim of the present study was to determine the relationship between serum levels of AMH, adiponectin and oxidative stress markers in PCOS patients. In this cross-sectional study, PCOS patients and healthy women (80 cases in total) were investigated. Serum levels of AMH, adiponectin, gonadotropins, androgens, total antioxidant capacity (TAC), nitric oxide (NO) and insulin resistance (IR) were measured by standard methods. An independent t test was used to compare the two groups and Pearson correlation coefficient was used to determine the relationship between variables. There was a significant difference between the means of AMH (5.16 ± 5.3 vs. 2.44 ± 2.5 ng/mL) (P=0.007) and adiponectin (24.55 ± 9.41 vs. 30.57 ± 14.2 μg/L) (P=0.029) among the PCOS and control groups, respectively. The correlation between AMH and adiponectin in the control group was statistically significant and negative (P=0.028, r=-0.35), while in the PCOS group it was not significant (P=0.11, r=-0.25). Various biochemical and hormonal factors differ between PCOS and healthy women. Different factors can influence AMH and adiponectin levels independently of PCOS in women of reproductive age.


Creating a competitive PSO: a case study.
Mount Carmel Health System, an integrated delivery system in Columbus, Ohio, became a Medicare+Choice contractor in response to unsatisfactory payment proposals from the Medicare contractors it serviced and to compete with the increasing number of managed care providers in its market. To meet HCFA's operational requirements, Mount Carmel upgraded and expanded its administrative and health information systems and solicited the support of its network physicians. It also developed a marketing strategy to promote its health plan. In the two years after instituting its provider-sponsored organization, Mount Carmel surpassed its original enrollment projections, decreased its patient management and utilization costs, and increased payments to its network members.


Cannabinoid Receptor Type 2: A Possible Target in SARS-CoV-2 (CoV-19) Infection?
In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.


Antibiotic prophylaxis in ERCP with failed cannulation.
Endoscopic retrograde cholangiopancreatography (ERCP) with failed biliary cannulation is associated with a high rate of adverse events, but the role of prophylactic antibiotics remains unclear. The primary aim was to investigate if prophylactically administered antibiotics affect the frequency of overall adverse complications in patients where biliary cannulation fails during ERCP. The secondary aim was to investigate if specific infectious complications, also were affected by the antibiotic prophylaxis. We analysed data from 96,818 ERCPs (2006-2018), from the Swedish National Quality Registry of Cholecystectomy and ERCP (GallRiks), excluding ERCPs with successful cannulation (n = 88,743), missing data (n = 2,014), or on-going antibiotic therapy (n = 1,062). In total 4,996 procedures were included, 2,124 received (42.5%) and 2,872 (57.5%) did not receive antibiotic prophylaxis. There were fewer overall complications in the group receiving prophylaxis (13.6% vs. 17.1%, p < .001), which corresponded to a 24% adjusted odds reduction in the multivariable analysis (odds ratio [OR] 0.76; 95% confidence interval [CI] 0.65-0.89). In the prophylaxis group, there was a lower overall rate of infectious complications (2.1% vs. 3.2%; p = .038; OR 0.68; 95% CI 0.47-0.98) and abscesses (0.8% vs. 1.4%; p = .040; OR 0.54; 95% CI 0.31-0.96). However, no significant differences were seen in the rate of cholangitis (1.3% vs. 1.7%; p = .182; OR 0.74; 95% CI 0.46-1.18). This national quality registry study of ERCPs with failed cannulation showed a significant reduction in overall and infectious complications when prophylactic antibiotics were administered.


Predictive genomics of adverse events after cardiac surgery.
Significant, yet highly individual, thrombotic and inflammatory responses to surgery provide an excellent opportunity for insight into the genomic impact upon a patient's postoperative course. Cardiac surgery elicits the most profound perioperative disturbance and is associated with the highest incidence of adverse outcomes of any elective surgical procedure. Thus, cardiac surgical patients are an ideal population in which to evaluate the influence of complex traits on perioperative morbidity and mortality. This review describes the application of fundamental genetics upon the occurrence of adverse outcomes after cardiac surgery and cardiac transplantation. Specific emphases include a brief primer of the principles of genetics concentrating on the effects of variation within the human genome upon clinical outcomes and the differences between so-called Mendelian traits and complex traits. Four important clinical diseases dealt with in this review as examples of the impact of genetic factors on clinical outcomes are the genetics of heparin-induced thrombocytopenia, heart transplantation rejection and vasculopathy, atrial fibrillation, and infection.


Expression profiling of tobacco leaf trichomes identifies genes for biotic and abiotic stresses.
Nicotiana tabacum (tobacco) plants have short and long glandular trichomes. There is evidence that tobacco trichomes play several roles in the defense against biotic and abiotic stresses. cDNA libraries were constructed from control and cadmium (Cd)-treated leaf trichomes. Almost 2,000 expressed sequence tag (EST) cDNA clones were sequenced to analyze gene expression in control and Cd-treated leaf trichomes. Genes for stress response as well as for primary metabolism scored highly, indicating that the trichome is a biologically active and stress-responsive tissue. Reverse transcription-PCR (RT-PCR) analysis demonstrated that antipathogenic T-phylloplanin-like proteins, glutathione peroxidase and several classes of pathogenesis-related (PR) proteins were expressed specifically or dominantly in trichomes. Cysteine-rich PR proteins, such as non-specific lipid transfer proteins (nsLTPs) and metallocarboxypeptidase inhibitors, are candidates for the sequestration of metals. The expression of osmotin and thaumatin-like proteins was induced by Cd treatment in both leaves and trichomes. Confocal laser scanning microscopy (CLSM) showed that glutathione levels in tip cells of both long and short trichomes were higher than those in other types of leaf cells, indicating the presence of an active sulfur-dependent protective system in trichomes. Our results revealed that the trichome-specific transcriptome approach is a powerful tool to investigate the defensive functions of trichomes against both abiotic and biotic stress. Trichomes are shown to be an enriched source of useful genes for molecular breeding towards stress-tolerant plants.


Relative weight at age 12 and risk of postmenopausal breast cancer.
Early adolescent weight may affect the risk of postmenopausal breast cancer, and this association may be modified by a family history of breast or ovarian cancer in a first-degree relative, and/or estrogen (ER) and progesterone (PR) receptor status of the disease. Relative weight at age 12 years (above, below, or average weight compared with peers) and family history were ascertained using a mailed questionnaire in 1986, in the Iowa Women's Health Study, a prospective cohort study of postmenopausal women. Incident breast cancer cases (including ER and PR status) were identified using the Iowa Surveillance, Epidemiology, and End Results Cancer Registry. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression, and were adjusted for breast cancer risk factors, including body mass index at age 18 years and body mass index at study baseline. Through 2003, 2,503 cases of postmenopausal breast cancer were identified among 35,941 women in the analytic cohort. Compared with women with average weight at age 12 years, there was no association of below average weight with risk of breast cancer (RR, 1.02; 95% CI, 0.92-1.13), whereas women with above average weight had a lower risk (RR, 0.85; 95% CI, 0.74-0.98). There was no evidence of an interaction between weight at age 12 years and family history (P = 0.44). The inverse association of above average weight with risk of breast cancer was strongest for PR- tumors (RR, 0.62; 95% CI, 0.43-0.89), intermediate for ER+ (RR, 0.80; 95% CI, 0.67-0.96) and ER- (RR, 0.77; 95% CI, 0.50-1.19) tumors, and weakest for PR+ tumors (RR, 0.90; 95% CI, 0.74-1.09). These associations were not modified by a family history (all P > 0.18). In a joint ER/PR analyses, the strongest inverse association with above average weight at age 12 years was seen for ER+/PR- (RR, 0.49; 95% CI, 0.29-0.85). Above average weight at age 12 years was inversely associated with risk of postmenopausal breast cancer, and was not modified by a family history of the disease. The inverse association was strongest for ER+/PR- tumors.


Semantic Attention and Scale Complementary Network for Instance Segmentation in Remote Sensing Images.
In this article, we focus on the challenging multicategory instance segmentation problem in remote sensing images (RSIs), which aims at predicting the categories of all instances and localizing them with pixel-level masks. Although many landmark frameworks have demonstrated promising performance in instance segmentation, the complexity in the background and scale variability instances still remain challenging, for instance, segmentation of RSIs. To address the above problems, we propose an end-to-end multicategory instance segmentation model, namely, the semantic attention (SEA) and scale complementary network, which mainly consists of a SEA module and a scale complementary mask branch (SCMB). The SEA module contains a simple fully convolutional semantic segmentation branch with extra supervision to strengthen the activation of interest instances on the feature map and reduce the background noise's interference. To handle the undersegmentation of geospatial instances with large varying scales, we design the SCMB that extends the original single mask branch to trident mask branches and introduces complementary mask supervision at different scales to sufficiently leverage the multiscale information. We conduct comprehensive experiments to evaluate the effectiveness of our proposed method on the iSAID dataset and the NWPU Instance Segmentation dataset and achieve promising performance.


Integrating network pharmacology and experimental verification to explore the mucosal protective effect of Chimonanthus nitens Oliv. Leaf Granule on ulcerative colitis.
Chimonanthus nitens Oliv. Leaf Granule (COG) is a commonly used clinical preparation of traditional Chinese medicine for the treatment of cold, but there are folk reports that it can treat diarrhea and other gastrointestinal diseases. Therefore, the mechanism of COG in the treatment of ulcerative colitis with diarrhea as the main symptom needs to be studied. Combined network pharmacology and experimental validation to explore the mechanism of COG in the treatment of ulcerative colitis. First, the main components of COG were characterized by liquid chromatography-mass spectrometry (LC-MS); subsequently, a network pharmacology approach was used to screen the effective chemical components and action targets of COG to construct a target network of COG for the treatment of ulcerative colitis (UC). The protein-protein interaction network (PPI) and literature reports were combined to identify the potential targets of COG for the treatment of UC. Finally, the predicted results of network pharmacology were validated by animal and cellular experiments. 19 components of COG were characterized by LC-MS, among which 10 bioactive components could act on 377 potential targets of UC. Key therapeutic targets were collected, including SRC, HSP90AA1, PIK3RI, MAPK1 and ESR1. KEGG results are enriched in pathways related to oxidative stress. Molecular docking analysis showed good binding activity of main components and target genes. Animal experiments showed that COG significantly relieved the colitis symptoms in mice, regulated the Treg/Th17 balance, and promoted the secretion of IL-10 and IL-4, along with the inhibition of IL-1β and TNF-α. Additionally, COG reduced the apoptosis of colon epithelial cells, and significantly improved the levels of SOD, MAO, GSH-px, and inhibited MDA, iNOS, eNOS in colon. Also, it increased the expression of tight junction proteins such as ZO-1, Claudin1, Occludin and E-cadherin. In vitro experiments, COG inhibited the oxidative stress and inflammatory injury of HCT116 cells induced by LPS. Combining network pharmacology and in vitro and in vivo experiments, COG was verified to have a good protective effect in UC, which may be related to enhancing antioxidation in colon tissues.


The "Sandwich Therapy": A Microsurgical Integrated Approach for Presternal Keloid Treatment.
Keloid therapy remains a great challenge for plastic surgeons, especially when the defect cannot be closed primarily, necessitating tissue transplantation. Here, we introduce a new treatment modality, called the sandwich therapy, for presternal keloids; the sandwich therapy incorporates preradiotherapy, superficial circumflex iliac artery perforator (SCIP) flap transplantation, and postradiotherapy. From December 2012 to October 2013, 12 patients received the "sandwich therapy." For the protocol, all patients went through 5 days of specific events: the precut procedure, preradiotherapy, resection and SCIP flap transplantation, donor site radiotherapy, and final presternal radiotherapy. All the flaps survived completely. No complication was observed during the perioperative period. With a mean follow-up of 12 months, only 1 case was reported with an incisional hypertrophic scar. In all patients, the main discomfort complaints were resolved postoperatively. A low-tension or without-tension closure could be achieved with SCIP flap transplantation. The perioperative radiotherapy could further lower the risk of keloid recurrence. The sandwich therapy provides a new surgical approach to presternal keloid treatment.


Epidural analgesia for pain relief in thoracic surgery.
The effectiveness and adverse effects of continuous epidural analgesia was studied in 104 patients undergoing thoracic operations at Siriraj Hospital. Patients were divided into 3 groups according to the type of surgical approach and the technique of epidural analgesia. Group 1 patients (n = 72) received thoracic epidural block using bupivacaine and morphine combined with light general anesthesia for exploratory thoracotomy; group 2 patients (n = 21) received the identical anesthetic technique, the operation was achieved through median sternotomy; group 3 patients (n = 11) had a similar type of operation to group 1, the anesthetic technique was lumbar epidural block using morphine and combined with light general anesthesia. Continuous epidural morphine infusion was given 0.1-0.4 mg/h during postoperation in all patients for providing adequate pain relief. The results revealed that a 10 cm visual analogue scale (VAS) pain scores were satisfactory and comparable in all groups. Lumbar epidural patients consumed a significantly larger dose of morphine than thoracic epidural groups (P < 0.01). Intraoperative hypotension occurred 43.05 per cent and 19.05 per cent in group 1 and 2, but none was found in group 3 (P < 0.05). Postoperative respiratory depression was found 54.16 per cent in group 1, 33.33 per cent in group 2 and 9.09 per cent in group 3 (P < 0.05), and was mostly mild to moderate, except three patients in group 1 and one in group 2 who needed mechanical ventilatory support. There were no differences among the groups in the incidence of nausea/vomiting and pruritus. It is concluded that both thoracic and lumbar epidural morphine provide excellent postthoracotomy pain relief, whereas, respiratory depression is more common with thoracic than lumbar epidural morphine.


Homicide by barbiturates and alcohol.
Death from the misuse of alcohol and barbiturates is frequently encountered in most medical examiner/coroner offices. The cause of death is often quite apparent from the pathological and toxicological findings; however, the manner of death often gives the examining official some difficulty. The usual dilemma is to unravel whether the dead individual intentionally took the lethal combination in order to cause his/her own death or whether the combination was unintentionally ingested without awareness of the potentially lethal combination. The manner of death in these cases is either suicidal, accidental, or undetermined. A case is presented in which alcohol and barbiturates are the causes of death, but the manner of death is somewhat unusual in that it was administered by a second party with premeditation, deliberation, and intent to kill.


Investigating the structure of the autism-spectrum quotient using Mokken scaling.
Traits similar to those shown in autism spectrum condition (ASC) are apparent in relatives of individuals with ASC, and in the general population without necessarily meeting diagnostic criteria for an ASC. We assess whether the Autism-Spectrum Quotient (AQ), a self-report measure, has hierarchical properties using Mokken scaling. Hierarchical scales allow the presence of a latent trait to be identified by discovering whether and how many specific items form an ordered array along it. Data were collected from 2 groups: (1) people with ASC (n = 449: 240 males, 209 females, M(age) 35.4 years, SD = 12.8) and (2) university students (n = 943: 465 males, 475 females, M(age) = 23.0 years, SD = 8.4). A single Mokken scale was obtained in the data from university students and 3 scales were obtained in the data from people with ASC. The scales all showed moderate Mokken scaling properties with the single scale obtained from university students showing weak invariant item ordering and 2 of the scales from people with ASC showing weak invariant item ordering. The AQ formed reliable Mokken scales. There was a large overlap between the scale from the university student sample and the sample with ASC, with the first scale, relating to social interaction, being almost identical. The present study confirms the utility of the AQ as a single instrument that can dimensionalize autistic traits in both university student and clinical samples of ASC, and confirms that items of the AQ are consistently ordered relative to one another.


[Weight estimation in Mexican elderly outpatients from antropometric measures from the SABE Study].
The weight is an anthropometric parameter routinely used in ambulatory and hospital settings, and takes its importance, because often there are clinical conditions that impede it´s taking in a traditional scale. There are equations to estimate weight. However, they have not been designed for Mexican ambulatory patients. To develop an equation to estimate weight in Mexican ambulatory patients from the Study of Health, Well Being and Aging, corresponding to Mexico city an surrounded area. The database of the Study of Health, Well Being and Aging of Mexico City was used, and adults of 60 years and older, who completed the anthropometric measures were included. Two groups of datasets were crated though random numbers, one for the design and the other for the validation of the equation. The equation was obtained from the first database and cross-validated in the second. The equations obtained were: (0.67)* (Knee height)+(0.46)* (Mid-arm circumference)+(0.60)* (waist circumference)+(0.38)* (hip circumference)+(0.53)* (calf circumference)-(0.17)* (Age in years)-80.01 and (0.69)* (Knee height)+(0.61)* (Mid-arm circumference)+(0.17)* (waist circumference)+(0.45)* (hip circumference)+(0.58)* (calf circumference)-(0.24)* (Age in years)-55.9 in men and women respectively. The correlation coefficients were 0.94 y 0.92 (p<0.001 for both). The differences between the real and estimated values were not significant. The equations developed in our analysis were confident and can be employed to estimate weight in ambulatory elderly. It is needed to test its validity in clinical scenarios were it is not possible to weight patients directly in the rest of the Mexican republic and adjust to specific populations.


New mechanism of kinetic exchange interaction induced by strong magnetic anisotropy.
It is well known that the kinetic exchange interaction between single-occupied magnetic orbitals (s-s) is always antiferromagnetic, while between single- and double-occupied orbitals (s-d) is always ferromagnetic and much weaker. Here we show that the exchange interaction between strongly anisotropic doublets of lanthanides, actinides and transition metal ions with unquenched orbital momentum contains a new s-d kinetic contribution equal in strength with the s-s one. In non-collinear magnetic systems, this s-d kinetic mechanism can cause an overall ferromagnetic exchange interaction which can become very strong for transition metal ions. These findings are fully confirmed by DFT based analysis of exchange interaction in several Ln(3+) complexes.


Outcomes of hip arthroscopy. A prospective analysis and comparison between patients under 25 and over 25 years of age.
To compare the results of hip arthroscopy in patients under the age of 25 with those over 25 years. From March 2006 until May 2010, data were collected on all patients who underwent hip arthroscopy for symptomatic intra-articular hip pathology. The patients were divided into two groups based on age (less than 25 years and over 25 years). Patients completed the modified Harris hip score (MHHS), non-arthritic hip score (NAHS) and hip dysfunction and osteoarthritis outcome score (HOOS) questionnaires at baseline then at 6 weeks, 6 months, 12 months and at latest follow-up. 88 patients who underwent 94 hip arthroscopies by the senior author. Mean age was 24.3 (range 11-57 years). The mean NAHS and HOOS subscales for pain and activities of daily living were worse at baseline in over 25 groups. Follow-up ranged from 9 to 68 months. 45 hips had greater than 3 year follow-up. The MHHS improved in both groups with a mean difference in the under-25 group of 16.22, and 20.88 in the over 25s. Improvements in the NAHS and HOOS subscales were also of a similar magnitude. There was no statistically significant difference between outcome scores of the two groups at the latest follow-up visit. We found a comparable improvement in outcome between those patients under 25 years and those over 25 years. We propose that hip arthroscopy is of potential benefit to patients with symptoms of femoroacetabular impingement regardless of age.


Molecular adaptation of photoprotection: triplet states in light-harvesting proteins.
The photosynthetic light-harvesting systems of purple bacteria and plants both utilize specific carotenoids as quenchers of the harmful (bacterio)chlorophyll triplet states via triplet-triplet energy transfer. Here, we explore how the binding of carotenoids to the different types of light-harvesting proteins found in plants and purple bacteria provides adaptation in this vital photoprotective function. We show that the creation of the carotenoid triplet states in the light-harvesting complexes may occur without detectable conformational changes, in contrast to that found for carotenoids in solution. However, in plant light-harvesting complexes, the triplet wavefunction is shared between the carotenoids and their adjacent chlorophylls. This is not observed for the antenna proteins of purple bacteria, where the triplet is virtually fully located on the carotenoid molecule. These results explain the faster triplet-triplet transfer times in plant light-harvesting complexes. We show that this molecular mechanism, which spreads the location of the triplet wavefunction through the pigments of plant light-harvesting complexes, results in the absence of any detectable chlorophyll triplet in these complexes upon excitation, and we propose that it emerged as a photoprotective adaptation during the evolution of oxygenic photosynthesis.


Bioactive properties of milk proteins with particular focus on anticariogenesis.
Beyond nutrition, there is an increasing amount of data and information to demonstrate a bioactive role for dairy components in adults including a role in prevention of dental caries. Specifically, the casein fraction and hydrolysates thereof have been the focus of researchers investigating cariogenicity prevention. Tooth enamel is a polymeric substance consisting of crystalline calcium phosphate embedded in a protein matrix. Dental caries develop by acidic demineralization (calcium and phosphorus solubilization) of tooth enamel. Demineralization occurs directly (acidic food consumption) or indirectly (by fermentation products of dental plaque odontopathogenic bacteria growing on residual food particles between teeth or adhering to the plaque). Research efforts with milk derived bioactive peptides have focused on inhibition of cariogenic, plaque-forming bacteria, inhibition of tooth enamel demineralization, and subsequent enamel remineralization. Caseinophosphopeptides (CPP) and glycomacropeptide (GMP) have been patented for use in common personal hygiene products to prevent dental caries. Research has shown CPP and GMP to be growth inhibitory to the cariogenic bacteria Streptococcus mutans and other species. Additionally, CPP forms nanoclusters with amorphous calcium phosphate (AMP) at the tooth surface to provide a reservoir of calcium and phosphate ions to maintain a state of super saturation with respect to tooth enamel. This would buffer plaque pH, and also provide ions for tooth enamel remineralization. Glycosidic structures attached to GMP are important to numerous bioactive properties of the peptide including anticariogenicity. Like CPP, GMP has shown inhibitory activity to enamel demineralization and promotes tooth enamel remineralization.


Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma.
The BTK inhibitor ibrutinib has demonstrated a remarkable therapeutic effect in mantle cell lymphoma (MCL). However, approximately one-third of patients do not respond to the drug initially. To identify the mechanisms underlying primary ibrutinib resistance in MCL, we analyzed the transcriptome changes in ibrutinib-sensitive and ibrutinib-resistant cell lines on ibrutinib treatment. We found that MYC gene signature was suppressed by ibrutinib in sensitive but not resistant cell lines. We demonstrated that MYC gene was structurally abnormal and MYC protein was overexpressed in MCL cells. Further, MYC knockdown with RNA interference inhibited cell growth in ibrutinib-sensitive as well as ibrutinib-resistant cells. We explored the possibility of inhibiting MYC through HSP90 inhibition. The chaperon protein is overexpressed in both cell lines and primary MCL cells from the patients. We demonstrated that MYC is a bona fide client of HSP90 in the context of MCL by both immunoprecipitation and chemical precipitation. Furthermore, inhibition of HSP90 using PU-H71 induced apoptosis and caused cell cycle arrest. PU-H71 also demonstrates strong and relatively specific inhibition of the MYC transcriptional program compared with other oncogenic pathways. In a MCL patient-derived xenograft model, the HSP90 inhibitor retards tumor growth and prolongs survival. Last, we showed that PU-H71 induced apoptosis and downregulated MYC protein in MCL cells derived from patients who were clinically resistant to ibrutinib. In conclusion, MYC activity underlies intrinsic resistance to ibrutinib in MCL. As a client protein of HSP90, MYC can be inhibited via PU-H71 to overcome primary ibrutinib resistance.


Infected cephalohematoma associated with sepsis and skull osteomyelitis: report of one case.
Osteomyelitis is rarely complicated by an infected cephalohematoma. We report a case of an infected cephalohematoma associated with Escherichia coli sepsis and osteomyelitis of the skull. This 37-day-old boy had E. coli sepsis, which had a poor response to antibiotic treatment. An infected cephalohematoma was found when he was 43 days old. Cranial computed tomography (CT) scanning showed cephalohematoma with abscess formation and underlying bony destruction over the left parietal region. Antibiotics alone could not eradicate the infection. Extensive incision, drainage, and debridement of the necrotic bone resulted in prompt improvement. Three weeks of ceftizoxime administered intravenously, followed by 3 weeks of cefixime given orally completed the treatment course.


Congenital myopathy-causing tropomyosin mutations induce thin filament dysfunction via distinct physiological mechanisms.
In humans, congenital myopathy-linked tropomyosin mutations lead to skeletal muscle dysfunction, but the cellular and molecular mechanisms underlying such dysfunction remain obscure. Recent studies have suggested a unifying mechanism by which tropomyosin mutations partially inhibit thin filament activation and prevent proper formation and cycling of myosin cross-bridges, inducing force deficits at the fiber and whole-muscle levels. Here, we aimed to verify this mechanism using single membrane-permeabilized fibers from patients with three tropomyosin mutations (TPM2-null, TPM3-R167H and TPM2-E181K) and measuring a broad range of parameters. Interestingly, we identified two divergent, mutation-specific pathophysiological mechanisms. (i) The TPM2-null and TPM3-R167H mutations both decreased cooperative thin filament activation in combination with reductions in the myosin cross-bridge number and force production. The TPM3-R167H mutation also induced a concomitant reduction in thin filament length. (ii) In contrast, the TPM2-E181K mutation increased thin filament activation, cross-bridge binding and force generation. In the former mechanism, modulating thin filament activation by administering troponin activators (CK-1909178 and EMD 57033) to single membrane-permeabilized fibers carrying tropomyosin mutations rescued the thin filament activation defect associated with the pathophysiology. Therefore, administration of troponin activators may constitute a promising therapeutic approach in the future.


Short planar gradient coils for MR microscopy using concentric return paths.
The aim of this work is to design a set of gradient coils with an optimal geometry for magnetic resonance microscopy studies. Designs for a three-axis gradient coil system particularly suited for studies with small radiofrequency coils are presented. The novel geometry involves a planar section with concentric return paths to keep the coil short. Reduction of the external field has been attempted by varying the positions of the return paths using a simulated annealing algorithm. A biplanar version of x- and z-directed prototype gradients was built and tested. A 2D-MR image of a grid phantom has been obtained on a 7-T MR instrument to demonstrate the theory. A three-axis set used as a surface gradient set has also been built and used to obtain high-resolution MR images.


H-NOX-mediated nitric oxide sensing modulates symbiotic colonization by Vibrio fischeri.
The bioluminescent bacterium Vibrio fischeri initiates a specific, persistent symbiosis in the light organ of the squid Euprymna scolopes. During the early stages of colonization, V. fischeri is exposed to host-derived nitric oxide (NO). Although NO can be both an antimicrobial component of innate immunity and a key signaling molecule in eukaryotes, potential roles in beneficial host-microbe associations have not been described. V. fischeri hnoX encodes a heme NO/oxygen-binding (H-NOX) protein, a member of a family of bacterial NO- and/or O(2)-binding proteins of unknown function. We hypothesized that H-NOX acts as a NO sensor that is involved in regulating symbiosis-related genes early in colonization. Whole-genome expression studies identified 20 genes that were repressed in an NO- and H-NOX-dependent fashion. Ten of these, including hemin-utilization genes, have a promoter with a putative ferric-uptake regulator (Fur) binding site. As predicted, in the presence of NO, wild-type V. fischeri grew more slowly on hemin than a hnoX deletion mutant. Host-colonization studies showed that the hnoX mutant was also 10-fold more efficient in initially colonizing the squid host than the wild type; similarly, in mixed inoculations, it outcompeted the wild-type strain by an average of 16-fold after 24 h. However, the presence of excess hemin or iron reversed this dominance. The advantage of the mutant in colonizing the iron-limited light-organ tissues is caused, at least in part, by its greater ability to acquire host-derived hemin. Our data suggest that V. fischeri normally senses a host-generated NO signal through H-NOX(Vf) and modulates the expression of its iron uptake capacity during the early stages of the light-organ symbiosis.


Molecular interface of S100A8 with cytochrome b558 and NADPH oxidase activation.
S100A8 and S100A9 are two calcium binding Myeloid Related Proteins, and important mediators of inflammatory diseases. They were recently introduced as partners for phagocyte NADPH oxidase regulation. However, the precise mechanism of their interaction remains elusive. We had for aim (i) to evaluate the impact of S100 proteins on NADPH oxidase activity; (ii) to characterize molecular interaction of either S100A8, S100A9, or S100A8/S100A9 heterocomplex with cytochrome b(558); and (iii) to determine the S100A8 consensus site involved in cytochrome b(558)/S100 interface. Recombinant full length or S100A9-A8 truncated chimera proteins and ExoS-S100 fusion proteins were expressed in E. coli and in P. aeruginosa respectively. Our results showed that S100A8 is the functional partner for NADPH oxidase activation contrary to S100A9, however, the loading with calcium and a combination with phosphorylated S100A9 are essential in vivo. Endogenous S100A9 and S100A8 colocalize in differentiated and PMA stimulated PLB985 cells, with Nox2/gp91(phox) and p22(phox). Recombinant S100A8, loaded with calcium and fused with the first 129 or 54 N-terminal amino acid residues of the P. aeruginosa ExoS toxin, induced a similar oxidase activation in vitro, to the one observed with S100A8 in the presence of S100A9 in vivo. This suggests that S100A8 is the essential component of the S100A9/S100A8 heterocomplex for oxidase activation. In this context, recombinant full-length rS100A9-A8 and rS100A9-A8 truncated 90 chimera proteins as opposed to rS100A9-A8 truncated 86 and rS100A9-A8 truncated 57 chimeras, activate the NADPH oxidase function of purified cytochrome b(558) suggesting that the C-terminal region of S100A8 is directly involved in the molecular interface with the hemoprotein. The data point to four strategic (87)HEES(90) amino acid residues of the S100A8 C-terminal sequence that are involved directly in the molecular interaction with cytochrome b(558) and then in the phagocyte NADPH oxidase activation.


Visual impairment and dysfunction in combat-injured servicemembers with traumatic brain injury.
The purpose of this study was to determine the frequencies of visual impairment and dysfunction among combat-injured Polytrauma Rehabilitation Center (PRC) inpatient and Polytrauma Network Site (PNS) outpatient military personnel with traumatic brain injury (TBI). A retrospective analysis of data from vision screenings of 68 PRC-inpatients with moderate to severe levels of TBI and 124 PNS-outpatients with mild TBI at the VA Palo Alto Health Care System was conducted. Eighty-four percent of PRC-inpatients and 90% of PNS-outpatients had TBIs associated with a blast event. The majority of patients in both the PRC and PNS populations had visual acuities of 20/60 or better (77.8% PRC, 98.4% PNS). Visual dysfunctions (e.g., convergence, accommodative, and oculomotor dysfunction) were common in both PRC and PNS populations. In the PRC-inpatient population, acuity loss of 20/100 to no light perception (13%) and visual field defects (32.3%) were found. In the PNS-outpatient population, acuity loss of 20/100 to no light perception (1.6%) and visual field defects (3.2%) were infrequently found. In both the PRC and PNS populations, visual field defects were more often associated with blast than non-blast events. Blast events were the most frequent mechanism of injury associated with TBI in combat-injured servicemembers. The vision findings suggest that combat troops exposed to blast with a resulting mild TBI are at risk for visual dysfunction, and combat troops with polytrauma injuries are at risk for visual dysfunction and/or visual impairment. The visual consequences of such injuries necessitate further study and support the need for appropriate evaluation and treatment in all severities of TBI.


Effects of administration of subtoxic doses of acetaminophen on liver and blood levels of insulin-like growth factor-1 in rats.
Acetaminophen (APAP) is widely used in the treatment of pain. Toxic doses of APAP cause acute liver failure, but therapeutic doses are believed to be safe. The purpose of this study is to investigate the effects of administration of subtoxic doses of APAP on liver and blood levels of insulin-like growth factor-1 (IGF-1) in rats. Low dose (100 mg/kg) and high dose (250 mg/kg) of APAP were intraperitoneally injected into Wistar albino rats. Following administration of therapeutic doses of APAP, there were no significant changes in serum transaminases and liver glutathione levels. Both doses of APAP induced a decrease in liver and blood levels of IGF-1 when compared with the controls. There was no significant difference in liver IGF-1 levels between the high-dose and low-dose APAP groups; however, there was a significant difference in blood IGF-1 levels between both the groups. The histological examination showed that low dose of APAP induced mild degree of structural change, while high dose of APAP induced severe structural damage. In conclusion, these results suggest that blood IGF-1 levels may have a value in predicting hepatic damage resulting from therapeutic doses of APAP.


A pilot, randomized, controlled clinical trial of lucinactant, a peptide-containing synthetic surfactant, in infants with acute hypoxemic respiratory failure.
Inhibition of surfactant function and abnormal surfactant synthesis lead to surfactant dysfunction in children with acute hypoxemic respiratory failure. We evaluated whether intratracheal lucinactant, a synthetic, peptide-containing surfactant, was safe and well-tolerated in infants with acute hypoxemic respiratory failure, and assessed its effects on clinical outcomes. Infants ≤ 2 yrs of age with acute hypoxemic respiratory failure were enrolled in a phase II, double-blind, multinational, placebo-controlled randomized trial across 36 pediatric intensive care units. Infants requiring mechanical ventilation with persistent hypoxemia meeting acute lung injury criteria were randomized to receive intratracheal lucinactant (175 mg/kg) or air placebo. One retreatment was allowed 12-24 hrs after initial dosing if hypoxemia persisted. Peri-dosing tolerability of intratracheal lucinactant and adverse experiences were assessed. Mechanical ventilation duration was analyzed using analysis of variance. The Cochran-Mantel-Haenszel test was used for categorical variables.We enrolled 165 infants (84 lucinactant; 81 placebo) with acute hypoxemic respiratory failure. There were no significant differences in baseline subject characteristics, with the exception of a lower positive end-expiratory pressure and higher tidal volume in placebo subjects. The incidence of transient peri-dosing bradycardia and desaturation was significantly higher in the lucinactant treatment group. There were no statistical differences between groups for other adverse events or mortality. Oxygenation improved in infants randomized to receive lucinactant as indicated by fewer second treatments (67% lucinactant vs. 81% placebo, p = .02) and a trend in improvement in partial pressure of oxygen in arterial blood to fraction of inspired oxygen from eligibility to 48 hrs after dose (p = .06). There was no significant reduction in duration of mechanical ventilation with lucinactant (geometric least square means: 4.0 days lucinactant vs. 4.5 days placebo; p = .254). In a subset of infants (n = 22), the duration of mechanical ventilation in children with acute lung injury (partial pressure of oxygen in arterial blood to fraction of inspired oxygen >200) was significantly shorter with lucinactant (least square means: 2.4 days lucinactant vs. 4.3 days placebo; p = .006). In mechanically ventilated infants with acute hypoxemic respiratory failure, treatment with intratracheal lucinactant appeared to be generally safe. An improvement in oxygenation and a significantly reduced requirement for retreatment suggests that lucinactant might improve lung function in infants with acute hypoxemic respiratory failure.


Gastrointestinal Mucormycosis: A Clinical Review.
Mucormycosis is a devastating fungal infection that is usually seen in immunocompromised hosts. It is caused by fungi of the subphylum Mucoromycotina, order Mucorales, with most cases caused by Mucor, Rhizopus, or Rhizomucor species. It can involve any organ system and can disseminate in severe cases. Lately, there has been an increased number of reports for mucormycosis infection in immunocompetent patients. Gastrointestinal system involvement is rare compared to other organ systems but has been increasingly reported in the literature. Mucormycosis can affect any part of the gastrointestinal tract and lead to different presentations depending on the area of involvement. Due to the paucity of the condition, there has been no specific guidelines on how to treat gastrointestinal mucormycosis. In this review, we discuss the risk factors of gastrointestinal mucormycosis, clinical presentation, approach to diagnosis, and most recent treatment modalities for gastrointestinal mucormycosis.


Kinetics of cellular responses to intraperitoneal Brugia pahangi infections in normal and immunodeficient mice.
Filarial infections evoke exuberant inflammatory responses in the peritoneal cavities of immunocompetent mice. Clearance of infection appears to be dependent on complex interactions between B1 and B2 B lymphocytes, T cells, eosinophils, macrophages, and the products of these cells. In an earlier communication, we described the course of infection in normal immunocompetent mice. In this study, we utilize mice with well-characterized mutations that disable one or more effector components of adaptive immunity in order to determine their roles in host protection. We characterize peritoneal exudate cells by flow cytometry and determine the kinetics of accumulation of each of the different cell types following infection with Brugia pahangi. We find that (i) four-color flow-cytometric analysis of peritoneal exudate cells using anti-CD3, -CD11b, -CD19, and -Gr1 can distinguish up to six different populations of cells; (ii) an initial influx of neutrophils occurs within 24 h of infection, independent of the adaptive immune status of mice, and these cells disappear by day 3; (iii) an early influx of eosinophils is seen at the site of infection in all strains studied, but a larger, second wave occurs only in mice with T cells; (iv) the presence of T cells and eosinophils is important in causing an increase in macrophage size during the course of infection; and (v) most unexpectedly, T-cell recruitment appears to be optimal only if B cells are present, since JHD mice recruit significantly fewer T cells to the site of infection.


Levodopa-induced dyskinesia: a pathological form of striatal synaptic plasticity?
The pathogenesis of the alterations in motor response that complicate levodopa therapy of Parkinson's disease remains obscure. Several experimental and clinical observations strongly suggest that changes in striatal activity may be crucial for this physiopathological condition. Accordingly, it has been postulated that dyskinesia might be due to abnormal activity of the corticostriatal pathway. Here, we review the physiological and pharmacological mechanisms underlying glutamatergic regulation of striatal neurons by the corticostriatal projection. In particular, we discuss the role of both (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors in the control of the short- and long-term efficacy of corticostriatal transmission. Indeed, repetitive cortical activation can generate either long-term depression or long-term potentiation (LTP) at corticostriatal synapses depending on the subtype of glutamate receptor activated during the induction phase of these forms of synaptic plasticity. Dopamine plays an important function in the regulation of both forms of synaptic plasticity. Dopamine denervation abolishes the physiological corticostriatal plasticity by producing biochemical and morphological changes within the striatum. We have recently observed a 'pathological' form of LTP at the corticostriatal synapse during energy deprivation. We speculate that this 'pathological' LTP, depending on the activation of NMDA glutamate receptors located on spiny striatal neurons, might play a role in the generation of levodopa-induced dyskinesia.


Giant vacuoles in the lining endothelium of the human Schlemm's canal after topical timolol maleate.
The outflow system was studied by light microscopy in nine human eyes that were treated with topical timolol maleate (0.5%) prior to enucleation for malignant melanoma of the choroid. The frequency of "giant vacuoles" in the lining endothelium of Schlemm's canal and the diameter of these structures was the same in a control group of eyes as in the timolol-treated series. There was no qualitative difference between the architecture of the meshwork in the control and treated groups. These morphologic findings suggested that timolol had no direct action on the outflow apparatus and did not reflect the intraocular pressure (IOP) lowering effect of the drug. The effects of anesthesia, surgical manipulations, and fixation by immersion may have masked any subtle drug effects.


Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases.
Activation of androgen receptor (AR) may have a role in the development of castration-resistant prostate cancer. Two intracellular tyrosine kinases, Ack1 (activated cdc42-associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals. However, the upstream signals that activate these kinases and lead to AR activation are incompletely characterized. In this study, we investigated AR phosphorylation in response to non-androgen ligand stimulation using phospho-specific antibodies. Treatment of LNCaP and LAPC-4 cells with epidermal growth factor (EGF), heregulin, Gas6 (ligand binding to the Mer receptor tyrosine kinase and activating Ack1 downstream), interleukin (IL)-6 or bombesin stimulated cell proliferation in the absence of androgen. Treatment of LNCaP and LAPC-4 cells with EGF, heregulin or Gas6 induced AR phosphorylation at Tyr-267, whereas IL-6 or bombesin treatment did not. AR phosphorylation at Tyr-534 was induced by treatment with EGF, IL-6 or bombesin, but not by heregulin or Gas6. Small interfering RNA-mediated knockdown of Ack1 or Src showed that Ack1 mediates heregulin- and Gas6-induced AR Tyr-267 phosphorylation, whereas Src mediates Tyr-534 phosphorylation induced by EGF, IL-6 and bombesin. Dasatinib, a Src inhibitor, blocked EGF-induced Tyr-534 phosphorylation. In addition, we showed that dasatinib also inhibited Ack1 kinase. Dasatinib inhibited heregulin-induced Ack1 kinase activity and AR Tyr-267 phosphorylation. In addition, dasatinib inhibited heregulin-induced AR-dependent reporter activity. Dasatinib also inhibited heregulin-induced expression of endogenous AR target genes. Dasatinib inhibited Ack1-dependent colony formation and prostate xenograft tumor growth in castrated mice. Interestingly, Ack1 or Src knockdown or dasatinib did not inhibit EGF-induced AR Tyr-267 phosphorylation or EGF-stimulated AR activity, suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr-267. These data suggest that specific tyrosine kinases phosphorylate AR at distinct sites and that dasatinib may exert antitumor activity in prostate cancer through inhibition of Ack1.


Malignant melanoma arising in a choroidal magnacellular nevus (melanocytoma).
A case is presented of a 55-year-old Caucasian male whose right eye was enucleated for a mixed spindle-A and spindle-B malignant melanoma in 1967. The ophthalmoscopic picture, fluorescein angiography, and overlying peculiar orange pigmentation were suggestive of a malignant lesion. Study of serial sections of the entire lesion made possible the histologic reconstruction of the lesion, clinicopathologic correlation of the yellow-orange pigment, and the location of the nevus and mixed spindle-cell melanoma components.