Effects of Early Placement of Transjugular Portosystemic Shunts in Patients With High-Risk Acute Variceal Bleeding: a Meta-analysis of Individual Patient Data.
Compared with drugs plus endoscopy, placement of transjugular portosystemic shunt within 72 hours of admission to the hospital (early or preventive transjugular intrahepatic portosystemic shunt [TIPS], also called preemptive TIPS) increases the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survive for 1 year. However, the benefit of preemptive TIPS is less clear for patients with a Child-Pugh score of B and active bleeding (CP-B+AB). We performed an individual data meta-analysis to assess the efficacy of preemptive TIPS in these patients and identify factors associated with reduced survival of patients receiving preemptive TIPS. We searched publication databases for randomized controlled trials and observational studies comparing the effects of preemptive TIPS versus endoscopy plus nonselective beta-blockers in the specific population of high-risk patients with cirrhosis and acute variceal bleeding (CP-B+AB or Child-Pugh C, below 14 points), through December 31, 2019. We performed a meta-analysis of data from 7 studies (3 randomized controlled trials and 4 observational studies), comprising 1327 patients (310 received preemptive TIPS and 1017 received drugs plus endoscopy). We built adjusted models to evaluate risk using propensity score for baseline covariates. Multivariate Cox regression models were used to assess the factors associated with survival time. The primary endpoint was effects of preemptive TIPS versus drugs plus endoscopy on 1-year survival in the overall population as well as CP-B+AB and Child-Pugh C patients. Overall, preemptive TIPS significantly increased the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survived for 1 year, compared with drugs plus endoscopy (hazard ratio [HR] 0.443; 95% CI 0.323-0.607; P < .001). This effect was observed in CP-B+AB patients (HR 0.524; 95% CI 0.307-0.896; P = .018) and in patients with Child-Pugh C scores below 14 points (HR 0.374; 95% CI 0.253-0.553; P < .001). Preemptive TIPS significantly improved control of bleeding and ascites without increasing risk of hepatic encephalopathy in Child-Pugh C and CP-B+AB patients, compared with drugs plus endoscopy. Cox analysis of patients who received preemptive TIPS showed that patients could be classified into 3 categories for risk of death, based on age, serum level of creatinine, and Child-Pugh score. In each of these risk categories, preemptive TIPS increased the proportion of patients who survived for 1 year, compared with drugs plus endoscopy. In a meta-analysis of data from 1327 patients with cirrhosis, acute variceal bleeding, and Child-Pugh score between 10 and 13 points or CP-B+AB, preemptive TIPS increased the proportion who survived for 1 year, in both subgroups separately, compared with drugs plus endoscopy.


Identifying neonatal intensive care (NICU) admissions using administrative claims data.
To define a method for identifying neonatal intensive care unit (NICU) admissions using administrative claims data. This was a retrospective cohort study using claims from Optum's de-identified Clinformatics ® Data Mart Database (CDM) from 2016 -2020. We developed a definition to identify NICU admissions using a list of codes from the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM), Current Procedural Terminology (CPT), and revenue codes frequently associated with NICU admissions. We compared agreement between codes using Kappa statistics and calculated positive predictive values (PPV) and 95% confidence intervals (CI). On average, revenue codes (3.3%) alone identified more NICU hospitalizations compared to CPT codes alone (1.5%), whereas the use of CPT and revenue (8.9%) and CPT or revenue codes (13.7%) captured the most NICU hospitalizations, which aligns with rates of preterm birth. Gestational age alone (4.2%) and birthweight codes alone (2.0%) identified the least number of potential NICU hospitalizations. Setting CPT codes as the standard and revenue codes as the "test,", revenue codes resulted in identifying 86% of NICU admissions (sensitivity) and 97% of non-NICU admissions (specificity). Using administrative data, we developed a robust definition for identifying neonatal admissions. The identified definition of NICU codes is easily adaptable, repeatable, and flexible for use in other datasets.


[Intensity of basal metabolism and ratio of oxidized energy substrates in children with craniocerebral trauma].
Twenty-five children aged 2-14 years with isolated and combined craniocerebral injury were examined. Some of them underwent urgent neurosurgical interventions. Mechanical injury and intervention were regarded as aggressive factors. The basic methods were indirect calorimetry and intravenous prolonged glucose and fat tolerance test. The results indicate that in general, the intensity of basal metabolism and the ratio of oxidized energy substrates in children with craniocerebral injury correspond to the course of standard postaggressive reaction. Time course of changes in RQ, structure and share of basic energy substrates in the total energy produced confirm a general biological regularity of postaggressive metabolism: fat is oxidized predominantly during the initial period, while on day 5 inversion of fat and glucose oxidation values is observed.


Cloning and DNA sequence analysis of the wild-type and mutant cyclic AMP receptor protein genes from Salmonella typhimurium.
The crp gene from Salmonella typhimurium, as well as two mutant adenylate cyclase regulation genes designated crpacr-3 and crpacr-4, were cloned into the EcoRI site of plasmid pUC8. Initially cloned on 5.6-kilobase fragments isolated from EcoRI digests of chromosomal DNA, these genes were further subcloned into the BamHI-EcoRI site of plasmid pBR322. When tested, Escherichia coli crp deletion strains harboring the clones regained their ability to pleiotropically ferment catabolite-repressible sugars. Also, the crpacr-containing strains displayed sensitivity to exogenous cyclic AMP (cAMP) when grown on eosin-methylene blue medium with xylose as the carbon source. The proteins encoded by the S. typhimurium wild-type and mutant crp genes were found to have similar molecular weights when compared with the wild-type cAMP receptor protein (CRP) from E. coli. DNA sequence analysis of the wild-type crp gene showed only a three-nucleotide difference from the E. coli sequence, suggesting little divergence of the crp gene between these organisms. The crpacr sequences, however, each contained single nucleotide changes resulting in amino acid substitutions at position 130 of the CRP. Based on the site at which these substitutions occur, the crpacr mutations are believed to affect CRP-cAMP interactions.


Implementation of Liver Cancer Education Among Health Care Providers and Community Coalitions in the Cherokee Nation.
The Cherokee Nation Comprehensive Cancer Control Program collaborated with the Cherokee Nation Hepatitis C Virus (HCV) Elimination Program within Cherokee Nation's Health Services to plan and implement activities to increase knowledge and awareness of liver cancer prevention among health care providers and the Cherokee Nation community. From August 2017 to April 2018, the 2 programs implemented liver cancer prevention interventions that focused on education of health care providers and community members. We used descriptive statistics to analyze data collected from a brief, retrospective pre-post survey for each intervention. We assessed overall awareness and knowledge of liver cancer and ability and intention to address it on a scale of 1 to 5. Project Extension for Community Healthcare Outcomes didactic sessions resulted in a 1.1-point improvement, provider education workshops resulted in a 1.4-point improvement, and presentations at community coalition meetings resulted in a 1.7-point improvement. Our study shows that HCV interventions can be used by public health and medical professionals interested in controlling HCV and related diseases such as liver cancer.


Persimmon leaf extract and astragalin inhibit development of dermatitis and IgE elevation in NC/Nga mice.
We previously found that persimmon leaf extract contains antiallergic substances that inhibit histamine release by human basophilic cell line KU812 in response to cross-linkage of FcepsilonRI. The purpose of this study was to identify substances in the persimmon leaf extract that are responsible for the effect and to examine their in vivo effects on the allergic mouse model. HPLC analysis of persimmon leaf extract was done to measure its content. Inhibitory activity of persimmon leaf extract or its major constituent of flavonoids (astragalin) on the histamine release by KU812 cells was examined. To investigate the effects of these substances in vivo, models of passive cutaneous anaphylaxis and atopic dermatitis mice (NC/Nga) were used. Persimmon leaf extract or astragalin inhibited histamine release from KU812 in response to cross-linkage of FcepsilonRI. Oral intake of both substances dose dependently inhibited passive cutaneous reactions. Moreover, oral administration of these substances to NC/Nga atopic dermatitis-model mice led to a striking suppression of the development of dermatitis, scratching behavior, and serum IgE elevation. Histologic analyses revealed that infiltration of inflammatory cells, especially degranulated mast cells, thickening of the epidermis, and prominent hyperkeratosis, were significantly reduced. Immunologic studies showed that the capacity of spleen T cells to produce both IL-4 and IL-13, but not IFN-gamma, was downregulated by means of oral intake of these substances. This study demonstrates a novel activity of astragalin and the dramatic effect of persimmon leaf extract and astragalin on atopic dermatitis-model mice.


Skull biomechanics: The energy absorbability of the human skull frontal bone during fracture under quasi-static loading.
Four human skulls were studied in order to determine the energy absorbed corresponding to a fracture due to quasi-static loading on the frontal bone. Using a dedicated experimental set up, the force-deformation characteristics of the specimens were recorded, calculating energy absorption. Mean values of 1975 +/- 703 N, 4.17 +/- 0.81 mm and 3.95 +/- 1.18 J were found for the peak force, maximum deformation and absorbed energy to fracture, respectively. Linear fractures were always seen in the frontal bone, with a similar pattern in three of the four skulls. These results can be used to develop bench-mark skull models to validate analytic models. (Journal of Applied Biomaterials & Biomechanics 2003; 1: 194-9).


[Isolated malignant lymphoma of the rectum(author's transl)].
A case of primary and isolated, diffuse reticulosarcoma of the rectum is reported. There has been a history of blood diarrhea for 12 years in a 60 years old man, with no change in his general condition. Treatment with cyclophosphamide was started and maintained for two and a half years with complete local regression, and very good clinical results.


Fluoride Adsorption on Goethite in Relation to Different Types of Surface Sites.
Metal (hydr)oxides have different types of surface groups. Fluoride ions have been used as a probe to assess the number of surface sites. We have studied the F(-) adsorption on goethite by measuring the F(-) and H(+) interaction and F(-) adsorption isotherms. Fluoride ions exchange against singly coordinated surface hydroxyls at low F(-) concentrations. At higher concentrations also the doubly coordinated OH groups are involved. The replacement of a surface OH(-) by F(-) suggests that all F charge (-1) is located at the surface in contrast to oxyanions which have a charge distribution in the interface due to the binding structure in which the anion only partially coordinates with the surface. Analysis of our F(-) data with the CD-MUSIC approach shows that the formation of the fluoride surface complex is accompanied by a redistribution of charge. This is supposed to be due to a net switch in the H bonding as a result of the change of the type of surface complex from donating (FeOH, FeOH(2)) to proton accepting (FeF). The modeled redistribution of charge is approximately equivalent with the change of a donating H bond into an accepting H bond. At high F(-) concentrations precipitation of F(-), as for instance FeF(3)(s), may occur. The rate of formation is catalyzed by the presence of high electrolyte concentrations. Copyright 2000 Academic Press.


Comparison of cost, effectiveness, and safety of injectable anticoagulants used for thromboprophylaxis after orthopedic surgery.
The cost, effectiveness, and safety of injectable anticoagulants used for thromboprophylaxis after orthopedic surgery were compared. This retrospective, observational, cross-sectional, cohort analysis of inpatient billing data was conducted from the institutional perspective. Patients who received dalteparin, enoxaparin, fondaparinux, or unfractionated heparin after orthopedic surgery were included in the analysis. The primary outcome measure was the mean aggregated cost per patient treated with each injectable anticoagulant. Secondary outcomes included the percentages of patients in each treatment group who had a venous thromboembolism (VTE) or major bleeding episode. Mean total adjusted costs were significantly lower for fondaparinux ($18,019) compared with other anticoagulants, with unfractionated heparin being the most costly ($20,835). Relative adjusted cost differences were 1.4% (p = 0.0127), 1.8% ( p = 0.0105), and 14.6% (p < 0.0001) higher for enoxaparin, dalteparin, and unfractionated heparin, respectively, compared with fondaparinux. Significantly fewer fondaparinux-treated patients had a VTE event compared with the other treatment groups. The use of dalteparin was associated with fewer major bleeding events, and no significant differences in the rate of major bleeding events were observed among groups treated with fondaparinux, enoxaparin, or unfractionated heparin. A retrospective analysis of inpatient billing data showed that, among orthopedic surgery patients, fondaparinux was associated with lower institutional cost and a lower frequency of VTE than were dalteparin, enoxaparin, and unfractionated heparin. Dalteparin was associated with a lower rate of major bleeding events than was fondaparinux, but there were no significant differences in such events among fondaparinux, enoxaparin, and unfractionated heparin.


Comparison of three immunodiagnostic assays for antemortem detection of Mycobacterium bovis stimulation in domestic cats.
Mycobacterium bovis causes disease in numerous mammalian species including humans, thus making research, surveillance, and control important in the eradication of tuberculosis. Domestic cats are susceptible to multiple mycobacterial species including Mycobacterium bovis; however, their role in the epidemiology of bovine tuberculosis is not fully documented. The current study was an evaluation of the immune response in specific pathogen-free (SPF) cats stimulated with sensitinogen, a heat-killed M. bovis product, using the rapid test, multiple antigen print immunoassay (MAPIA), and bovine-purified protein derivative (bPPD) single skin test. Six cats were inoculated with sensitinogen subcutaneously on days 0 and 24; 2 noninoculated cats and 49 non-SPF cats were controls. Serial serum samples were collected during 135 days and assayed for M. bovis antibodies by rapid test and MAPIA. On day 123, bPPD skin test was performed and read at 48 and 72 hr. The bPPD test at 72 hr had a mean skin thickness of 0.3 mm for stimulated cats and 0.1 mm for controls. Rapid test identified 4 of 6 stimulated cats after bPPD injection. The MAPIA detected antibody against MPB83, 16/83, 16 kDa, and M. bovis culture filtrate (MBCF) antigens. All assays differentiated between stimulated and control cats; however, 7 of 49 non-SPF control cats had a reaction for either antigen MBCF or 16/83. These preliminary studies show potential for antemortem detection of M. bovis among domestic cats. Additional studies to better characterize virulent M. bovis infection in cats would be of value.


Lipoprotein lipase activity in the adipose tissue of rats adapted to controlled feeding schedules.
1. The relationships between nutritional state, lipoprotein lipase activity in epididymal fat-pads, and the concentrations of glucose, insulin and unesterified fatty acids in the plasma were studied in rats that had been adapted for 3 weeks to one of two controlled feeding schedules. In one of these, rats had access to food for 14h during each 24h period, and in the other, they had access to food for 14h during each 48h period. Groups of animals were killed at different times during the 14h when they had access to food and during the following period when they were deprived of food. 2. Low lipoprotein lipase activity, low concentrations of plasma glucose and insulin and high concentrations of plasma unesterified fatty acids were found in rats deprived of food for 34h. Feeding resulted in increases in lipoprotein lipase activity and in the concentrations of glucose and insulin in the plasma. Enzyme activity continued to increase during the first 6-9h of the feeding period. 3. After adapted rats had been deprived of food for 12-16h there was a marked and unexpected increase in lipoprotein lipase activity; this occurred even when the rats were kept in an isolated environment. 4. The findings suggest that factors other than the absolute concentrations of insulin and glucose in the blood can exert a considerable influence on lipoprotein lipase activity in the epididymal fat-pad of a rat.


The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells.
Vitamin D is a potent immune system regulator. The active form of vitamin D (1,25(OH)(2)D(3)) suppresses the development of animal models of human autoimmune diseases. 1,25(OH)(2)D(3) decreased the proliferation of all T helper (h) cells and decreased the production of IFN-gamma, IL-2, and IL-5. In Th2 cells 1,25(OH)(2)D(3) increased the production of IL-4. Quiescent CD4+ T cells express vitamin D receptors but only at a low level, which increased five-fold following activation. 1,25(OH)(2)D(3) treatment of Th0 cells, but not Th1 or Th2 cells, induced the expression of the transcription factor GATA-3. Microarray technology identified over 102 targets of 1,25(OH)(2)D(3) in CD4+ T cells. Of the 102 genes, 57 genes were down-regulated and 45 were up-regulated by 1,25(OH)(2)D(3) treatment of the CD4+ T cells. Two of the identified genes are regulators of NFkB. Other genes of interest included the IL-2Rbeta gene and IgE binding factor. Th2 and Th0 cells produced more IgE binding factor after treatment with 1,25(OH)(2)D(3) while Th1 cell IgE binding factor expression was unaffected by 1,25(OH)(2)D(3) addition. It is unclear why some of the genes identified are expressed in CD4+ T cells and furthermore why 1,25(OH)(2)D(3) regulates the expression of these genes. Clearly CD4+ T cells can be direct targets of vitamin D. The targets of vitamin D in CD4+ T cells depend on the state of activation and differentiation status of the cells.


Prevalence of antibody to hepatitis C in patients with liver disease.
We studied the seroprevalence of antibody to hepatitis C virus (HCV) in patients with liver disease using the Abbott HCV EIA. Twenty-four patients with acute sporadic nonA nonB hepatitis, 19 patients with chronic hepatitis, 28 patients with cirrhosis and 47 patients with hepatocellular carcinoma (HCC) were assayed. The seroprevalence was 8.3% (2/24) in acute hepatitis; 10.5% (2/19) in chronic hepatitis; 3.6% (1/28) in cirrhosis and 14.9% (7/47) in hepatocellular carcinoma. The seroprevalence rates were lower in all categories of liver disease compared to figures reported in developed countries. Possible reasons included a delayed or missed seroconversion in the acute hepatitis group. Other etiologies like hepatitis B and alcohol may play a more important role in chronic liver disease. On the other hand, the seroprevalence locally may actually be low. Sporadic, non-blood transfusion appears to be a common method of acquiring the infection.


Salicylic acid: an old dog, new tricks, and staphylococcal disease.
Aspirin has been shown to cause a reduction in the virulence of Staphylococcus aureus-associated endocarditis. A new study reveals that salicylic acid, the major metabolite of aspirin, acts at the level of transcription to downregulate the production of fibrinogen, fibronectin, and alpha-hemolysin - virulence factors necessary for bacterial replication in host tissues and, now, potential therapeutic targets.


Adherence: a concept analysis.
This paper is a report of an analysis of the concept of adherence. The transition in terminology from compliance to adherence, and more recently to concordance, requires re-clarification of 'adherence' as a concept in nursing practice. Differences exist in the use of the term adherence and how or if it differs from compliance or concordance. Using the Medical Subject Headings terms adherence, non-adherence and treatment refusal, the Cumulative Index to Nursing and Allied Health Literature, Medline, PsychINFO and Cochrane library databases were searched for publications between 1970 and 2007. Method. The evolutionary analytic method was used to identify and explore transitions in the concept of adherence over time and across healthcare disciplines. A representative sample of papers was identified from the disciplines of nursing, medicine, psychology and pharmacy. We identified 114 papers: 27 from nursing, 39 from psychology, 33 from general medicine and 15 from pharmacology sources. The final sample included eight from pharmacy and 15 from mental health, medicine and nursing. We found no distinct differentiation between adherence and compliance. The surrogate terms serving as manifestations of adherence are concordance, agreement, cooperation and partnership. The most common definition found was as follows: 'Adherence can be defined as the extent to which patients follow the instructions they are given for prescribed treatments'. No definition of adherence exists that reflects a patient-centred approach, the dynamic nature of adherence behaviour and the power imbalance implied by these terms. This concept analysis of adherence is a preliminary step towards broadening nurses' appreciation of the complexity of patient adherence behaviour.


RNA interference in biology and medicine.
First discovered in plants the nematode Caenorhabditis elegans, the production of small interfering RNAs (siRNAs) that bind to and induce the degradation of specific endogenous mRNAs is now recognized as a mechanism that is widely employed by eukaryotic cells to inhibit protein production at a post-transcriptional level. The endogenous siRNAs are typically 19- to 23-base double-stranded RNA oligonucleotides, produced from much larger RNAs that upon binding to target mRNAs recruit RNases to a protein complex that degrades the targeted mRNA. Methods for expressing siRNAs in cells in culture and in vivo using viral vectors, and for transfecting cells with synthetic siRNAs, have been developed and are being used to establish the functions of specific proteins in various cell types and organisms. RNA interference methods provide several major advantages over prior methods (antisense DNA or antibody-based techniques) for suppressing gene expression. Recent preclinical studies suggest that RNA interference technology holds promise for the treatment of various diseases. Pharmacologists have long dreamed of the ability to selectively antagonize or eliminate the function of individual proteins--RNAi technology may eventually make that dream a reality.


Is progressive multifocal leukoencephalopathy a chronic disease because of defective interfering particles or temperature-sensitive mutants of JC virus?
JC virus was examined for temperature sensitivity and for evidence of defective interfering particles as a means of explaining the slow chronic nature of progressive multifocal leukoencephalopathy (PML). JC virus direct from the brain tissue of seven persons with PML was not temperature sensitive as indicated by in vitro assay at 37 and 39 degrees C. In fact, more cells contained viral antigen at 39 than at 37 degrees C. The amount of infectious virus also was increased at 39 degrees C. Virions isolated directly from diseased brain tissue had a higher buoyant density than did virus from the same PML patient passaged in culture and containing genomic deletions. In contrast to DNA from culture-passed virus, DNA extracted from virions direct from brain tissue was homogeneous in length. In 13 separate cases examined, the viral DNA direct from the brain was homogeneous although variations in length were noted among DNAs from different cases. Restriction enzyme cleavage patterns identified all as JC virus DNA. It was concluded that neither temperature sensitivity nor DI particles can be used to explain the slow, progressive nature of PML.


[Clopidogrel resistance].
Platelets play a critical role in pathogenesis of atherothrombotic diseases such as acute coronary syndromes and ischemic stroke. Clopidogrel, a thienopyridine derivative is an effective antiplatelet drug mostly used in combination with aspirin or as a single drug in aspirin intolerant patients. However, despite its proven efficacy in various clinical trials, some patients exhibit impaired response to clopidogrel and have activated platelets while on usual clopidogrel treatment. Although definition and mechanism(s) of this therapeutic failure are poorly understood, it is associated with higher morbidity and mortality as in aspirin resistance. Various causes have been implicated in clopidogrel resistance and alternative therapies are recommended. The aim of this review is to evaluate possible mechanisms, its clinical relevance and alternative treatments of this significant issue.


Vaccinia-related kinase 3 (VRK3) sets the circadian period and amplitude by affecting the subcellular localization of clock proteins in mammalian cells.
In the eukaryotic circadian clock machinery, negative feedback repression of CLOCK (CLK) and BMAL1 transcriptional activity by PERIOD (PER) and CRYPTOCHROME (CRY) underlies the basis for 24 h rhythmic gene expression. Thus, precise regulation of the time-dependent nuclear entry of circadian repressors is crucial to generating normal circadian rhythms. Here, we sought to identify novel kinase(s) that regulate nuclear entry of mammalian CRY1 (mCRY1) with an unbiased screening using red fluorescent protein (RFP)-tagged human kinome expression plasmids in mammalian cells. Transient expression of human vaccinia-related kinase 3 (hVRK3) reduced the nuclear presence of mCRY1. hVRK3 expression also induced alterations in the subcellular localization of other core clock proteins, including mCRY2, mPER2, and BMAL1. In contrast, the subcellular localization of mCLK was not changed. Given that singly expressed mCLK mostly resides in the cytoplasm and that nuclear localization sequence (NLS) mutation of hVRK3 attenuated the effect of hVRK3 co-expression on subcellular localization, ectopically expressed hVRK3 presumably reduces the retention of proteins in the nucleus. Finally, downregulation of hvrk3 using siRNA reduced the amplitude and lengthened the period of the cellular bioluminescence rhythm. Taken together, these data suggest that VRK3 plays a role in setting the amplitude and period length of circadian rhythms in mammalian cells.


Dynamic clustering and re-dispersion in concentrated colloid-active gel composites.
We study the dynamics of quasi-two-dimensional concentrated suspensions of colloidal particles in active gels by computer simulations. Remarkably, we find that activity induces a dynamic clustering of colloids even in the absence of any preferential anchoring of the active nematic director at the particle surface. When such an anchoring is present, active stresses instead compete with elastic forces and re-disperse the aggregates observed in passive colloid-liquid crystal composites. Our quasi-two-dimensional "inverse" dispersions of passive particles in active fluids (as opposed to the more common "direct" suspensions of active particles in passive fluids) provide a promising route towards the self-assembly of new soft materials.


Early management of aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study.
The overall results are presented of early medical management and delayed operation among 249 patients studied during the period 1974 to 1977, treated within 3 days of subarachnoid hemorrhage (SAH) and evaluated 90 days after aneurysm rupture. The results included 36.2% mortality, 17.9% survival with serious neurological sequelae, and 46% with a favorable outcome. Of the patients admitted in good neurological condition, 28.7% had died and only 55.7% had a favorable recovery at 90 days after SAH. These figures represent the results despite effective reduction in early rebleeding by antifibrinolytic therapy and successful surgery in those patients reaching operation. Further therapeutic advances are needed for patients hospitalized within a few days after SAH.


[Study of the virulence of Actinobacillus pleuropneumoniae in finishing pigs as a basis for vaccination development].
For vaccine licensing data about efficiency and duration of protection are essential. Within the scope of the developement of a new subunit vaccine against Actinobacillus pleuropneumoniae (A.pp.) the protective efficiency over the whole length of the fattening period must be proven. This required infection experiments in finishing pigs. Eight pigs in the age of six months were infected experimentally into the trachea with an A.pp. serotyp 2 strain. To our knowledge data about the susceptibility of pigs of this age do not exist, so that the infectious dose for pigs of this age and this route of infection had to be determined. Two pigs each were infected with different doses of 10(10), 6 x 10(5), 8 x 10(3) and 2 x 10(3) CFU (colony forming units). The aim of the study was to produce a typical pleuropneumonia with fever and severe respiratory symptoms as well as characteristic pathomorphological lung alterations without loss of animals during the acute stage of infection. The pathogen should be cultivated from lung tissue. The recommended dose for testing the efficiency of vaccines turned out to be approximately 10(3) CFU A.pp. serotyp 2.


Enhanced identification and biological validation of differential gene expression via Illumina whole-genome expression arrays through the use of the model-based background correction methodology.
Despite the tremendous growth of microarray usage in scientific studies, there is a lack of standards for background correction methodologies, especially in single-color microarray platforms. Traditional background subtraction methods often generate negative signals and thus cause large amounts of data loss. Hence, some researchers prefer to avoid background corrections, which typically result in the underestimation of differential expression. Here, by utilizing nonspecific negative control features integrated into Illumina whole genome expression arrays, we have developed a method of model-based background correction for BeadArrays (MBCB). We compared the MBCB with a method adapted from the Affymetrix robust multi-array analysis algorithm and with no background subtraction, using a mouse acute myeloid leukemia (AML) dataset. We demonstrated that differential expression ratios obtained by using the MBCB had the best correlation with quantitative RT-PCR. MBCB also achieved better sensitivity in detecting differentially expressed genes with biological significance. For example, we demonstrated that the differential regulation of Tnfr2, Ikk and NF-kappaB, the death receptor pathway, in the AML samples, could only be detected by using data after MBCB implementation. We conclude that MBCB is a robust background correction method that will lead to more precise determination of gene expression and better biological interpretation of Illumina BeadArray data.


Interaction of bacteria and stem cells in health and disease.
Adult stem and progenitor cells possess unique qualities of proliferative capacity and phenotypic plasticity making their potential interactions with pathogenic and commensal bacteria a significant factor in health and disease. This interaction may result in the hindrance of regenerative capacity and degenerative disease. In other contexts, bacterial-stem cell cross-talk plays an important role in regulating stem cell renewal and maintaining homeostasis. Some stems cells are involved in combating infections and modulating immune responses. The results of these interactions contribute significantly to the outcome of infectious disease. The unique characteristics of stem and progenitor cells also make them attractive targets for bacterial pathogenicity strategies. Several bacterial species have been shown to utilize stem cells as cellular niches or as a means to manipulate host-pathogen interactions. In some cases, bacteria can reprogram end-differentiated tissue cells towards stem-like cells, taking advantage of their unique properties for dissemination and persistence. The ability of bacteria to interfere in stem cell regulatory pathways can also contribute to hyperplastic growth and the development of cancer. In this review, we present current knowledge on the diverse interactions between bacteria and stem cells highlighting the consequences for health and disease.


Clinical course and proposed treatment strategy for ERCP-related duodenal perforation: a multicenter analysis.
Endoscopic retrograde cholangiopancreatography (ERCP)-related duodenal perforation is rare but can cause high mortality. Our aim was to assess the clinical outcomes of these events. A total of 59 patients who were diagnosed as having ERCP-related duodenal perforation at six institutions between 2000 and 2007 were enrolled in this multicenter retrospective study. We evaluated complications and mortality associated with ERCP-related duodenal perforation according to injury detection time (IDT), peritoneal irritation signs (PIS), systemic inflammation signs (SIS), and treatment modality in these patients. Of the 59 patients, 41 (69.5 %) and 18 (30.5 %) underwent medical and surgical treatment, respectively. Duodenal perforation-related death was observed in five patients, who had received medical therapy (n = 2) and surgical therapy (n = 3). Among medically treated patients, seven patients (17.1 %) underwent endoscopic clipping immediately after the injury; surgery was not required as a salvage therapy and there were no complications or deaths among these patients. The remaining 34 patients received antibiotics combined with therapeutic fasting and intravenous hydration. Duodenal perforation-related complications depended significantly on IDT (P = 0.0001), treatment modality (P = 0.008), PIS (P = 0.003), and SIS (P = 0.010). The duodenal perforation-related mortality was significantly related to IDT (P = 0.008) and PIS (P = 0.001). IDT, PIS, and SIS appear to be important prognostic factors following ERCP-related duodenal perforation. Medical therapy can be suggested as an initial treatment strategy for ERCP-related duodenal perforation, and if possible, endoscopic clipping is strongly recommended. However, surgical treatment should be considered if the perforation is not expected to seal spontaneously, or if the continuing leakage causes PIS or SIS.


Nucleic acid chemistry in the organic phase: from functionalized oligonucleotides to DNA side chain polymers.
DNA-incorporating hydrophobic moieties can be synthesized by either solid-phase or solution-phase coupling. On a solid support the DNA is protected, and hydrophobic units are usually attached employing phosphoramidite chemistry involving a DNA synthesizer. On the other hand, solution coupling in aqueous medium results in low yields due to the solvent incompatibility of DNA and hydrophobic compounds. Hence, the development of a general coupling method for producing amphiphilic DNA conjugates with high yield in solution remains a major challenge. Here, we report an organic-phase coupling strategy for nucleic acid modification and polymerization by introducing a hydrophobic DNA-surfactant complex as a reactive scaffold. A remarkable range of amphiphile-DNA structures (DNA-pyrene, DNA-triphenylphosphine, DNA-hydrocarbon, and DNA block copolymers) and a series of new brush-type DNA side-chain homopolymers with high DNA grafting density are produced efficiently. We believe that this method is an important breakthrough in developing a generalized approach to synthesizing functional DNA molecules for self-assembly and related technological applications.


The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.
The Mitochondrial Complex I Assembly (MCIA) complex is essential for the biogenesis of respiratory Complex I (CI), the first enzyme in the respiratory chain, which has been linked to Alzheimer's disease (AD) pathogenesis. However, how MCIA facilitates CI assembly, and how it is linked with AD pathogenesis, is poorly understood. Here we report the structural basis of the complex formation between the MCIA subunits ECSIT and ACAD9. ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a fatty acid β-oxidation (FAO) enzyme to a CI assembly factor. We provide evidence that ECSIT phosphorylation downregulates its association with ACAD9 and is reduced in neuronal cells upon exposure to amyloid-β (Aβ) oligomers. These findings advance our understanding of the MCIA complex assembly and suggest a possible role for ECSIT in the reprogramming of bioenergetic pathways linked to Aβ toxicity, a hallmark of AD.


Work stressors, depressive symptoms and sleep quality among US Navy members: a parallel process latent growth modelling approach across deployment.
The present study examined whether work stressors contribute to sleep problems and depressive symptoms over the course of deployment (i.e. pre-deployment, post-deployment and 6-month reintegration) among US Navy members. Specifically, we examined whether depressive symptoms or sleep quality mediate the relationships between work stressors and these outcomes. Participants were 101 US Navy members who experienced an 8-month deployment after Operational Enduring Freedom/Operation Iraqi Freedom. Using piecewise latent growth models, we found that increased work stressors were linked to increased depressive symptoms and decreased sleep quality across all three deployment stages. Further, increases in work stressors from pre- to post-deployment contributed to poorer sleep quality post-deployment via increasing depressive symptoms. Moreover, sleep quality mediated the association between increases in work stressors and increases in depressive symptoms from pre- to post-deployment. These effects were maintained from post-deployment through the 6-month reintegration. Although preliminary, our results suggest that changes in work stressors may have small, but significant implications for both depressive symptoms and quality of sleep over time, and a bi-directional relationship persists between sleep quality and depression across deployment. Strategies that target both stress and sleep could address both precipitating and perpetuating factors that affect sleep and depressive symptoms.


Enhancer elements activate the weak 3' splice site of alpha-tropomyosin exon 2.
We have identified four purine-rich sequences that act as splicing enhancer elements to activate the weak 3' splice site of alpha-tropomyosin exon 2. These elements also activate the splicing of heterologous substrates containing weak 3' splice sites or mutated 5' splice sites. However, they are unique in that they can activate splicing whether they are placed in an upstream or downstream exon, and the two central elements can function regardless of their position relative to one another. The presence of excess RNAs containing these enhancers could effectively inhibit in vitro pre-mRNA splicing reactions in a substrate-dependent manner and, at lower concentrations of competitor RNA, the addition of SR proteins could relieve the inhibition. However, when extracts were depleted by incubation with biotinylated exon 2 RNAs followed by passage over streptavidin agarose, SR proteins were not sufficient to restore splicing. Instead, both SR proteins and fractions containing a 110-kD protein were necessary to rescue splicing. Using gel mobility shift assays, we show that formation of stable enhancer-specific complexes on alpha-tropomyosin exon 2 requires the presence of both SR proteins and the 110-kD protein. By analogy to the doublesex exon enhancer elements in Drosophila, our results suggest that assembly of mammalian exon enhancer complexes requires both SR and non-SR proteins to activate selection of weak splice sites.


Interface Electrode Morphology Effect on Carrier Concentration and Trap Defect Density in an Organic Photovoltaic Device.
Formation of Schottky barrier contact (SBC) leads reconstruction of charges at the metal/semiconductor (MS) interface because of the wave function overlap between semiconductor and metal contact. Not only is the Schottky barrier contact formation a signature of the material's work function, but also it is sensitive to the interface trap states, the crystal orientation of the interacting materials, and other interface properties. In this work, the effect of aluminum cathode morphology on the polymer Schottky diode and bulk heterojunction (BHJ) photovoltaic device performance is studied. The electron collecting contacts in Schottky diode and BHJ device have been deposited using aluminum in pellet and nanoparticle forms. Devices fabricated by using Al nanoparticle showed improvement in dark as well as photocurrent density. Significant enhancement in JSC leads to overall improved power conversion efficiency. Enhanced performance in Schottky structured diode and OPV device have been correlated with electrode microstructure and its interface properties such as improved electrically active contact and enhanced charge transport. Electrical conductivity is discussed based on enhanced electrical coherence across organic semiconductor and electrode interface. Therefore, the contribution of electrical enhancement leads to improvement in short-circuit current density (JSC) in BHJ solar cell which is due to reduced trap density. Further, PCE was correlated with the density of interface trap states studied by drive level capacitance profiling technique.


Deubiquitylating Enzymes in Cancer and Immunity.
Deubiquitylating enzymes (DUBs) maintain relative homeostasis of the cellular ubiquitome by removing the post-translational modification ubiquitin moiety from substrates. Numerous DUBs have been demonstrated specificity for cleaving a certain type of ubiquitin linkage or positions within ubiquitin chains. Moreover, several DUBs perform functions through specific protein-protein interactions in a catalytically independent manner, which further expands the versatility and complexity of DUBs' functions. Dysregulation of DUBs disrupts the dynamic equilibrium of ubiquitome and causes various diseases, especially cancer and immune disorders. This review summarizes the Janus-faced roles of DUBs in cancer including proteasomal degradation, DNA repair, apoptosis, and tumor metastasis, as well as in immunity involving innate immune receptor signaling and inflammatory and autoimmune disorders. The prospects and challenges for the clinical development of DUB inhibitors are further discussed. The review provides a comprehensive understanding of the multi-faced roles of DUBs in cancer and immunity.


Cell cycle in the fucus zygote parallels a somatic cell cycle but displays a unique translational regulation of cyclin-dependent kinases.
In eukaryotic cells, the basic machinery of cell cycle control is highly conserved. In particular, many cellular events during cell cycle progression are controlled by cyclin-dependent kinases (CDKs). The cell cycle in animal early embryos, however, differs substantially from that of somatic cells or yeasts. For example, cell cycle checkpoints that ensure that the sequence of cell cycle events is correct have been described in somatic cells and yeasts but are largely absent in embryonic cells. Furthermore, the regulation of CDKs is substantially different in the embryonic and somatic cells. In this study, we address the nature of the first cell cycle in the brown alga Fucus, which is evolutionarily distant from the model systems classically used for cell cycle studies in embryos. This cycle consists of well-defined G1, S, G2, and M phases. The purine derivative olomoucine inhibited CDKs activity in vivo and in vitro and induced different cell cycle arrests, including at the G1/S transition, suggesting that, as in somatic cells, CDKs tightly control cell cycle progression. The cell cycle of Fucus zygotes presented the other main features of a somatic cell cycle, such as a functional spindle assembly checkpoint that targets CDKs and the regulation of the early synthesis of two PSTAIRE CDKs, p32 and p34, and the associated histone H1 kinase activity as well as the regulation of CDKs by tyrosine phosphorylation. Surprisingly, the synthesis after fertilization of p32 and p34 was translationally regulated, a regulation not described previously for CDKs. Finally, our results suggest that the activation of mitotic CDKs relies on an autocatalytic amplification mechanism.


The Severe Respiratory Insufficiency Questionnaire for Subjects With COPD With Long-Term Oxygen Therapy.
Respiratory insufficiency in COPD may present as hypoxic and/or hypercapnic respiratory failure treated with long-term oxygen therapy (LTOT) and/or noninvasive ventilation (NIV) with LTOT. The Severe Respiratory Insufficiency Questionnaire (SRI) is a tool for the assessment of health-related quality of life (HRQOL) in subjects receiving NIV. However, it remains unclear whether the SRI is also capable of assessing and discriminating HRQOL in subjects receiving LTOT. Stable subjects with COPD receiving LTOT or NIV + LTOT (NIV) were prospectively recruited and completed the SRI, lung function tests, and blood gases. Confirmatory factor analysis for construct validity and internal consistency reliability were calculated. One hundred fifty-five subjects were included (113 LTOT, 42 NIV). The Cronbach α coefficient of the 7 subscales ranged between 0.69 and 0.89 (LTOT) and between 0.79 and 0.93 (NIV), respectively. In both groups, confirmatory factor analysis revealed a one-factor model for the SRI summary scale; in 5 subscales, one- or 2-factor models could be established. Group differences in the SRI subsets were all P <.05 (except for physical functioning) with higher scores in subjects receiving NIV. The SRI showed high reliability and validity in subjects with COPD receiving LTOT. Subjects receiving LTOT had lower SRI scores, indicating a poorer HRQOL compared with subjects with established NIV and LTOT.


A First Methodological Development and Validation of ReTap: An Open-Source UPDRS Finger Tapping Assessment Tool Based on Accelerometer-Data.
Bradykinesia is a cardinal hallmark of Parkinson's disease (PD). Improvement in bradykinesia is an important signature of effective treatment. Finger tapping is commonly used to index bradykinesia, albeit these approaches largely rely on subjective clinical evaluations. Moreover, recently developed automated bradykinesia scoring tools are proprietary and are not suitable for capturing intraday symptom fluctuation. We assessed finger tapping (i.e., Unified Parkinson's Disease Rating Scale (UPDRS) item 3.4) in 37 people with Parkinson's disease (PwP) during routine treatment follow ups and analyzed their 350 sessions of 10-s tapping using index finger accelerometry. Herein, we developed and validated ReTap, an open-source tool for the automated prediction of finger tapping scores. ReTap successfully detected tapping blocks in over 94% of cases and extracted clinically relevant kinematic features per tap. Importantly, based on the kinematic features, ReTap predicted expert-rated UPDRS scores significantly better than chance in a hold out validation sample (n = 102). Moreover, ReTap-predicted UPDRS scores correlated positively with expert ratings in over 70% of the individual subjects in the holdout dataset. ReTap has the potential to provide accessible and reliable finger tapping scores, either in the clinic or at home, and may contribute to open-source and detailed analyses of bradykinesia.


Periodicity in Attachment Organelle Revealed by Electron Cryotomography Suggests Conformational Changes in Gliding Mechanism of Mycoplasma pneumoniae.
Mycoplasma pneumoniae, a pathogenic bacterium, glides on host surfaces using a unique mechanism. It forms an attachment organelle at a cell pole as a protrusion comprised of knoblike surface structures and an internal core. Here, we analyzed the three-dimensional structure of the organelle in detail by electron cryotomography. On the surface, knoblike particles formed a two-dimensional array, albeit with limited regularity. Analyses using a nonbinding mutant and an antibody showed that the knoblike particles correspond to a naplike structure that has been observed by negative-staining electron microscopy and is likely to be formed as a complex of P1 adhesin, the key protein for binding and gliding. The paired thin and thick plates feature a rigid hexagonal lattice and striations with highly variable repeat distances, respectively. The combination of variable and invariant structures in the internal core and the P1 adhesin array on the surface suggest a model in which axial extension and compression of the thick plate along a rigid thin plate is coupled with attachment to and detachment from the substrate during gliding. Human mycoplasma pneumonia, epidemic all over the world in recent years, is caused by a pathogenic bacterium,Mycoplasma pneumoniae This tiny bacterium, about 2 µm in cell body length, glides on the surface of the human trachea to infect the host by binding to sialylated oligosaccharides, which are also the binding targets of influenza viruses. The mechanism of mycoplasmal gliding motility is not related to any other well-studied motility systems, such as bacterial flagella and cytoplasmic motor proteins. Here, we visualized the attachment organelle, a cellular architecture for gliding, three dimensionally by using electron cryotomography and other conventional methods. A possible gliding mechanism has been suggested based on the architectural images.


Contribution of the anaerobic blood culture vial for the recovery of Candida glabrata: A retrospective multicentric study.
Although Candida spp are aerobic microorganisms, some Candida strains, mainly Candida glabrata, can be recovered from anaerobic blood culture vials. We assessed the contribution of the anaerobic vials for the diagnosis of candidemia, especially for C. glabrata. We conducted a multicenter retrospective study including eight university or regional hospitals. A single episode of monomicrobial candidemia per patient was included from September 1st, 2016, to August 31st, 2019. The characteristics of all aerobic and anaerobic blood culture vials sampled within 2 h before and after the first positive blood culture vials were recorded (type of vials, result, and for positive vials time-to-positivity and Candida species). Overall, 509 episodes of candidemia were included. The main species were C. albicans (55.6%) followed by C. glabrata (17.1%), C. parapsilosis (4.9%), and C. tropicalis (4.5%). An anaerobic vial was positive in 76 (14.9%) of all episodes of which 56 (73.8%) were due to C. glabrata. The number of C. glabrata infections only positive in anaerobic vials was 1 (2.6%), 1 (11.1%), and 15 (37.5%) with the BACT/ALERT 3D the BACT/ALERT VIRTUO and the BACTEC FX instrument, respectively (P < 0.01). The initial positivity of an anaerobic vial was highly predictive of the isolation of C. glabrata with the BACTEC FX (sensitivity of 96.8%). C. glabrata time-to-positivity was shorter in anaerobic vial than aerobic vial with all instruments. Anaerobic blood culture vials improve the recovery of Candida spp mainly C. glabrata. This study could be completed by further analyses including mycological and pediatric vials. Although Candida spp are aerobic microorganisms, C. glabrata is able to grow in anaerobic conditions. In blood culture, the time-to-positivity of C. glabrata is shorter in anaerobic than aerobic vials. Only the anaerobic vial was positive in up to 15 (37.5%) C. glabrata bloodstream infections.


Long-term effectiveness of luteinizing hormone-releasing hormone agonist or antiandrogen monotherapy in elderly men with localized prostate cancer (T1-2): a retrospective study.
To evaluate the long-term effectiveness, side effects and compliance rates of two types of drugs (luteinizing hormone-releasing hormone [LHRH] agonist and antiandrogen) that were used individually to treat patients with localized prostate cancer (T1-2) at our institution. Ninety-seven patients who were diagnosed in the period from April 1997 to January 2000 as having clinically localized prostate cancer (T1-2) received either LHRH agonist (leuprolide acetate 7.5 mg/month) monotherapy (group 1, n = 62) or antiandrogen monotherapy (group 2, n = 35; 18 received bicalutamide 50 mg q.d., 13 received nilutamide 150 mg t.i.d. and 4 received flutamide 250 mg t.i.d.). The mean age in both groups was 76 years. The mean follow-up time was (50.8 +/- 8.5) months in group 1 and (43.1 +/- 2.2) months in group 2. Prostate-specific antigen (PSA) levels rose in only 1 of the 62 patients (1.6%) in group 1, and in 20 of the 35 patients (57.1%) in group 2. In group 2, 10 of the 20 patients (50%) with increasing PSA levels were treated with LHRH salvage therapy, and eight (80%) responded. Hot flashes (54.8%) and lethargy (41.9%) were the most common side effects in group 1. In contrast, nipple-tenderness (40%) and light-dark adaptation (17.1%) were more often seen in group 2. Only 1 of the 62 patients (1.6%) in group 1 switched to another medication because of adverse side effects; whereas 8 of the 35 patients (22.9%) in group 2 did so. Unlike antiandrogen monotherapy, LHRH agonist monotherapy provided long-term durable control of localized prostate cancer (T1-2). It can also be an effective treatment option for patients whose disease failed to respond to antiandrogen monotherapy. The limitations of our study are the lack of health outcomes analysis and a small sample size.


The PHI (PHI-27)/corticotropin-releasing factor/enkephalin immunoreactive hypothalamic neuron: possible morphological basis for integrated control of prolactin, corticotropin, and growth hormone secretion.
By using the indirect immunofluorescence technique, one and the same neuron in the parvocellular part of the paraventricular nucleus has been shown to stain with antisera against three different peptides: PHI (PHI-27), corticotropin-releasing factor (CRF), and enkephalin. This could explain the well-known parallel increase in plasma prolactin, corticotropin, and growth hormone levels--for example, under certain types of stress--as being due to a concomitant release of PHI-like, CRF-like, and enkephalin-like peptides from the same nerve endings in the median eminence. A hypothetical mechanism for the co-ordinated release of these three anterior pituitary hormones is discussed.


Specific gut microbiome members are associated with distinct immune markers in pediatric allogeneic hematopoietic stem cell transplantation.
Increasing evidence reveals the importance of the microbiome in health and disease and inseparable host-microbial dependencies. Host-microbe interactions are highly relevant in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), i.e., a replacement of the cellular components of the patients' immune system with that of a foreign donor. HSCT is employed as curative immunotherapy for a number of non-malignant and malignant hematologic conditions, including cancers such as acute lymphoblastic leukemia. The procedure can be accompanied by severe side effects such as infections, acute graft-versus-host disease (aGvHD), and death. Here, we performed a longitudinal analysis of immunological markers, immune reconstitution and gut microbiota composition in relation to clinical outcomes in children undergoing HSCT. Such an analysis could reveal biomarkers, e.g., at the time point prior to HSCT, that in the future could be used to predict which patients are of high risk in relation to side effects and clinical outcomes and guide treatment strategies accordingly. In two multivariate analyses (sparse partial least squares regression and canonical correspondence analysis), we identified three consistent clusters: (1) high concentrations of the antimicrobial peptide human beta-defensin 2 (hBD2) prior to the transplantation in patients with high abundances of Lactobacillaceae, who later developed moderate or severe aGvHD and exhibited high mortality. (2) Rapid reconstitution of NK and B cells in patients with high abundances of obligate anaerobes such as Ruminococcaceae, who developed no or mild aGvHD and exhibited low mortality. (3) High inflammation, indicated by high levels of C-reactive protein, in patients with high abundances of facultative anaerobic bacteria such as Enterobacteriaceae. Furthermore, we observed that antibiotic treatment influenced the bacterial community state. We identify multivariate associations between specific microbial taxa, host immune markers, immune cell reconstitution, and clinical outcomes in relation to HSCT. Our findings encourage further investigations into establishing longitudinal surveillance of the intestinal microbiome and relevant immune markers, such as hBD2, in HSCT patients. Profiling of the microbiome may prove useful as a prognostic tool that could help identify patients at risk of poor immune reconstitution and adverse outcomes, such as aGvHD and death, upon HSCT, providing actionable information in guiding precision medicine.


New Methods for the Quantification of Ingested Nano- and Ultrafine Plastics in Seabirds.
Plastic ingestion has been documented in a plethora of taxa. However, there is a significant gap in the detection of nano- and ultrafine particles due to size limitations of commonly used techniques. Using two Australian seabird species as case studies, the flesh-footed shearwater (FFSH) Ardenna carneipes and short-tailed shearwater (STSH) A. tenuirostris, we tested a novel approach of flow cytometry to quantify ingested particles <70 μm in the fecal precursor (guano; colon and cloacal contents) of both species. This method provided the first baseline data set for these species for plastics in the 200 nm-70 μm particle size ranges and detected a mean of 553.50 ± 91.21 and 350.70 ± 52.08 plastics (count/mg fecal precursor, wet mass) in STSH and FFSH, respectively, whereas Fourier transform infrared spectroscopy (FT-IR) provided accurate measurements of polymer compositions and quantities in the size range above 5.5 × 5.5 μm2. The abundance of nano- and ultrafine particles in the guano (count/mg) was not significantly different between species (p-value = 0.051), suggesting that foraging distribution or prey items, but not species, may contribute to the consumption of small plastics. In addition, there was no correlation between macroplastics in the stomach compared to the fecal precursor, indicating that small particles are likely bioaccumulating (e.g., through shedding and digestive fragmentation) and/or being directly ingested. Combining flow cytometry with FT-IR provides a powerful quantitative and qualitative analysis tool for detecting particles orders of magnitude smaller than that are currently explored with wider applications across taxa and marine environments.


Uniaxial Deformation and Crazing in Glassy Polymer-Grafted Nanoparticle Ultrathin Films.
The deformation behavior of neat, glassy polymer-grafted nanoparticle (PGN) monolayer films is studied using coarse-grained molecular dynamics simulations and experiments on polystyrene-grafted silica. In both the simulations and experiments, apparent crazing behavior is observed during deformation. The PGN systems show a relatively more uniform, perforated sheet craze structure and significantly higher strain at break than reference homopolymers of the same length. Short chain, unentangled PGN monolayers are also simulated for comparison; these are brittle and break apart without crazing. The entangled PGN simulations are analyzed in detail for systems at both high and moderate graft density. Stress-strain curves show three distinct regions: yielding and strain localization, craze widening, and strain hardening preceding catastrophic failure. The PGN stress-strain behavior appears more similar to that of longer chain, highly entangled homopolymer films than to the reference homopolymer films of the same length as the graft chains, suggesting that the particles effectively add additional entanglement points. The moderate graft density particles have higher strain-to-failure and maximum stress than the high graft density particles. We suggest this increased robustness for lower graft density systems is due to their increased interpenetration of graft chains between neighboring particles, which leads to increased interparticle entanglements per chain.


A small epidemiological survey for vivax malaria in Kimpo-gun, Kyonggi-do, Korea undertaken after detecting two consecutive cases.
On July and August 1997, two 15-year-old mates of a football team of Tongjin Middle School in northern Kyonggi-do, Korea were consecutively diagnosed as vivax malaria by peripheral blood smear. They had no histories of travelling abroad or drug abuse. They witnessed that other mates in the team were ill of fever in the same period. A small survey was therefore undertaken to determine whether vivax malaria was outbroken locally. A total of 57 students of the team living together in a dormitory was examined for history of fever, presence of splenomegaly, blood smear and anti-P. vivax antibody test by immunofluorescent antibody test (IFAT). Except for the above two patients, only one case revealed a marginal titer of IFAT. No other positive findings of vivax malaria were found. In the results of this local survey, no more cases of vivax malaria were revealed except the two sporadic cases.


Correlation of a quinidine-induced platelet-specific antibody with development of thrombocytopenia.
The rapidity by which drug-dependent antiplatelet antibodies can develop is not known, since patients are only studied during or after the episode of thrombocytopenia. This report describes the development of quinidine-induced immune thrombocytopenia in a healthy volunteer during a drug study. The thrombocytopenia developed within two weeks of initiation of quinidine therapy. During the thrombocytopenic episode, but not before receiving the drug, the patient had an IgG antiplatelet antibody that bound to control platelets in the absence of the drug. This antibody was absent when the drug was discontinued and the platelet count rose. The patient's acute serum also induced the release of serotonin from control platelets, and the reaction was enhanced by quinidine. This indicates that drug-dependent antiplatelet antibodies can develop rapidly and supports the hypothesis that quinidine-induced thrombocytopenia is due to a quinidine-dependent platelet-specific IgG.


The kinetics of effector binding to phosphofructokinase. The influence of effectors on the allosteric conformational transition.
1. The extent of the allosteric transition from the R into the T conformation of rabbit skeletal muscle phosphofructokinase induced by Mg2+-1,N6-etheno-ATP was determined by stopped-flow fluorimetry from the amplitude of the slow phase of the Mg2+-1,N6-etheno-ATP fluorescence enhancement [Roberts & Kellet (1979) Biochem. J. 183, 349--360]. 2. The amplitude of the slow phase was decreased by low concentrations of the activators cyclic AMP and fructose 1,6-bisphosphate, but increased in a complex manner by the inhibitor citrate. 3. Mg2+-1,N6-etheno-ATP and Mg2+-ATP are unable to induce the T conformation to a detectable extent in the presence of saturating cyclic AMP, but can do so readily in the presence of saturating fructose 1,6-bisphosphate. 4. The conformational transitions induced in enzyme alone by different ligands were observed by changes in intrinsic protein fluorescence. In general, an R-type conformation has diminished protein fluorescence compared with a T-type conformation. 5. Mg2+-ATP exerts a complex effect on protein fluorescence; both the enhancement at low concentrations and the quenching at high concentrations of Mg2+-ATP result from the binding of Mg2+-ATP to the inhibitory site and the ensuing allosteric transition. Enhancement reflects the extent of the allosteric transition and involves both tyrosine and tryptophan, probably in the region of the active site; quenching reflects occupation of the inhibitory site and involves tyrosine at the inhibitory site. 6. The mechanism of the allosteric transition from the R into the T conformation induced by Mg2+-1,N6-etheno-ATP at low concentrations occurs predominantly by a 'prior-isomerization' pathway; at higher concentrations a limited contribution from a 'substrate-guided' pathway occurs. 7. The allosteric behaviour of phosphofructokinase with respect to Mg2+-ATP and Mg2+-1,N6-ethenol-ATP binding may be accounted for in terms of the simple, concerted model.


Validation of phage display method for protease inhibitor selection using synthetic hybrid peptides.
A recombinant Haematobia irritans irritans trypsin inhibitor (HiTI - Mw 7030 kDa)) phagemid library was constructed and displayed functionally on the tip of the filamentous M13 phage. A combinatorial library of 7.2 x 10(6) mutants was created with HiTI mutations restricted to the P1'-P3' and P5' positions of the reactive site. This combinatorial library was selected for trypsin-like Pr2 proteases of Metarhizium anisopliae fungus, and 11 HiTI mutants containing the following substitutions: K17G, S18R, D19G, S21A, among 60 sequenced clones, were obtained. In order to confirm the inhibitory activity of the selected sequences, we transferred the selected sequence to the shortest protease inhibitor, the sunflower trypsin inhibitor (SFTI), for inhibitory activity analysis. The hybrid peptide containing the mutated sequence (SFTI-Mut, GRCTRGRGLACFPD-NH2; Ki = 14 µM) presented an apparent inhibition constant (Ki(app)) for Pr2 proteases ≈20-fold lower than the control peptide containing the original HiTI sequence (SFTI-HiTI, GRCTRKSDLSCFPD-NH2; Ki = 259 µM). In conclusion, the present work enabled the selection of a specific HiTI mutant for Pr2 proteases of M. anisopliae fungus using a HiTI combinatorial library on M13 phage surface. Selection of strong binders by phage display and their validation as inhibitors using synthetic hybrid peptides proved to be a powerful technique to generate specific serine protease inhibitors suitable for studies of drug design and enzyme-inhibitor interaction.


Vitamin D3- and retinoic acid-induced monocytic differentiation: interactions between the endogenous vitamin D3 receptor, retinoic acid receptors, and retinoid X receptors in U-937 cells.
Retinoic acid (RA) and 1,25 alpha-dihydroxycholecalciferol (VitD3) are potent regulators of hematopoletic differentiation. Yet, little is known as to how the RA and VitD3 receptor network operates in hematopoietic cells, and whether receptor interactions can explain the interplay between the RA- and VitD3-signaling pathways during differentiation. Therefore, we analyzed the expression, DNA binding, and transcriptional activity of the endogenous RA and VitD3 receptors [retinoic acid receptors (RARs), retinoid X receptors (RXRs), and VitD3 receptor (VDR)] in the U-937 cell line, in which RA and VitD3 induce distinct monocytic differentiation pathways. VitD3 induction resulted in the formation of VDR/RXR DNA-binding complexes on both VitD3 response elements and RA response elements (RAREs). However, transcriptional activation was only observed from a VitD3 response element-driven reporter construct. Several DNA-binding complexes were detected on RAREs in undifferentiated cells. Stimulation by RA resulted in increased RAR beta/RXR DNA binding, activated RARE-dependent transcription, and increased expression of RAR-beta. Concomitant stimulation by VitD3 inhibited the RA-stimulated formation of RAR beta/RXR heterodimers, favoring VDR/RXR binding to the RARE. Also, VitD3 inhibited the expression of CD23 and CD49f, characteristic markers of retinoid-induced U-937 cell differentiation. In contrast, neither the RA-stimulated, RARE-mediated transcription nor the induced RAR-beta expression was suppressed by VitD3, suggesting that VitD3 selectively inhibited the retinoid-induced differentiation program but not the RARE-mediated signal. These results demonstrate a complex role for VitD3 in modifying the retinoid differentiation pathway and may have implications for differentiation-inducing therapy of hematopoietic tumors.


Dynamics of bacterial communities in alfalfa and mung bean sprouts during refrigerated conditions.
Sprouts are considered a healthy ready-to-eat food and has gained popularity in recent years. The objective of the present study was to determine the dynamics of sprouts' microbiome during cold storage to the end of their shelf-life at home. The microbiological quality of fresh alfalfa (Medicago sativa) and mung bean (Vigna radiata) sprouts from two commercial brands was tested and the number of APC ranges from 5.0 to 8.7 log CFU/g in alfalfa and 6.7 to 9.3 log CFU/g in mung bean sprouts. In the case of alfalfa, but not mung beans, there were differences in the mean numbers of APC between the two brands. The number of coliform bacteria ranges from 4.3 to 7.7 log CFU/g in alfalfa and 4.1 to 8.1 log CFU/g in mung bean sprouts. Four independent batches of sprouts were used for DNA preparation and were sampled immediately after purchase and once a week during subsequent storage in refrigerator until the end of their shelf-life. Microbial population of the sprouts was determined using next generation sequencing of 16S rRNA amplicons. Alfalfa sprouts were dominated by Pseudomonas throughout the storage time with relative abundance of >60% at 3 weeks. Fresh mung bean sprouts were dominated by both Pseudomonas and Pantoea, but Pantoea became the dominant taxa after 2 weeks of storage, with >46% of relative abundance. The bacterial communities associated with sprouts were largely dependent on the sprout type, and less dependent on the brand. The species richness and diversity declined during storage and the development of spoilage. Among the 160 genera identified on sprouts, 23 were reported to contain known spoilage-associated species and 30 genera comprise potential human pathogenic species. This study provides new insight into the microbiome dynamics of alfalfa and mung bean sprouts during cold storage.


Fasting inhibits colorectal cancer growth by reducing M2 polarization of tumor-associated macrophages.
Dietary restriction has been recognized as a healthy and natural therapy for cancer. It is reported that different forms of dietary restriction can promote anti-tumor immunity. However, it is not clear how fasting affects tumor-associated macrophages (TAMs). This study aims to investigate the relationship between fasting and antitumor immunity in terms of tumor-associated macrophages. In vivo, the results showed that alternate day fasting for 2 weeks inhibitted the tumor growth of mice without causing a reduction of body weight. Meanwhile, M2 polarization of tumor-associated macrophages in tumor tissues of alternate day fasting group was also decreased. In vitro, fasting induced the autophagy of CT26 cells, decreased the generation of extracellular adenosine by supressing the expression of CD73 in CT26 cells. Decreasing adenosine inhibitted M2 polarization of RAW264.7 cells through inactivating JAK1/STAT3 signal pathway in fasting condition. Eventually, the proliferation of CT26 cancer cells declined on account of fasting-facilitated antitumor immunity. These results suggested that fasting suppressed M2 polarization of tumor-associated macrophages to inhibit tumor growth through decreasing the level of adenosine in the tumor microenvironment both in vivo and in vitro. This process was associated with increasing autophagy of tumor cells.


Collagen VI related muscle disorders.
Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), two conditions which were previously believed to be completely separate entities. BM is a relatively mild dominantly inherited disorder characterised by proximal weakness and distal joint contractures. UCMD was originally described as an autosomal recessive condition causing severe muscle weakness with proximal joint contractures and distal hyperlaxity. Here we review the clinical phenotypes of BM and UCMD and their diagnosis and management, and provide an overview of the current knowledge of the pathogenesis of collagen VI related disorders.


Comorbidities in Patients With Chronic Obstructive Pulmonary Disease and Pulmonary Rehabilitation Outcomes.
The objective of this study was to evaluate the impact of comorbidities as potential predictors of the response to pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD). The study included 165 patients with COPD with exercise limitations. Comorbidity was classified as cardiac, metabolic, orthopedic, behavioral health problems, or other diseases. Number of comorbidities was grouped as 0, 1, or ≥2. Outcomes were defined as improvement in exercise capacity (maximal exercise capacity, 6-minute walk test, and constant workload cycle exercise duration) and quality of life (Chronic Respiratory Questionnaire). We assessed the effect of comorbidities on improvement in outcomes and the impact of the number of comorbidities on the percentage of patients reaching the minimal clinically important difference for each outcome. Most patients (n = 160; 96%) were elderly males (mean age 70 years) with COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II to IV. Sixty-four percent of patients had at least 1 comorbidity. The ≥2 comorbidity group (n = 29) had a higher modified Charlson index and more patients required continuous supplemental oxygen. Absolute differences in dyspnea scores in patients with cardiac disease and orthopedic problems compared with those without these comorbidities were 2.6 ± 0.87; 95% CI 0.89 to 4.32; p = .003, and -3.25 ± 1.23; 95% CI -5.69 to -0.82; p = .009, respectively. Comorbidities had no significant effect on other exercise outcomes or quality of life. Patients with cardiac disease experienced greater improvement in the dyspnea score compared with patients with no cardiac disease, whereas patients with orthopedic problems had a smaller but also clinically significant improvement in dyspnea after pulmonary rehabilitation.


Prognostic significance of the long pentraxin PTX3 in acute myocardial infarction.
Inflammation has a pathogenetic role in acute myocardial infarction (MI). Pentraxin-3 (PTX3), a long pentraxin produced in response to inflammatory stimuli and highly expressed in the heart, was shown to peak in plasma approximately 7 hours after MI. The aim of this study was to assess the prognostic value of PTX3 in MI compared with the best-known and clinically relevant biological markers. In 724 patients with MI and ST elevation, PTX3, C-reactive protein (CRP), creatine kinase (CK), troponin T (TnT), and N-terminal pro-brain natriuretic peptide (NT-proBNP) were assayed at entry, a median of 3 hours, and the following morning, a median of 22 hours from symptom onset. With respect to outcome events occurring over 3 months after the index event, median PTX3 values were 7.08 ng/mL in event-free patients, 16.12 ng/mL in patients who died, 9.12 ng/mL in patients with nonfatal heart failure, and 6.88 ng/mL in patients with nonfatal residual ischemia (overall P<0.0001). Multivariate analysis including CRP, CK, TnT, and NT-proBNP showed that only age > or =70 years (OR, 2.11; 95% CI, 1.04 to 4.31), Killip class >1 at entry (OR, 2.20; 95% CI, 1.14 to 4.25), and PTX3 (>10.73 ng/mL) (OR, 3.55; 95% CI, 1.43 to 8.83) independently predicted 3-month mortality. Biomarkers predicting the combined end point of death and heart failure in survivors were the highest tertile of PTX3 and of NT-proBNP and a CK ratio >6. In a representative contemporary sample of patients with MI with ST elevation, the acute-phase protein PTX3 but not the liver-derived short pentraxin CRP or other cardiac biomarkers (NT-proBNP, TnT, CK) predicted 3-month mortality after adjustment for major risk factors and other acute-phase prognostic markers.


Pseudo-wound infection after a caesarean section: Case report of unrecognized Pyoderma Gangrenosum.
Pyoderma Gangrenosum (PG) is a rare auto-inflammatory disease, characterized by painful ulcerative skin-lesions often developing at sites of injury or surgery because of the typical pathergy phenomena. We describe an unusual case of PG after a caesarean section with excessive extra-cutaneous manifestation within internal organs. A 21-year-old Dutch primigravida developed signs of sepsis after a caesarean section. Despite antibiotic treatment, fast clinical deterioration occurred. Exploration of the wound showed necrosis of the uterus and surrounding tissues. Due to the progression of necrosis, consecutive debridement procedures were executed resulting in a substantial abdominal wall defect. The progressive clinical course of the necrosis combined with absence of positive wound cultures and histology of prominent interstitial neutrophilic infiltration, led to the diagnosis 'Pyoderma Gangrenosum'. Treatment with high dose corticosteroids led to rapid regression of the disease. After several weeks, the abdominal wall defect was surgically corrected under systemic corticosteroid therapy. This case of PG is unique due to the excessive extra-cutaneous presentation, which contributed to delayed diagnosis. Several surgical interventions in the active stage of disease resulted in expansion of PG and substantial morbidity for the patient. Post-operative PG can mimic infectious diseases, but treatment is substantially different. This case of extensive PG highlights the importance of timely recognition and treatment of the disease to reduce iatrogenic morbidity.


Reference frames for spinal proprioception: limb endpoint based or joint-level based?
Many sensorimotor neurons in the CNS encode global parameters of limb movement and posture rather than specific muscle or joint parameters. Our investigations of spinocerebellar activity have demonstrated that these second-order spinal neurons also may encode proprioceptive information in a limb-based rather than joint-based reference frame. However, our finding that each foot position was determined by a unique combination of joint angles in the passive limb made it difficult to distinguish unequivocally between a limb-based and a joint-based representation. In this study, we decoupled foot position from limb geometry by applying mechanical constraints to individual hindlimb joints in anesthetized cats. We quantified the effect of the joint constraints on limb geometry by analyzing joint-angle covariance in the free and constrained conditions. One type of constraint, a rigid constraint of the knee angle, both changed the covariance pattern and significantly reduced the strength of joint-angle covariance. The other type, an elastic constraint of the ankle angle, changed only the covariance pattern and not its overall strength. We studied the effect of these constraints on the activity in 70 dorsal spinocerebellar tract (DSCT) neurons using a multivariate regression model, with limb axis length and orientation as predictors of neuronal activity. This model also included an experimental condition indicator variable that allowed significant intercept or slope changes in the relationships between foot position parameters and neuronal activity to be determined across conditions. The result of this analysis was that the spatial tuning of 37/70 neurons (53%) was unaffected by the constraints, suggesting that they were somehow able to signal foot position independently from the specific joint angles. We also investigated the extent to which cell activity represented individual joint angles by means of a regression model based on a linear combination of joint angles. A backward elimination of the insignificant predictors determined the set of independent joint angles that best described the neuronal activity for each experimental condition. Finally, by comparing the results of these two approaches, we could determine whether a DSCT neuron represented foot position, specific joint angles, or none of these variables consistently. We found that 10/70 neurons (14%) represented one or more specific joint-angles. The activity of another 27 neurons (39%) was significantly affected by limb geometry changes, but 33 neurons (47%) consistently elaborated a foot position representation in the coordinates of the limb axis.


Pesticide exposures to migrant farmworkers in Eastern NC: detection of metabolites in farmworker urine associated with housing violations and camp characteristics.
The purpose of this paper is to present and evaluate descriptively bivariate associations between urinary metabolites of pesticides and herbicides and migrant camp conditions, violations, and personal worker behaviors at home for farmworkers who do not apply pesticides. We studied 183 migrant farmworker camps in eastern North Carolina in 2010. Data and urine samples were collected from 371 men. Predictor measures included violations in six domains of housing regulations and nonviolation characteristics and personal behaviors that might impact urinary metabolites. Cockroaches and bathroom violations were predictive of increased exposure to pyrethroids and cyfluthrin/chlorpyrifos, respectively. Changing and storing clothing and shoes in sleeping rooms increased the number of detects for the diazinon metabolite. Farmworkers had exposures to multiple chemicals. No single housing domain was identified as critical to mitigating housing-related exposure; specific attention should be paid to changing and storing soiled clothing in sleeping rooms, and insect infestations.


Ultrasonography in transient synovitis and early Perthes' disease.
We used ultrasonography to examine 36 children suffering from transient synovitis and 12 children with early Perthes' disease. Widening of the joint space was revealed by ultrasonography in all affected hips with either disease. In the patients with transient synovitis, capsular distension was attributed to synovial effusion, while in the patients with Perthes' disease it was produced by thickening of the synovial membrane. Neither capsular distension nor thickening of the joint cartilage was seen in the contralateral normal hip in the patients with transient synovitis, but they were common in early Perthes' disease. Ultrasonography may provide significant diagnostic clues to differentiate early Perthes' from transient synovitis.


Management of air leaks post-surgical lung resection.
Airleaks are one of the most common complications associated with elective lung resection. There have been many techniques and modern advancements in thoracic surgery, however airleaks persist. This review article will discuss several interventions ranging from conservative noninvasive to surgical management of the persistent airleak. These techniques include stopping of suction on the plueravac, fibrin patches, pleurodesis, use of endobronchial valves (EBVs), return to OR for operative intervention, and lastly to send patients home with mini pleuravacs.


Spectroscopic and magnetic investigations of a spin-frustrated Mn-doped CoAl2O4 spinel.
Single-phase polycrystalline spin-frustrated spinel oxides Co1-xMnxAl2O4 (0 ≤ x ≤ 0.3) have been prepared to investigate the optical and magnetic properties. Linear variation of the lattice parameter along with the characteristic hyperfine electron paramagnetic resonance (EPR) signal establish the fact that the Mn2+ ions are incorporated at Co2+ sites of the CoAl2O4 lattice. Optical absorption spectra reveal three absorption features in wavelength regions: 250-400 nm, 500-700 nm and 1000-1700 nm. The optical band gap associated with the d-d transition increases from 1.84 eV to 1.88 eV with 30% Mn substitution. Temperature dependent magnetization measurements indicate a clear transformation of the magnetic ground state from the collinear antiferromagnetic state (for x = 0) to the spin-glass-like state (for x = 0.1) to the cluster-glass-like state (for x = 0.2 and 0.3) with the increase of Mn concentration. In addition, our time dependent isothermal remanent magnetization (IRM) study further fortifies the above transformation of the magnetic ground state. The value of the magnetic frustration parameter moderately decreases with Mn substitution, but the compositional variation is not monotonous.


In patients undergoing coronary artery bypass grafting, is endoscopic harvesting superior to open radial artery harvesting?
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'In patients undergoing coronary artery bypass grafting, is endoscopic radial artery harvesting (ERAH) superior to open radial artery harvesting in terms of postoperative complications, mortality, graft quality and patency rates?'. Altogether 130 papers were found using the reported search, of which 5 represented the best evidence to answer the clinical question. Two studies were meta-analyses and 3 were randomized trials. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. In terms of graft quality, 2 randomized studies showed preserved endothelial integrity and vasoreactivity with ERAH, whereas 1 randomized study found superior endothelial function with open radial artery harvesting. Importantly, 3 studies showed graft patency was not compromised with ERAH. One meta-analysis reported no differences in graft patency between groups at 1 year [odds ratio (OR) 1.24] and up to 3-5-years follow-up (OR 1.81), as well as similar perioperative myocardial infarction rates (OR 0.80). Two meta-analyses found similar mortality in the perioperative period (OR 0.62-0.78) and up to 5 years (OR 0.64-0.67); ERAH reduced the incidence of perioperative wound complications (P-values 0.001-0.03); however, harvest times were increased with ERAH (P < 0.0005). We conclude that ERAH is non-inferior to open radial artery harvesting in terms of mortality, graft quality and patency rates, but superior in terms of reducing perioperative wound complications, with good cosmetic effect. However, these benefits come at the cost of increased harvesting time.


Is corticosteroid coinjection necessary for radiosynoviorthesis of patients with hemophilia?
Radiation synovectomy is frequently combined with intraarticular corticosteroid injection in the treatment of rheumatoid arthritis to reduce local inflammation and lymphatic clearance of radiocolloid. However, this practice is not universally accepted because corticosteroids have local and systemic toxicity such as osteonecrosis and cartilage damage and whether simultaneous corticosteroid injection together with radiocolloids is necessary in other forms of chronic synovitis like patients with hemophilia remains to be determined. In this study, we performed radiosynoviorthesis in 14 joints of 12 patients with hemophilia with chronic knee synovitis without corticosteroid coadministration and measured radiocolloid leakage from the joint space. Five mCi Y-90 radiocolloid was injected under local anesthesia and the needle was flushed with additional lidocaine injection instead of corticosteroid. The joint was then manipulated through a full range of extension and flexion to distribute the particles homogeneously throughout the joint space. The joint was then splinted for 48 hours to minimize leakage from the joint space. After the immobilization period, radiocolloid leakage was evaluated using a gamma camera with a 20% window centered over the maximum Bremsstrahlung photopeak of Y-90. Regions of interest were drawn to the injection site on the knee joint and to the ipsilateral inguinal lymph node area. Leakage of radiocolloid was calculated by dividing the background-corrected counts/pixel at the inguinal region by the counts/pixel at the injection site. One of 12 patients who had knee arthroplasty was previously found to have a high amount of leakage. In this patient, 70% of radiocolloid at the injection site drained into the pelvic lymph nodes. In the remaining 11 patients, no lymph nodes were visualized in the groin area and the measured average leakage for these patients was 2.3% (range, 0-13). We concluded that in cases of appropriate particle size and strict immobilization of knee joints, leakage of radiocolloid was minimal and steroid coinjection might not be necessary for radiosynoviorthesis of patients with hemophilia with chronic knee synovitis.


Exogenous recombinant interleukin-2 abrogates anterior-chamber-associated immune deviation.
Alloantigens placed into the anterior chamber of the eye elicit antigen-specific suppression of systemic delayed-type hypersensitivity (DTH) responses and severe impairment of skin allograft rejection. This pattern of immunological impairment has been termed anterior-chamber-associated immune deviation (ACAID). We have previously proposed that ACAID is the underlying mechanism responsible for immunologic privilege within the anterior chamber of the eye. The present study examined the role of interleukin 2 (IL-2) in the induction of ACAID. As previously shown, intracameral inoculation of P815 cells into allogeneic BALB/c recipients resulted in antigen specific suppression of DTH responses. However, subcutaneous administration of recombinant IL-2 along with intracameral inoculation of P815 cells prevented ACAID and permitted the development of positive DTH responsiveness in BALB/c hosts. In order to abrogate ACAID, exogenous IL-2 was required only during the first 72 hr following anterior chamber presentation of alloantigens. Collectively, the results indicate that induction of ACAID and the antigen-specific suppression of systemic DTH responses are due to IL-2 deficiency during the early stages of antigen perception. This in turn implies that the immunological privilege within the anterior chamber of the eye may pivot on the deficiency of a single lymphokine, interleukin 2.


Survey of Machine Learning Techniques in Drug Discovery.
Drug discovery, which is the process of discovering new candidate medications, is very important for pharmaceutical industries. At its current stage, discovering new drugs is still a very expensive and time-consuming process, requiring Phases I, II and III for clinical trials. Recently, machine learning techniques in Artificial Intelligence (AI), especially the deep learning techniques which allow a computational model to generate multiple layers, have been widely applied and achieved state-of-the-art performance in different fields, such as speech recognition, image classification, bioinformatics, etc. One very important application of these AI techniques is in the field of drug discovery. We did a large-scale literature search on existing scientific websites (e.g, ScienceDirect, Arxiv) and startup companies to understand current status of machine learning techniques in drug discovery. Our experiments demonstrated that there are different patterns in machine learning fields and drug discovery fields. For example, keywords like prediction, brain, discovery, and treatment are usually in drug discovery fields. Also, the total number of papers published in drug discovery fields with machine learning techniques is increasing every year. The main focus of this survey is to understand the current status of machine learning techniques in the drug discovery field within both academic and industrial settings, and discuss its potential future applications. Several interesting patterns for machine learning techniques in drug discovery fields are discussed in this survey.


Cloning and functional expression of a human liver organic cation transporter.
Polyspecific organic cation transporters in the liver mediate the elimination of a wide array of endogenous amines and xenobiotics. In contrast to our understanding of the mechanisms of organic cation transport in rat liver, little is known about the mechanisms of organic cation transport in the human liver. We report the cloning, sequencing, and functional characterization of the first human polyspecific organic cation transporter from liver (hOCT1). hOCT1 (554 amino acids) is 78% identical to the previously cloned organic cation transporter from rat, rOCT1 [Nature (Lond.) 372:549-552 (1994)]. In Xenopus laevis oocytes injected with the cRNA of hOCT1, the specific uptake of the organic cation 3H-1-methyl-4-phenylpyridinium (3H-MPP+) was significantly enhanced (8-fold) over that in water-injected oocytes. Uptake of 3H-MPP+ was saturable (K(m) = 14.6 +/- 4.39 microM) and sensitive to membrane potential. Both small monovalent organic cations such as tetraethylammonium and N1-methylnicotinamide and bulkier organic cations (e.g., vecuronium and decynium-22) inhibited the uptake of 3H-MPP+. In addition, the bile acid taurocholate inhibited the uptake of 3H-MPP+ in oocytes expressing hOCT1. Northern analysis demonstrated that the mRNA transcript of hOCT1 is expressed primarily in the human liver, whereas the mRNA transcript of rOCT1 is found in rat kidney, liver, intestine, and colon [Nature (Lond.) 372:549-552 (1994)]. In comparison to rOCT1, hOCT1 exhibits notable differences in its kinetic characteristics and tissue distribution. The functional expression of hOCT1 will provide a powerful tool for elucidation of the mechanisms of organic cation transport in the human liver and understanding of the mechanisms involved in the disposition and hepatotoxicity of drugs.


Depression, Hopelessness and Social Support among Breast Cancer Patients: in Highly Endogamous Population
Aim: The aim of this study was to assess the relationship between different demographic variables, hopelessness, depression and social support of Breast cancer patients in Qatari's population. Design: This is an observational cohort hospital based study. Subjects and Methods: The study included 678 breast cancer patients. The questionnaires included a demographic questionnaire, the Beck Hopelessness Scale (BHS), Back Depression Scale (BDS) and Multidimensional Scale of Perceived Social Support (MSPSS). The demographic questionnaire was used to assess patients' basic information including gender, age, marital status, education, family size, and place of residence. Medical information regarding cancer stage, the time passed since diagnosis, treatment, and duration of disease were recorded. Results: The mean age of the studied women was 47.7±10.2 years. Among the studied patients, 34.7% were Qataris and 65.3% were Arab expatriates. Nearly 39.2% of the patients were in pre-menopausal status and 60.8% in post-menopausal status. 86.1% of women were married. 14.6% were illiterate women, 20.9% were university graduates and 37.2% were housewives. Smoking habit was less common in studied Arab women (9.1%), but, sheesha smoking was more common, 17.7%. Daily physical activity indicated 25.7% were walking 30 minutes per-day and 14% were walking 60 minutes per day. 30.4% of them had consanguineous parents. Breast feeding was practiced among 67.7% of women and over 73% were considered overweight and obese. Furthermore, over 75% of breast cancer women were at the Stage 3 (40.9%) and Stage 4 (35.8%) of cancer. The percentage of patients who underwent mastectomy and lumpectomy were 49.3 % and 50.7%, respectively. It was observed that 27.7% of BDI patients had moderate depression and 19.5% of the BDI patients had severe depression and with mean and standard deviation 25.1±7.7. Also, the mean and SD of BDI for consanguineous has showed statistically significant 28.4±5.7 than non- consanguineous 23.2± 8.0 (p<0.001). All socio-demographic variables showed statistically significant differences with the total BHS score. The highest score belongs to the family sub-dimension. Conclusion: The present study indicates that hopelessness of the patients with breast cancer decreased with the increase in their social support. Therefore, activating patient social support systems is of importance in increasing their levels of hope. The present study revealed the coexistence of the socio-demographic, physical, psychological, and cognitive problems faced by patients with cancer.


No change in glomerular heparan sulfate structure in early human and experimental diabetic nephropathy.
Heparan sulfate (HS) proteoglycans are major anionic glycoconjugates of the glomerular basement membrane and are thought to contribute to the permeability properties of the glomerular capillary wall. In this study we evaluated whether the development of (micro) albuminuria in early human and experimental diabetic nephropathy is related to changes in glomerular HS expression or structure. Using a panel of recently characterized antibodies, glomerular HS expression was studied in kidney biopsies of type I diabetic patients with microalbuminuria or early albuminuria and in rat renal tissue after 5 months diabetes duration. Glomerular staining, however, revealed no differences between control and diabetic specimens. A significant (p < 0.05) approximately 60% increase was found in HS N-deacetylase activity, a key enzyme in HS sulfation reactions, in diabetic glomeruli. Structural analysis of glomerular HS after in vivo and in vitro radiolabeling techniques revealed no changes in HS N-sulfation or charge density. Also HS chain length, protein binding properties, as well as disaccharide composition did not differ between control and diabetic glomerular HS samples. These results indicate that in experimental and early human diabetic nephropathy, increased urinary albumin excretion is not caused by loss of glomerular HS expression or sulfation and suggest other mechanisms to be responsible for increased glomerular albumin permeability.