Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.
Human astrocytes express Fas yet are resistant to Fas-induced apoptosis. Here, we report that calcium/calmodulin-dependent protein kinase II (CaMKII) is constitutively activated in human astrocytes and protects the cells from apoptotic stimulation by Fas agonist. Once stimulated, Fas recruits Fas-associated death domain and caspase-8 for the assembly of the death-inducing signaling complex (DISC); however, caspase-8 cleavage is inhibited in the DISC. Inhibition of CaMKII kinase activity inhibits the expression of phosphoprotein enriched astrocytes-15 kDa/phosphoprotein enriched in diabetes (PEA-15/PED) and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (c-FLIP), thus releasing their inhibition of caspase-8 cleavage. Inhibition of PEA-15/PED or c-FLIP by small interfering RNA sensitizes human astrocytes to Fas-induced apoptosis. In contrast, inhibition of CaMKII, PEA-15, or c-FLIP does not affect the sensitivity of human astrocytes to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL death receptors (DR4, DR5) are weakly expressed at mRNA, protein, and cell surface levels and thus fail to mediate the assembly of the DISC in human astrocytes. Overexpression of DR5 restores TRAIL signaling pathways and sensitizes the human astrocytes to TRAIL-induced apoptosis if CaMKII kinase activity or expression of PEA-15 and c-FLIP is inhibited; the results suggest that CaMKII-mediated pathways prevent TRAIL-induced apoptosis in human astrocytes under conditions in which TRAIL death receptors are upregulated. This study has therefore identified the molecular mechanisms that protect normal human astrocytes from apoptosis induced by Fas ligand and TRAIL.


HIV Testing, Linkage to HIV Medical Care, and Interviews for Partner Services Among Women - 61 Health Department Jurisdictions, United States, Puerto Rico, and the U.S. Virgin Islands, 2015.
Diagnoses of human immunodeficiency virus (HIV) infection among women declined 17% during 2011-2015, and a total of 7,498 women received a diagnosis of HIV infection in 2015 (1). Although black or African American (black) women accounted for only 12% of the U.S. female population, 60% of women with newly diagnosed HIV infection were black (1,2). By the end of 2014, an estimated 255,900 women were living with HIV infection (3), including approximately 12% who did not know they were infected; in addition, approximately 45% of women who had received a diagnosis had not achieved viral suppression (3). HIV testing is an important public health strategy for identifying women with HIV infection and linking them to HIV medical care. Analysis of CDC-funded program data submitted by 61 health departments in 2015 indicated that among 4,749 women tested who received a diagnosis of HIV infection, 2,951 (62%) had received a diagnosis in the past (previous diagnosis), and 1,798 (38%) were receiving a diagnosis for the first time (new diagnosis). Of those who had received a previous diagnosis, 87% were not in HIV medical care at the time of the current test. Testing and identifying women who are living with HIV infection but who are not in care (regardless of when they received their first diagnosis) and rapidly linking them to care so they can receive antiretroviral therapy and become virally suppressed are essential for reducing HIV infection among all women.


Ceria-vesicle nanohybrid therapeutic for modulation of innate and adaptive immunity in a collagen-induced arthritis model.
Commencing with the breakdown of immune tolerance, multiple pathogenic factors, including synovial inflammation and harmful cytokines, are conjointly involved in the progression of rheumatoid arthritis. Intervening to mitigate some of these factors can bring a short-term therapeutic effect, but other unresolved factors will continue to aggravate the disease. Here we developed a ceria nanoparticle-immobilized mesenchymal stem cell nanovesicle hybrid system to address multiple factors in rheumatoid arthritis. Each component of this nanohybrid works individually and also synergistically, resulting in comprehensive treatment. Alleviation of inflammation and modulation of the tissue environment into an immunotolerant-favourable state are combined to recover the immune system by bridging innate and adaptive immunity. The therapy is shown to successfully treat and prevent rheumatoid arthritis by relieving the main symptoms and also by restoring the immune system through the induction of regulatory T cells in a mouse model of collagen-induced arthritis.


Nifedipine versus terbutaline, tocolytic effectiveness and maternal and neonatal adverse effects: a randomized, controlled pilot trial.
Although previous evidence suggests advantages of nifedipine over terbutaline as tocolytic agents, in some jurisdictions, terbutaline is approved for use and nifedipine is not. In women in preterm labour, we compared the impact of terbutaline versus nifedipine on inhibition of uterine contractions, preterm birth, neonatal sepsis, intracranial haemorrhage or necrotizing enterocolitis, death or admission to a neonatal intensive care unit and maternal adverse reactions. We randomized 32 women to nifedipine and 34 to terbutaline. We found no difference between groups in tocolysis or preterm birth. No serious maternal adverse effects or serious neonatal adverse outcome occurred in either group. Less serious maternal adverse effects less common with terbutaline included flushing (2.94% versus 43.7%) and headache (5.9% versus 31.2%). The administration of terbutaline increased tremor (76.4% versus 0%), nausea (58.8% versus 9.4%) and dizziness (29.4% versus 6.25%). The total number of side effects, and the proportion of women experiencing one or more side effects, proved greater with terbutaline. In this study, terbutaline and nifedipine performed similarly in their tocolytic effects. Each drug has specific side effects, although overall, nifedipine was associated with fewer adverse effects.


Effects of body weight, adrenal status, and estrogen priming on hypothalamic progestin receptors in male and female rats.
Some laboratories have reported sex differences in the effect of estrogen priming on neural progestin receptor concentration, whereas others find no such differences. The present studies sought to identify experimental variables which might differentially influence the measurable level of hypothalamic cytosol progestin receptors in adult male and female rats. The influence of three variables, body weight, adrenal status, and estrogen priming regimen, was evaluated. Treatment with low doses of estrogen (2 or 8 micrograms of estradiol benzoate (EB) 48 hr before sacrifice) was slightly but not significantly more effective in elevating hypothalamic progestin receptor content in age-matched females than in males despite the 40% greater body weights of males. When the same doses of EB were administered per 200 gm of body weight to animals with and without adrenal glands, both basal and estrogen-induced levels of hypothalamic progestin receptor were significantly higher in adrenalectomized/gonadectomized rats than in rats which were gonadectomized only, regardless of sex. There was no significant effect of sex or any interaction between sex, adrenal status, or estrogen priming dose. The only significant sex difference in brain progestin receptors occurred when weight-matched males and females received multiple injections of higher priming doses of estrogen (three daily injections of 10 micrograms of EB). Under these conditions, females showed up to 2-fold higher levels of hypothalamic progestin receptors than males, regardless of adrenal status. These data suggest that sex differences may exist in the neural progestin receptor systems of male and female rats, but the relationship of these differences to sex differences in neuroendocrine function or behavior is not clear.


[Use of 1- and 2-thionaphthylacetates as cholinesterase substrates].
1- and 2-thionaphthylacetates were tested as cholinesterase substrates. It was shown that the butyrilcholinesterase from horse serum can hydrolize these compounds. The hydrolysis velocity of 1-thionaphthylacetate was comparable with hydrolysis velocity of acetylthiocholine (the well known cholinesterase substrate), but 2-thionaphthylacetate was hydrolysed more slowly. The values of the kinetic parameters V and K(m) for butyrylcholinesterase hydrolysis of 1- and 2-thionaphthylacetates were determined. It was offered to use 1-thionaphthylacetates as the substrate for cholinesterases.


Promoter methylation analysis of O6-methylguanine-DNA methyltransferase in glioblastoma: detection by locked nucleic acid based quantitative PCR using an imprinted gene (SNURF) as a reference.
Epigenetic silencing of the MGMT gene by promoter methylation is associated with loss of MGMT expression, diminished DNA-repair activity and longer overall survival in patients with glioblastoma who, in addition to radiotherapy, received alkylating chemotherapy with carmustine or temozolomide. We describe and validate a rapid methylation sensitive quantitative PCR assay (MS-qLNAPCR) using Locked Nucleic Acid (LNA) modified primers and an imprinted gene as a reference. An analysis was made of a database of 159 GBM patients followed between April 2004 and October 2008. After bisulfite treatment, methylated and unmethylated CpGs were recognized by LNA primers and molecular beacon probes. The SNURF promoter of an imprinted gene mapped on 15q12, was used as a reference. This approach was used because imprinted genes have a balanced copy number of methylated and unmethylated alleles, and this feature allows an easy and a precise normalization. Concordance between already described nested MS-PCR and MS-qLNAPCR was found in 158 of 159 samples (99.4%). The MS-qLNAPCR assay showed a PCR efficiency of 102% and a sensitivity of 0.01% for LNA modified primers, while unmodified primers revealed lower efficiency (69%) and lower sensitivity (0.1%). MGMT promoter was found to be methylated using MS-qLNAPCR in 70 patients (44.02%), and completely unmethylated in 89 samples (55.97%). Median overall survival was of 24 months, being 20 months and 36 months, in patients with MGMT unmethylated and methylated, respectively. Considering MGMT methylation data provided by MS-qLNAPCR as a binary variable, overall survival was different between patients with GBM samples harboring MGMT promoter unmethylated and other patients with any percentage of MGMT methylation (p = 0.003). This difference was retained using other cut off values for MGMT methylation rate (i.e. 10% and 20% of methylated allele), while the difference was lost when 50% of MGMT methylated allele was used as cut-off. We report and clinically validate an accurate, robust, and cost effective MS-qLNAPCR protocol for the detection and quantification of methylated MGMT alleles in GBM samples. Using MS-qLNAPCR we demonstrate that even low levels of MGMT promoter methylation have to be taken into account to predict response to temozolomide-chemotherapy.


Prevalence and Risk Factors of Toxoplasma gondii Infection Among Five Wild Rodent Species from Five Provinces of China.
Toxoplasma gondii, an intracellular zoonotic parasite, can infect humans and various animals worldwide. Wild rodents plan an important role as intermediate hosts of T. gondii. Some studies on T. gondii from wild rodents have been published, but the investigation data of T. gondii in wild rodents in China are limited. Therefore, brain tissue samples from 382 wild rodents in four provinces and one autonomous region of China were screened by PCR amplification of T. gondii B1 gene. Furthermore, the wild rodents were identified as five species based on their morphological characteristics, including Citellus dauricus (n = 35 from Heilongjiang), Lasiopodomys brandti (n = 81 from Inner Mongolia), Apodemus agrarius (n = 12 from Heilongjiang), Rattus norvegicus (n = 2 from Heilongjiang; n = 99 from Zhejiang; n = 54 from Shanxi), and Mus musculus (n = 99 from Guangxi). The overall prevalence of T. gondii in these wild rodents was 5.24% (20/382) in this study. At different regions, the highest prevalence of T. gondii was in Guangxi (12.12%) compared with other regions (0% in Heilongjiang; 2.47% in Inner Mongolia; 2.02% in Zhejiang; 7.41% in Shanxi). At different climates, the higher prevalence was found in temperate/mesothermal climates (7.07%) compared with continental/microthermal climates (3.26%). Also, the results showed that M. musculus had the highest prevalence of T. gondii infection (12.12%) among the rodent species sampled. Moreover, sampling year was significantly related to the prevalence of T. gondii in investigated wild rodents (p = 0.0117). This is the first report of T. gondii in wild rodents from Zhejiang, Guangxi, Shanxi, Heilongjiang provinces and Inner Mongolia autonomous region in China, providing the fundamental information for further prevention and control of toxoplasmosis in China.


Human hepatocytes as a tool for studying toxicity and drug metabolism.
Drugs are usually biotransformed into new chemical species that may have either toxic or therapeutic effects. Drug metabolism studies are routinely performed in laboratory animals but, due to metabolic interspecies differences when compared to man, they are not accurate enough to anticipate the metabolic profile of a drug in humans. Human hepatocytes in primary culture provide the closest in vitro model to human liver and the only model that can produce a metabolic profile of a given drug that is very similar to that found in vivo. However their availability is limited due to the restricted access to suitable tissue samples. The scarcity of human liver has led to optimising the cryopreservation of adult hepatocytes for long-term storage and regular supply. Human hepatocytes in primary culture express typical hepatic functions and express drug metabolising enzymes. Moreover, qualitative and quantitative similarities between in vitro and in vivo metabolism of drugs were observed. Different strategies have been envisaged to prolong cell survival and delay the spontaneous decay of the differentiated phenotype during culture. Thus, hepatocytes represent the most appropriate model for the evaluation of integrated drug metabolism, toxicity/metabolism correlations, mechanisms of hepatotoxicity, and the interactions (inhibition and induction) of xenobiotics and drug-metabolising enzymes. However, in view of limitations of primary hepatocytes, efforts are made to develop alternative cellular models (i.e. metabolic competent CYP-engineered cells stably expressing individual CYPs and transient expression of CYPs by transduction of hepatoma cells with recombinant adenoviruses). In summary, several cellular tools are available to address key issues at the earliest stages of drug development for a better candidate selection and hepatotoxicity risk assessment.


Data hiding in image and video: Part II--designs and applications.
This paper applies the solutions to the fundamental issues addressed in Part I to specific design problems of embedding data in image and video. We apply multilevel embedding to allow the amount of embedded information that can be reliably extracted to be adaptive with respect to the actual noise conditions. When extending the multilevel embedding to video, we propose strategies for handling uneven embedding capacity from region to region within a frame as well as from frame to frame. We also embed control information to facilitate the accurate extraction of the user data payload and to combat such distortions as frame jitter. The proposed algorithm can be used for a variety of applications such as copy control, access control, robust annotation, and content-based authentication.


The progression of myopia in school age children: data from the Columbia Medical Plan.
The purpose of this study was to characterize the clinical course of myopia in a selected pediatric population. The computerized records of a health maintenance organization provided longitudinal data on 501 children aged 5 to 15 years. We examined the influence of age at diagnosis, gender, race, and initial refraction on progression of myopia. Mean follow-up was 34 months, with 75% of children having follow-up longer than 16 months. The mean rate of myopic progression was greater for children whose myopia was diagnosed at a younger age (5-7 years, -0.56 diopters/year versus 11-15 years, -0.28 diopters/year; p < 0.0001). Children with more than one diopter of myopia at first diagnosis progressed faster than children with less than or equal to one diopter of myopia (mean rate -0.48 diopter/year versus -0.41 diopter/year; p = 0.05). Cumulative event rate curves suggest a gender effect in the prepuberty years of 8 to 10, with myopia progressing faster in girls than boys (p = 0.003). Progression of myopia did not differ between white and non-white children. More rapidly progression of myopia is associated with younger age at initial diagnosis and greater severity of initial myopic refraction.


Replication of Merkel cell polyomavirus induces reorganization of promyelocytic leukemia nuclear bodies.
Merkel cell polyomavirus (MCPyV) is associated with Merkel cell carcinoma (MCC), a rare but aggressive skin cancer. The virus is highly prevalent: 60-80 % of adults are seropositive; however, cells permissive for MCPyV infection are unknown. Consequently, very little information about the MCPyV life cycle is available. Until recently, MCPyV replication could only be studied using a semi-permissive in vitro replication system (Neumann et al., 2011; Feng et al., 2011, Schowalter et al., 2011). MCPyV replication most likely depends on subnuclear structures such as promyelocytic leukemia protein nuclear bodies (PML-NBs), which are known to play regulatory roles in the infection of many DNA viruses. Here, we investigated PML-NB components as candidate host factors to control MCPyV DNA replication. We showed that PML-NBs change in number and size in cells actively replicating MCPyV proviral DNA. We observed a significant increase in PML-NBs in cells positive for MCPyV viral DNA replication. Interestingly, a significant amount of cells actively replicating MCPyV did not show any Sp100 expression. While PML and Daxx had no effect on MCPyV DNA replication, MCPyV replication was increased in cells depleted for Sp100, strongly suggesting that Sp100 is a negative regulator of MCPyV DNA replication.


On the problems of constructing minimal realizations for two-dimensional filters.
The input-output behavior of a two-dimensional linear filter is defined by a formal power series in two variables. If the power series is rational the dynamics of the filter is described by updating equations on finite dimensional local state spaces. The class of realizations considered in this paper is constituted by doubly indexed dynamical systems of reduced structure. The construction of the class of minimal realizations is based on matrix representation techniques of noncommutative power series.


Co-circulation of Chikungunya Virus during the 2015-2017 Zika Virus Outbreak in Pernambuco, Brazil: An Analysis of the Microcephaly Epidemic Research Group Pregnancy Cohort.
Co-circulation of arthropod-borne viruses, particularly those with shared mosquito vectors like Zika (ZIKV) and Chikungunya (CHIKV), is increasingly reported. An accurate differential diagnosis between ZIKV and CHIKV is of high clinical importance, especially in the context of pregnancy, but remains challenging due to limitations in the availability of specialized laboratory testing facilities. Using data collected from the prospective pregnancy cohort study of the Microcephaly Epidemic Research Group, which followed up pregnant persons with rash during the peak and decline of the 2015-2017 ZIKV epidemic in Recife, Pernambuco, Brazil, this study aims to describe the geographic and temporal distribution of ZIKV and CHIKV infections and to investigate the extent to which ZIKV and CHIKV infections may be clinically differentiable. Between December 2015 and June 2017, we observed evidence of co-circulation with laboratory confirmation of 213 ZIKV mono-infections, 55 CHIKV mono-infections, and 58 sequential ZIKV/CHIKV infections (i.e., cases with evidence of acute ZIKV infection with concomitant serological evidence of recent CHIKV infection). In logistic regressions with adjustment for maternal age, ZIKV mono-infected cases had lower odds than CHIKV mono-infected cases of presenting with arthralgia (aOR, 99% CI: 0.33, 0.15-0.74), arthritis (0.35, 0.14-0.85), fatigue (0.40, 0.17-0.96), and headache (0.44, 0.19-1.90). However, sequential ZIKV/CHIKV infections complicated discrimination, as they did not significantly differ in clinical presentation from CHIKV mono-infections. These findings suggest clinical symptoms alone may be insufficient for differentiating between ZIKV and CHIKV infections during pregnancy and therefore laboratory diagnostics continue to be a valuable tool for tailoring care in the event of arboviral co-circulation.


High microvessel density determines a poor outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus chemotherapy.
Diffuse large B-cell lymphoma is a clinically and molecularly heterogeneous disease. Gene expression profiling studies have shown that the tumor microenvironment affects survival and that the angiogenesis-related signature is prognostically unfavorable. The contribution of histopathological microvessel density to survival in diffuse large B-cell lymphomas treated with immunochemotherapy remains unknown. The purpose of this study is to assess the prognostic impact of histopathological microvessel density in two independent series of patients with diffuse large B-cell lymphoma treated with immunochemotherapy. One hundred and forty-seven patients from the Leukemia Lymphoma Molecular Profiling Project (training series) and 118 patients from the Catalan Lymphoma-Study group-GELCAB (validation cohort) were included in the study. Microvessels were immunostained with CD31 and quantified with a computerized image analysis system. The stromal scores previously defined in 110 Leukemia Lymphoma Molecular Profiling Project cases were used to analyze correlations with microvessel density data. Microvessel density significantly correlated with the stromal score (r=0.3209; P<0.001). Patients with high microvessel density showed significantly poorer overall survival than those with low microvessel density both in the training series (4-year OS 54% vs. 78%; P=0.004) and in the validation cohort (57% vs. 81%; P=0.006). In multivariate analysis, in both groups high microvessel density was a statistically significant unfavorable prognostic factor independent of international prognostic index [training series: international prognostic index (relative risk 2.7; P=0.003); microvessel density (relative risk 1.96; P=0.002); validation cohort: international prognostic index (relative risk 4.74; P<0.001); microvessel density (relative risk 2.4; P=0.016)]. These findings highlight the impact of angiogenesis in the outcome of patients with diffuse large B-cell lymphoma and the interest of evaluating antiangiogenic drugs in clinical trials.


Placentophagia: a biobehavioral enigma (or De gustibus non disputandum est).
Although ingestion of the afterbirth during delivery is a reliable component of parturitional behavior of mothers in most mammalian species, we know almost nothing of the direct causes or consequences of the act. Traditional explanations of placentophagia, such as general or specific hunger, are discussed and evaluated in light of recent experimental results. Next, research is reviewed which has attempted to distinguish between placentophagia as a maternal behavior and placentophagia as an ingestive behavior. Finally, consequences of the behavior, which may also be viewed as ultimate causes in an evolutionary sense, are considered, such as the possibility of beneficial effects on maternal behavior or reproductive competence, on protection against predators, and on immunological protection afforded either the mother or the young.


Dietary long-chain (n-3) fatty acids facilitate immune cell activation in sedentary, but not exercise-trained rats.
Dietary long-chain (n-3) fatty acids from fish oil and low intensity exercise have been reported, independently, to inhibit tumor growth in rats. The mechanism for these effects is not known but may be related to diet and exercise-induced alterations in immune function. To study the individual and combined effects of these interventions on anticancer immune responses, healthy Fischer 344 rats were fed, for 4 wk, one of two semi-purified diets (polyunsaturated to saturated fatty acid ratio = 0.9), which differed only in the composition of fat (200 g/kg) and provided long-chain (n-3) fatty acids at 0 or 33 g/kg of total fat. Rats were randomly assigned to groups in a 2 x 2 experimental design to swim 3 h/d or to remain sedentary. For sedentary rats, dietary (n-3) fatty acids increased (P < 0.05) splenic natural killer (NK) cell cytotoxicity and the percentage of activated (CD71+) T and B cells and macrophages in spleen after concanavalin A stimulation. For exercise-trained rats, feeding the high (n-3) diet decreased (P < 0.05) the percentage of CD71+ T helper and B cells after stimulation. NK cell cytotoxicity, and the percentages of CD71+ T cells, B cells and macrophages after stimulation in the high (n-3)-fed exercise-trained group were not different than those of the low (n-3)-fed sedentary group. Thus individually, but not in combination, long-chain (n-3) fatty acids and low intensity exercise may be advantageous by augmenting cell-mediated immune function and NK cell cytotoxicity in healthy rats.


A novel HMGA2::KITLG fusion in a dedifferentiated liposarcoma with amplification of MDM2 and HMGA2.
High-mobility group AT-hook 2 (HMGA2) is rearranged in various types of mesenchymal tumors, particularly lipomas. HMGA2 is also co-amplified with mouse double minute 2 (MDM2) in well-differentiated liposarcoma/dedifferentiated liposarcoma (WDLPS/DDLPS). We report a case of relapsed DDLPS with a novel in-frame fusion between HMGA2 and KITLG, which encodes the ligand for KIT kinase, a critical protein involved in gametogenesis, hematopoiesis, and melanogenesis. The HMGA2 breakpoint is in intron 3, a commonly observed location for HMGA2 rearrangements, while the KITLG breakpoint is in intron 2, leading to a fusion protein that contains almost the entire coding sequence of KITLG. By immunohistochemical staining, tumor cells expressed KIT and showed phosphorylated MAPK, a major KIT downstream target. We suggest an oncogenic mechanism that involves the overexpression of KITLG caused by its rearrangement with HMGA2, leading to the constitutive activation of KIT kinase. While MDM2 amplification was observed in both the primary tumor and the relapsed tumor, the HMGA2::KITLG was only present in the relapsed tumor, indicating the role of HMGA2::KITLG in disease progression.


TMD and GOHAI indices of Brazilian institutionalised and community-dwelling elderly.
Considering the controversy in the literature regarding several aspects of temporomandibular dysfunction (TMD) in elderly populations and the absence of reliable data on elderly Brazilians in this field, this study consisted of an evaluation of TMD prevalence and the self-perception of oral health among institutionalised and community-dwelling elderly in São José dos Campos, Brazil. Two hundred and fifteen community-dwelling and 185 institutionalised elderly people were evaluated by the Helkimo anamnestic (Ai) and clinical dysfunction (Di) indices and answered a questionnaire using the Geriatric Oral Health Assessment Index (GOHAI). The major prevalence of TMD symptoms was for the Ai0 (symptom-free) group (69.5%), while the major prevalence of clinical signs was for the DiI (mild) group (56%). Women presented a higher AiII classification than men (chi(2) test, p = 0.049). Community-dwelling elderly presented a significantly lower Ai0 classification than the institutionalised ones (Two ratios equality test, p < 0.001). There was no relationship between the institutionalised status and the clinical dysfunction index for Di0 and DiIII classification (Two ratios equality test, p = 0.194 and 0.535 respectively). The institutionalised elderly presented greater (One-way ANOVA = 0.005) self-perception of oral health (33.45) than did the community-dwelling group (32.66). There were only weak Pearson's correlations among the anamnestic (-33.0%) or clinical (-14.7%) findings by the TMD and GOHAI indices. Symptom-free (Ai0) institutionalised elderly presented better scores in all GOHAI dimensions and elderly representing an absence of clinical TMD signs (Di0) presented higher GOHAI physical dimension scores in both groups. The prevalence of TMD symptoms among this sample of elderly individuals was relatively low, self-perception of oral health was reasonable and a weak, inverse correlation was found between TMD signs and symptoms and elderly self-perception of oral health measured by the GOHAI index.


National survey of pediatricians' violence prevention counseling.
Recommendations for child health care providers to counsel patients and their families on violence prevention have been issued by a number of major health care organizations. To assess the knowledge, attitudes, training, and practices of pediatricians concerning violence prevention counseling in the areas of family violence, discipline, television viewing, peer violence, and guns in the home. Survey. A national random sample of 1350 pediatricians, divided equally among residents in their final year of training, practitioners who had completed their residency training within the last 5 years, and those who had completed their training more than 5 years ago. Knowledge, attitudes, training, and current practices regarding violence prevention counseling. The overall response rate was 41%. When providing health supervision to patients, most pediatricians never or rarely screen for family and community violence, peer violence, and weapons. For example, 68% of residents and 73% of practitioners never or rarely screen for domestic violence, 56% of residents and 67% of practitioners never or rarely ask adolescents about their involvement in physical fighting, and 54% of residents and 56% of practitioners never or rarely identify families who have guns in the home. Regarding preparation for providing violence prevention counseling, 76% of residents and 83% of practitioners rated their training as inadequate. Receiving training in the prevention of child/adolescent violence in medical school (P<.001), residency (P<.001), or fellowship/continuing medical education (P=.002) were major determinants of more frequent violence prevention counseling. Pediatricians who believed that parents rarely or never follow through on a physician's advice about safe gun storage, switching to nonviolent disciplining techniques, or limiting their child's television viewing were less likely to ask or advise patients in these areas. Pediatricians are not adequately prepared to provide violence prevention counseling, and few currently screen for exposure to family and community violence, peer violence, and access to weapons. Comprehensive information about violence prevention should be integrated into medical education, and the efficacy of violence prevention counseling strategies should be evaluated.


Direct measurement of oxygen consumption rates from attached and unattached cells in a reversibly sealed, diffusionally isolated sample chamber.
Oxygen consumption is a fundamental component of metabolic networks, mitochondrial function, and global carbon cycling. To date there is no method available that allows for replicate measurements on attached and unattached biological samples without compensation for extraneous oxygen leaking into the system. Here we present the Respiratory Detection System, which is compatible with virtually any biological sample. The RDS can be used to measure oxygen uptake in microliter-scale volumes with a reversibly sealed sample chamber, which contains a porphyrin-based oxygen sensor. With the RDS, one can maintain a diffusional seal for up to three hours, allowing for the direct measurement of respiratory function of samples with fast or slow metabolic rates. The ability to easily measure oxygen uptake in small volumes with small populations or dilute samples has implications in cell biology, environmental biology, and clinical diagnostics.


Dysregulation of LncRNAs in Placenta and Pathogenesis of Preeclampsia.
Preeclampsia, a gestational disease characterized by hypertension and proteinuria twenty weeks into pregnancy, is one of the leading causes of fetal and maternal mortality. Although multiple genetic and environmental factors are found to be related to the preeclampsia risk, the pathogenic pathways remain largely undefined. The placenta plays a critical role in the fetal development by carrying out the barrier, fetal-maternal exchange, and endocrine functions during pregnancy. Accumulated data indicated that the expression of multiple long noncoding RNA (LncRNA) is dysregulated in preeclamptic placentas. Moreover, manipulation of LncRNA expression led to functional alterations in trophoblast cell cultures, including changes in proliferation, differentiation, apoptosis, and migration. This article reviews published data on this subject and provides detailed information on the regulation and function of LncRNAs IGF2/H19, MEG3, SPRY4-IT1, HOTAIR, MALAT1, and FLT1P1 and CEACAMP8 in placental trophoblasts. The potential mechanisms underlying the action of these LncRNAs are also discussed to facilitate a better understanding on the potential role of these LncRNAs for the pathogenesis of preeclampsia. It is elaborated that some lncRNAs probably contribute to the pathogenesis of preeclampsia through methylation, Notch-EGFL7 signaling pathway and Wnt/β-catenin pathway.


Selective Direct Toxicity of Cocaine on Fetal Mouse Neurons: Teratogenic Implications of Neurite and Apoptotic Neuronal Loss.
This chapter reviews epidemiologic clinical surveys and experimental animal studies, indicating that cocaine may induce severe teratogenic effects on the developing brain. Evidence for direct toxic effects is next presented. Using cocultures of embryonic brain cells, we demonstrate that cocaine selectively affects neuronal cells, first causing a dramatic reduction in the number and length of neurites, then extensive neuronal death by apoptosis. By contrast, cocaine affected neither the abundance of astroglial cells nor their glial fibrillary acidic protein content. These effects are not due to cocaine metabolites. The contributions of indirect and direct effects that could account for cocaine neuroteratogenicity are finally discussed.


Contribution of NK, NK T, gamma delta T, and alpha beta T cells to the gamma interferon response required for liver protection against Trypanosoma cruzi.
In the present work, we show that intracellular Trypanosoma cruzi is rarely found in the livers of acutely infected mice, but inflammation is commonly observed. The presence of numerous intrahepatic amastigotes in infected gamma interferon (IFN-gamma)-deficient mice corroborates the notion that the liver is protected by an efficient local immunity. The contribution of different cell populations was suggested by data showing that CD4- and CD8-deficient mice were able to restrain liver parasite growth. Therefore, we have characterized the liver-infiltrating lymphocytes and determined the sources of IFN-gamma during acute T. cruzi infection. We observed that natural killer (NK) cells increased by day 7, while T and B cells increased by day 14. Among CD3+ cells, CD4+, CD8+, and CD4- CD8- cell populations were greatly expanded. A large fraction of CD3+ cells were positive for PanNK, a beta1 integrin expressed by NK and NK T cells. However, these lymphocytes were not classic NK T cells because they did not express NK1.1 and showed no preferential usage of Vbeta8. Otherwise, liver NK T (CD3+ NK1.1+) cells were not increased in acutely infected mice. The majority of PanNK+ CD4+ and PanNK+ CD8+ cells expressed T-cell receptor alphabeta (TCRalphabeta), whereas PanNK+ CD4- CD8- cells were positive for TCRgammadelta. In fact, gammadelta T cells showed the most remarkable increase (40- to 100-fold) among liver lymphocytes. Most importantly, intracellular analysis revealed high levels of IFN-gamma production at day 7 by NK cells and at day 14 by CD4+, CD8+, and CD4- CD8- TCRgammadelta+ cells. We concluded that NK cells are a precocious source of IFN-gamma in the livers of acutely infected mice, and, as the disease progresses, conventional CD4+ and CD8+ T cells and gammadelta T cells, but not classic NK-T cells, may provide the IFN-gamma required for liver protection against T. cruzi.


Association between intrahospital transfer and hospital-acquired infection in the elderly: a retrospective case-control study in a UK hospital network.
Intrahospital transfers have become more common as hospital staff balance patient needs with bed availability. However, this may leave patients more vulnerable to potential pathogen transmission routes via increased exposure to contaminated surfaces and contacts with individuals. This study aimed to quantify the association between the number of intrahospital transfers undergone during a hospital spell and the development of a hospital-acquired infection (HAI). A retrospective case-control study was conducted using data extracted from electronic health records and microbiology cultures of non-elective, medical admissions to a large urban hospital network which consists of three hospital sites between 2015 and 2018 (n=24 240). As elderly patients comprise a large proportion of hospital users and are a high-risk population for HAIs, the analysis focused on those aged 65 years or over. Logistic regression was conducted to obtain the OR for developing an HAI as a function of intrahospital transfers until onset of HAI for cases, or hospital discharge for controls, while controlling for age, gender, time at risk, Elixhauser comorbidities, hospital site of admission, specialty of the dominant healthcare professional providing care, intensive care admission, total number of procedures and discharge destination. Of the 24 240 spells, 2877 cases were included in the analysis. 72.2% of spells contained at least one intrahospital transfer. On multivariable analysis, each additional intrahospital transfer increased the odds of acquiring an HAI by 9% (OR=1.09; 95% CI 1.05 to 1.13). Intrahospital transfers are associated with increased odds of developing an HAI. Strategies for minimising intrahospital transfers should be considered, and further research is needed to identify unnecessary transfers. Their reduction may diminish spread of contagious pathogens in the hospital environment.


Lack of knowledge of physical activity guidelines: can physical activity promotion campaigns do better?
To identify the prevalence of knowledge of the current UK physical activity guidelines which were introduced in 2011 and prior physical activity guidelines (30 min on 5 days each week) within two large samples of UK adult's. To investigate whether knowledge of physical activity guidelines differs according to demographics such as ethnicity, age, education and employment status. Descriptive cross-sectional study comparing two distinctive adult samples. National survey and online-administered survey conducted in England. The 2007 Health Survey for England provides data on knowledge of physical activity guidelines from 2860 UK adults (56% women, 89% white, 63% under 45 years old). In 2013, an online survey was disseminated and data were collected from 1797 UK adults on knowledge of the most recent physical activity guidelines. The 2013 sample was 70% women, 92% white and 57% under 45 years old. All adults in both samples were >18 years old and without illnesses/disorders likely to restrict physical activity. Knowledge of physical activity guidelines in 2007 and 2013. Demographic correlates of knowledge of moderate-to-vigorous physical activity guidelines. 18% of the 2013 sample accurately recalled the current physical activity guidelines compared with 11% of the 2007 sample who accurately recalled the previous guidelines. The differences in knowledge of physical activity guidelines existed for marital status, gender, age, education and employment status within both 2007 and 2013 samples (p<0.05). Men with lower education and employment status (unemployed including student and retired) and older adults were less likely to know physical activity guidelines (p<0.05). Knowledge of physical activity guidelines remained higher in the 2013 sample after controlling for demographic differences (p<0.05). Disadvantaged population groups are less knowledgeable about physical activity guidelines. Although knowledge of physical activity guidelines appears to have increased in recent years demographic disparities are still evident. Efforts are needed to promote health information among these groups.


[Pain therapy in gynecologic neoplasms].
A great number of patients with gynaecological malignant diseases suffer from severe pain, caused, for example, by bone metastases of breast cancer or tumour infiltration of the pelvis and the lumbar plexus in uterine cancer. Several methods of treatment are available depending upon the origin of pain. It is possible to achieve pain relief by radiotherapy or by cytostatic therapy. Sometimes, anaesthesiological and neurosurgical measures are successful, but the most important method is treatment with analgesics. Strong opioids are given, if pain relief is insufficient under treatment with non-narcotic drugs or weak opioids, like codeine. Morphine and other strong opioids are not reserved for pain control only in terminally sick women, as they can be administered successfully for long periods without severe side effects. If possible, the oral route should be selected. If vomiting occurs, or if patients are unable to take oral medication, morphine can be given peridurally, intrathecally or by infusion. Often, an additional treatment is necessary with different medicaments like tricyclic antidepressants and corticosteroids.


Replication and extension of the military family stress model: The after deployment adaptive parenting tools ADAPT4U study.
The military family stress (MFS) model conceptualizes that wartime deployments and post-traumatic stress disorder (PTSD) symptoms are associated with couple, parenting, and child adjustment difficulties. The aim of this study was to replicate and extend the military family stress model by examining the associations among deployment length, PTSD symptoms, marital functioning, parenting practices, and child adjustment in a replication sample of both National Guard and Reserve (NG/R) as well as active-duty service member families. The MFS model is extended to test whether these relationships vary between mothers and fathers. The sample included 208 families enrolled in a randomized controlled trial of a parenting program for military families (94.4% of fathers and 21.6% of mothers were deployed). Replicating the MFS model, we specified parenting, marital quality, and child adjustment as latent variables and conducted multi-group structural equation models. Parenting practices were positively associated with marital quality and child adjustment. PTSD symptoms were negatively associated with marital quality. The indirect effect from PTSD symptoms to parenting practices through marital quality was marginally significant. The indirect effect from marital quality to child adjustment through parenting practices was significant. There were no significant gender differences between the two structural models. This study provides empirical support for the MFS model. Results demonstrate that deployment-related stressors are significantly associated with parent and family functioning. Parenting programs for military families might effectively target similar risk processes among both mothers and fathers.


Addition of local cryotherapy for treatment of post-mastectomy lymphedema.
Worldwide, lymphedema can present as a significant health issue. Left untreated, it can have long-term medical and psychological consequences for patients. Cryotherapy is a new physical therapy modality used for many purposes including reduction of pain, inflammation, and edema. It is thought to decrease interstitial fluid volume through many mechanisms. Therefore, it is reasonable to think that cryotherapy might have a positive effect in treatment of lymphedema. The goal of this study was to investigate how local cryotherapy in combination with standard therapy affects patient outcomes. Forty post-mastectomy female patients aged 40-60 years old with lymphedema were referred to the outpatient clinics of the Faculty of Physical Therapy at South Valley University for medical treatment and follow-up by the vascular surgery department. Patients were randomly divided into two groups of equal size. Traditional physical therapy programs (manual lymphatic drainage, pneumatic compression, bandaging, breathing exercises, circulatory exercises, shoulder mobilizations, and ROM exercises) were combined with pulsed local cryotherapy three times per week for 12 weeks in Group (A). For 12 weeks, Group (B) received only traditional physical therapy three times per week. Patients were evaluated using circumferential measurement with tape at the wrist, below the elbow, and above the elbow level, as well as ultrasonography to assess skin thickness before the start of physical therapy, 6 weeks later, and at the end of the treatment (after 12 weeks). Results indicate that cryotherapy is an effective adjunct modality for the treatment of secondary lymphedema and should be added to physical therapy protocols for lymphedema rehabilitation.


Intentional abstinence among homeless and unstably housed persons living with HIV/AIDS.
Some persons living with HIV/AIDS (PLWHA) engage in periods of sexual abstinence. Baseline data from a larger study of homeless/unstably housed PLWHA indicated that 20% (125/644) intentionally abstained from sex in the past 90 days. Reasons included: (1) 'not interested' (n = 78); (2) did not want to infect someone (n = 46); and (3) did not have a partner (n = 37). Abstinence was less likely among all who had a main partner. Among men who have sex with men (MSM), abstinence was less likely among those with a detectable viral load. It was more likely among heterosexual men who were experiencing current housing problems and who had at least a high school education. Among women, abstinence was less likely among African Americans and those whose social networks were more aware of their HIV status. Better understanding of motivations to abstain may improve how programs serving PLWHA address this issue.


Lung cancer screening update.
Low-dose computed tomography (ld-CT) for lung cancer screening in high-risk subjects is performed within clinical trials and has started to be used in routine clinical practice. The technique is well defined, even if some methodological problems are still debated, such as the measurements of pulmonary nodules, the size to define them as clinically significant, the management of small or non-solid nodules and the best diagnostic work-up to optimize diagnostic accuracy. The data derived from an IEO observational study, started in 2000, shows a high prevalence and incidence of early stage lung cancer detected at ld-CT, demonstrating the need to prolong observation for a long period of time. The high survival rate of patients with screening-detected cancer has recently been debated in a number of papers using statistical models, but the advantage of the yearly ld-CT for the individuals is unquestionable; its benefit on the population base has still to be demonstrated by ongoing randomized trials.


Hemorrhagic fever viruses as biological weapons: medical and public health management.
To develop consensus-based recommendations for measures to be taken by medical and public health professionals if hemorrhagic fever viruses (HFVs) are used as biological weapons against a civilian population. The Working Group on Civilian Biodefense included 26 representatives from academic medical centers, public health, military services, governmental agencies, and other emergency management institutions. MEDLINE was searched from January 1966 to January 2002. Retrieved references, relevant material published prior to 1966, and additional sources identified by participants were reviewed. Three formal drafts of the statement that synthesized information obtained in the evidence-gathering process were reviewed by the working group. Each draft incorporated comments and judgments of the members. All members approved the final draft. Weapons disseminating a number of HFVs could cause an outbreak of an undifferentiated febrile illness 2 to 21 days later, associated with clinical manifestations that could include rash, hemorrhagic diathesis, and shock. The mode of transmission and clinical course would vary depending on the specific pathogen. Diagnosis may be delayed given clinicians' unfamiliarity with these diseases, heterogeneous clinical presentation within an infected cohort, and lack of widely available diagnostic tests. Initiation of ribavirin therapy in the early phases of illness may be useful in treatment of some of these viruses, although extensive experience is lacking. There are no licensed vaccines to treat the diseases caused by HFVs.


Synthesis, biological evaluation and structural determination of beta-aminoacyl-containing cyclic hydrazine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors.
Inhibitors of dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes. A series of beta-aminoacyl-containing cyclic hydrazine derivatives were synthesized and evaluated as DPP-IV inhibitors. One member of this series, (R)-3-amino-1-(2-benzoyl-1,2-diazepan-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one (10f), showed potent in vitro activity, good selectivity and in vivo efficacy in mouse models. Also, the binding mode of compound 10f was determined by X-ray crystallography.


Optimizing the Impact of Pragmatic Clinical Trials for Veteran and Military Populations: Lessons From the Pain Management Collaboratory.
Pragmatic clinical trials (PCTs) are well-suited to address unmet healthcare needs, such as those arising from the dual public health crises of chronic pain and opioid misuse, recently exacerbated by the COVID-19 pandemic. These overlapping epidemics have complex, multifactorial etiologies, and PCTs can be used to investigate the effectiveness of integrated therapies that are currently available but underused. Yet individual pragmatic studies can be limited in their reach because of existing structural and cultural barriers to dissemination and implementation. The National Institutes of Health, Department of Defense, and Department of Veterans Affairs formed an interagency research partnership, the Pain Management Collaboratory. The partnership combines pragmatic trial design with collaborative tools and relationship building within a large network to advance the science and impact of nonpharmacological approaches and integrated models of care for the management of pain and common co-occurring conditions. The Pain Management Collaboratory team supports 11 large-scale, multisite PCTs in veteran and military health systems with a focus on team science with the shared aim that the "whole is greater than the sum of the parts." Herein, we describe this integrated approach and lessons learned, including incentivizing all parties; proactively offering frequent opportunities for problem-solving; engaging stakeholders during all stages of research; and navigating competing research priorities. We also articulate several specific strategies and their practical implications for advancing pain management in active clinical, "real-world," settings.


DAMPening COVID-19 Severity by Attenuating Danger Signals.
COVID-19 might lead to multi-organ failure and, in some cases, to death. The COVID-19 severity is associated with a "cytokine storm." Danger-associated molecular patterns (DAMPs) are proinflammatory molecules that can activate pattern recognition receptors, such as toll-like receptors (TLRs). DAMPs and TLRs have not received much attention in COVID-19 but can explain some of the gender-, weight- and age-dependent effects. In females and males, TLRs are differentially expressed, likely contributing to higher COVID-19 severity in males. DAMPs and cytokines associated with COVID-19 mortality are elevated in obese and elderly individuals, which might explain the higher risk for severer COVID-19 in these groups. Adenosine signaling inhibits the TLR/NF-κB pathway and, through this, decreases inflammation and DAMPs' effects. As vaccines will not be effective in all susceptible individuals and as new vaccine-resistant SARS-CoV-2 mutants might develop, it remains mandatory to find means to dampen COVID-19 disease severity, especially in high-risk groups. We propose that the regulation of DAMPs via adenosine signaling enhancement might be an effective way to lower the severity of COVID-19 and prevent multiple organ failure in the absence of severe side effects.


Estradiol selectively regulates metabolic substrates across memory systems in models of menopause.
Estrogen loss at menopause is thought to contribute to specific memory problems commonly encountered by women who are transitioning through or who have experienced menopause. Work in preclinical models suggests that estrogens bidirectionally regulate cognition through direct actions on different neural systems called memory systems, enhancing some types of learning and memory while impairing others. The energy load in the brain during cognitive activity is notoriously high, requiring sufficient provisions of metabolic substrates such as glucose, lactate, or ketones for optimal cognition. Thus, it is possible that estrogens bidirectionally regulate energy substrate availability within each system to produce the improvements and impairments in learning and memory. Indeed, estradiol increases extracellular levels of glucose in the hippocampus, a shift that corresponds to the hormone's beneficial effects on hippocampus-sensitive cognition. In contrast, estradiol decreases levels of lactate and ketones in the striatum, a shift that corresponds to the impairing effects of estradiol on striatum-sensitive cognition. Menopause may thus be associated with both cognitive improvements and impairments depending on estradiol status and on the problem to be solved. We propose that regulation of neural metabolism is one likely mechanism for these bidirectional effects of estradiol on cognition.


The role of autoreactive T-cells in the pathogenesis of idiopathic thrombocytopenic purpura.
Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease mediated by antiplatelet autoantibodies. The major target of these autoantibodies is a platelet membrane glycoprotein, GPIIb-IIIa, which is a receptor for fibrinogen and other ligands. We recently identified CD4+ T-cells autoreactive to GPIIb-IIIa in ITP patients. These T-cells are considered pathogenic because they help B-cells produce antibodies that bind to normal platelet surfaces. GPIIb-IIIa-reactive T-cells respond to chemically reduced and tryptic peptides of GPIIb-IIIa but not to native GPIIb-IIIa, indicating that the epitopes they recognize are "cryptic" determinants generated at a subthreshold level by the processing of native GPIIb-IIIa under normal circumstances. Although GPIIb-IIIa-reactive T-cells are also detected in healthy individuals, they are activated in vivo only in ITP patients. Activation of GPIIb-IIIa-specific T-cells and the subsequent production of pathogenic anti-GPIIb-IIIa antibodies can be induced by functional antigen-presenting cells in the spleen that present cryptic GPIIb-IIIa peptides to these T-cells. The pathogenic process of ITP can be explained as a continuous loop in which B-cells produce antiplatelet autoantibodies, splenic macrophages phagocytose antibody-coated platelets and present GPIIb-IIIa-derived cryptic peptides, and GPIIb-IIIa-reactive CD4+ T-cells exert their helper activity. Further studies examining the mechanisms that induce the processing and presentation of cryptic peptides derived from the platelet antigen at disease onset will clarify how the pathogenic autoantibody response in ITP is initiated.


Coronary heart disease risk factors in women: focus on gender differences.
Cardiovascular disease is the leading cause of death in Louisiana and in the United States. Louisiana women have the second highest mortality rate for cardiovascular disease in the country. The major risk factors in both men and women include cigarette smoking, hypertension, dyslipidemia, diabetes mellitus, obesity, sedentary lifestyle, and poor nutrition. A body of evidence is accumulating to support the existence of nontraditional risk factors such as elevated homocysteine levels and antioxidants. Gender-specific risks and interventions also exist in the form of oral contraceptives and hormone replacement therapy respectively. Raloxifene and other selective estrogen receptive modulators may alter the regimens of hormone replacement therapy in the future. This article reviews cardiac risk factors focusing on gender differences, the arguments for and against hormone replacement therapy as it relates to coronary disease, and some practical aspects of hormone replacement therapy that physicians encounter when considering hormone replacement therapy in the postmenopausal woman.


Evaluation of manometric temperature measurement, a process analytical technology tool for freeze-drying: part I, product temperature measurement.
This study examines the factors that may cause systematic errors in the manometric temperature measurement (MTM) procedure used to evaluate product temperature during primary drying. MTM was conducted during primary drying using different vial loads, and the MTM product temperatures were compared with temperatures directly measured by thermocouples. To clarify the impact of freeze-drying load on MTM product temperature, simulation of the MTM vapor pressure rise was performed, and the results were compared with the experimental results. The effect of product temperature heterogeneity in MTM product temperature determination was investigated by comparing the MTM product temperatures with directly measured thermocouple product temperatures in systems differing in temperature heterogeneity. Both the simulated and experimental results showed that at least 50 vials (5 mL) were needed to give sufficiently rapid pressure rise during the MTM data collection period (25 seconds) in the freeze dryer, to allow accurate determination of the product temperature. The product temperature is location dependent, with higher temperature for vials on the edge of the array and lower temperature for the vials in the center of the array. The product temperature heterogeneity is also dependent upon the freeze-drying conditions. In product temperature heterogeneous systems, MTM measures a temperature close to the coldest product temperature, even if only a small fraction of the samples have the coldest product temperature. The MTM method is valid even at very low product temperature (-45 degrees C).


Hematoma and abscess of the nasal septum in children.
To evaluate the clinical characteristics and treatment outcome of hematoma and abscess of the nasal septum (HANS) in children. Retrospective case series. Pediatric tertiary care facility. Consecutive series of 20 children (age, 2 months to 15 years; mean age, 7 years) who were admitted to the hospital for treatment of HANS after nasal trauma during an 18-year period. In addition to receiving antibiotics, all patients underwent general anesthetic for incision and evacuation of the collection of blood and pus together with nasal packing. All patients had a history of nasal trauma. The HANS was a consequence of child abuse (2 patients younger than 2 years), minor nasal trauma (14 patients aged 1 to 10 years), and sports injury (4 patients older than 10 years). The diagnosis was made 1 to 14 days (mean, 5.9 days) after the episode of trauma. Nasal obstruction was the most common symptom found and was present in all but 1 patient. Pain, rhinorrhea, and fever occurred in 50%, 35%, and 25% of patients, respectively. Nasal fracture was present in 3 children. Abscess was found at surgery in 12 patients and was universally associated with septal cartilage destruction. Hematoma was present in 8 patients and associated with cartilage destruction in 2 patients. Organisms cultured were Staphylococcus aureus, Streptococcus pneumoniae, and group A beta-hemolytic streptococcus and were obtained from all 12 patients with septal abscess and from 1 patient with septal hematoma. Corrective nasal surgery has been performed in 5 patients, 4 of whom had a history of septal abscess. The diagnosis of HANS must be considered in all children who have acute onset of nasal obstruction and a history of recent nasal trauma to minimize the risk of nasal deformity and prevent the development of septic complications.


Risk factors for pharyngalgia and xerostomia undergoing supraglottic jet oxygenation and ventilation in gastrointestinal endoscopy: a retrospective study.
Supraglottic jet oxygenation/ventilation (SJOV) can reduce hypoxemia in sedated endoscopy but may increase minor side effects like pharyngalgia and xerostomia. This study aimed to identify risk factors for pharyngalgia/xerostomia with SJOV during gastrointestinal endoscopy. From January 1 to December 31, 2021, 5313 patients with propofol sedation and SJOV underwent gastrointestinal endoscopy or removal of gastrointestinal polyps was analyzed retrospectively. Data included patient characteristics, operation details, postoperative adverse events, and potential risk factors for postoperative adverse events. Parameters considered as potential risk factors were identified based on study results published previously and based on the researcher's idea and clinical experience. The patient factors and the incidence of pharyngalgia/xerostomia at 30 min post-procedure were assessed. Descriptive statistics were calculated using SPSS software. Evaluation potential risk factors using univariate and multivariate logistic regression. Pharyngalgia/xerostomia occurred in 18.7% of patients at 30 min after procedure. A multivariable analysis showed that procedure time and pharyngalgia/xerostomia within 2 weeks were independent risk factors. Procedure time had the strongest association with postoperative pharyngalgia/xerostomia (OR, 8.09 [95% CI, 4.197-6.312]). No factors were significantly associated with hypoxemia risk (1.7% incidence). There were no barotrauma or other serious morbidity or mortality. Procedure duration and recent pharyngalgia/xerostomia increased risk of pharyngalgia/xerostomia with SJOV during endoscopy. Limiting SJOV duration may reduce side effects in susceptible patients. No predictors of hypoxemia were identified.


Adverse Events of COVID-19 Vaccination among the Saudi Population: A Systematic Review and Meta-Analysis.
This systematic review and meta-analysis aimed to synthesize the evidence on the adverse events (AEs) of coronavirus disease 2019 (COVID-19) vaccinations in Saudi Arabia. A computerized search in MEDLINE via PubMed and OVID, Scopus, CENTRAL, and Web of Science was conducted using relevant keywords. The NIH tools were used for the quality assessment. A total of 14 studies (16 reports) were included. The pooled analysis showed that the incidence of AEs post-COVID-19 vaccination was 40.4% (95% CI:6.4% to 87%). Compared to the AstraZeneca vaccine, the Pfizer-BioNTech vaccine was associated with a lower risk ratio (RR) of wheezing (RR = 0.04), fever (RR = 0.32), chills (RR = 0.41), headache (RR = 0.47), dizziness (RR = 0.49), and joint pain (RR = 0.51). The Pfizer-BioNTech vaccine was associated with significantly higher RR of general allergic reactions (RR = 1.62), dyspnea (RR = 1.68), upper respiratory tract symptoms (RR = 1.71), and lymphadenopathy (RR = 8.32). The current evidence suggests that the incidence of AEs following COVID-19 vaccines is 40%; however, most of these AEs were mild and for a short time. The overall number of participants with AEs was higher in the Pfizer group compared to the AstraZeneca group; however, the AstraZeneca vaccine was associated with a higher RR of several AEs.


Targeted endometrial cancer therapy as a future prospect.
Among female-specific cancers worldwide, endometrial cancer is the third most common after breast cancer and cervical cancer. In addition, it is the most common gynecological cancer in the USA and Europe. The incidence of this disease appears to be increasing. The cause of this increase is multifactorial, but a few possible factors involved are increasing obesity, an aging population leading to more postmenopausal women and greater tamoxifen use. Surgery is generally the primary treatment of this disease and postoperative radiation therapy in some patients with high or intermediate risk may prevent locoregional recurrences. Adjuvant chemotherapy improves progression-free survival in advanced or recurrent cancer. However, overall survival in patients with advanced disease is poor. Hence, better therapy is needed and targeted molecular therapies are emerging as possible treatment candidates. These include molecules that target VEGF, mTOR, tyrosine kinases, human EGF receptors and FGF receptors. Therapies targeting specific molecular features should be evaluated in future strategies in the treatment of endometrial cancer.


A retrospective and observational analysis of harmful excipients in medicines for hospitalised neonates in Latvia.
Medicines used in neonates contain different excipients, which may not be safe in this age group. To analyse the frequency at which hospitalised neonates are exposed to harmful excipients (HEs) and to identify substitution possibilities for medicines containing HEs. Retrospective, observational study at a university paediatric hospital from 1 September 2015 till 29 February 2016. All hospitalised neonates who received a prescription for medicines containing an HE were included. Neonates were divided into four groups according to gestational age (<28 weeks; 28 to <32 weeks; 32 to <37 weeks and ≥37 weeks). The following excipients were analysed: parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol and benzalkonium chloride. Excipients were identified from the Summaries of Product Characteristics. 296 (102(34.5%) preterm) neonates included in the study received 1472 prescriptions for 106 medicines. The most often used formulations were intravenous (48/106; 45.3%) and oral solid formulations (20; 18.9%). The total number of different excipients was 169. In total, 29/106 (27.4%) medicines contained at least one HE. In total 82/102 (80.4%) preterm and 118/194 (60.8%) term neonates received medications with at least one HE. Substitution was possible for 9/29 (31.0%) HE-containing medicines. Use of HEs can be reduced by using HE-free products available on the European market. However, medicine substitution was possible in only a small number of cases. Therefore the main focus should be on information and education of the hospital specialists about HEs used in medicines and their adverse reactions.


Epigenetic Alterations Affecting Transcription Factors and Signaling Pathways in Stromal Cells of Endometriosis.
Endometriosis is characterized by growth of endometrial-like tissue outside the uterine cavity. Since its pathogenesis may involve epigenetic changes, we used Illumina 450K Methylation Beadchips to profile CpG methylation in endometriosis stromal cells compared to stromal cells from normal endometrium. We validated and extended the Beadchip data using bisulfite sequencing (bis-seq), and analyzed differential methylation (DM) at the CpG-level and by an element-level classification for groups of CpGs in chromatin domains. Genes found to have DM included examples encoding transporters (SLC22A23), signaling components (BDNF, DAPK1, ROR1, and WNT5A) and transcription factors (GATA family, HAND2, HOXA cluster, NR5A1, OSR2, TBX3). Intriguingly, among the TF genes with DM we also found JAZF1, a proto-oncogene affected by chromosomal translocations in endometrial stromal tumors. Using RNA-Seq we identified a subset of the DM genes showing differential expression (DE), with the likelihood of DE increasing with the extent of the DM and its location in enhancer elements. Supporting functional relevance, treatment of stromal cells with the hypomethylating drug 5aza-dC led to activation of DAPK1 and SLC22A23 and repression of HAND2, JAZF1, OSR2, and ROR1 mRNA expression. We found that global 5hmC is decreased in endometriotic versus normal epithelial but not stroma cells, and for JAZF1 and BDNF examined by oxidative bis-seq, found that when 5hmC is detected, patterns of 5hmC paralleled those of 5mC. Together with prior studies, these results define a consistent epigenetic signature in endometriosis stromal cells and nominate specific transcriptional and signaling pathways as therapeutic targets.


Gamma-tubulin is required for proper recruitment and assembly of Kar9-Bim1 complexes in budding yeast.
Microtubule plus-end-interacting proteins (+TIPs) promote the dynamic interactions between the plus ends (+ends) of astral microtubules and cortical actin that are required for preanaphase spindle positioning. Paradoxically, +TIPs such as the EB1 orthologue Bim1 and Kar9 also associate with spindle pole bodies (SPBs), the centrosome equivalent in budding yeast. Here, we show that deletion of four C-terminal residues of the budding yeast gamma-tubulin Tub4 (tub4-delta dsyl) perturbs Bim1 and Kar9 localization to SPBs and Kar9-dependent spindle positioning. Surprisingly, we find Kar9 localizes to microtubule +ends in tub4-delta dsyl cells, but these microtubules fail to position the spindle when targeted to the bud. Using cofluorescence and coaffinity purification, we show Kar9 complexes in tub4-delta dsyl cells contain reduced levels of Bim1. Astral microtubule dynamics is suppressed in tub4-delta dsyl cells, but it are restored by deletion of Kar9. Moreover, Myo2- and F-actin-dependent dwelling of Kar9 in the bud is observed in tub4-delta dsyl cells, suggesting defective Kar9 complexes tether microtubule +ends to the cortex. Overproduction of Bim1, but not Kar9, restores Kar9-dependent spindle positioning in the tub4-delta dsyl mutant, reduces cortical dwelling, and promotes Bim1-Kar9 interactions. We propose that SPBs, via the tail of Tub4, promote the assembly of functional +TIP complexes before their deployment to microtubule +ends.


Measurement of the Charge-Averaged Elastic Lepton-Proton Scattering Cross Section by the OLYMPUS Experiment.
We report the first measurement of the average of the electron-proton and positron-proton elastic scattering cross sections. This lepton charge-averaged cross section is insensitive to the leading effects of hard two-photon exchange, giving more robust access to the proton's electromagnetic form factors. The cross section was extracted from data taken by the OLYMPUS experiment at DESY, in which alternating stored electron and positron beams were scattered from a windowless gaseous hydrogen target. Elastic scattering events were identified from the coincident detection of the scattered lepton and recoil proton in a large-acceptance toroidal spectrometer. The luminosity was determined from the rates of Møller, Bhabha, and elastic scattering in forward electromagnetic calorimeters. The data provide some selectivity between existing form factor global fits and will provide valuable constraints to future fits.


Analysis of the Information Capacity of Neuronal Molecular Communications Under Demyelination and Remyelination.
Demyelination of neurons can compromise the communication performance between the cells as the absence of myelin attenuates the action potential propagated through the axonal pathway. In this work, we propose a hybrid experimental and simulation model for analyzing the demyelination effects on neuron communication. The experiment involves locally induced demyelination using Lysolecithin and from this, a myelination index is empirically estimated from analysis of cell images. This index is then coupled with a modified Hodgkin-Huxley computational model to simulate the resulting impact that the de/myelination processes has on the signal propagation along the axon. The effects of signal degradation and transfer of neuronal information are simulated and quantified at multiple levels, and this includes (1) compartment per compartment of a single neuron, (2) bipartite synapse and the effects on the excitatory post-synaptic potential, and (3) a small network of neurons to understand how the impact of de/myelination has on the whole network. By using the myelination index in the simulation model, we can determine the level of attenuation of the action potential concerning the myelin quantity, as well as the analysis of internal signalling functions of the neurons and their impact on the overall spike firing rate. We believe that this hybrid experimental and in silico simulation model can result in a new analysis tool that can predict the gravity of the degeneration through the estimation of the spiking activity and vice-versa, which can minimize the need for specialised laboratory equipment needed for single-cell communication analysis.


Km genotyping by polymerase chain reaction (PCR) using allele-specific amplification primers.
We developed a method for identifying genetic polymorphisms of the human immunoglobulin kappa light chain, namely the Km allotypes, by allele-specific amplification by means of the polymerase chain reaction (PCR). This procedure consisted of first and second PCR. In the first PCR, the 353 bp fragment of the human immunoglobulin kappa light chain constant gene was amplified without differentiating individual alleles. In the second PCR, the specific sequence in each of the three alleles Km*1, Km*1,2 and Km*3, in the first PCR product was specifically amplified using allele-specific primers. The product of the second PCR was separated by electrophoresis on a polyacrylamide gel and the band was observed by means of UV trans-illumination after staining with ethidium bromide. From DNA extracted from lymphocytes, the specific sequence of each Km allele was selectively amplified, and the Km genotype was identified. Moreover, the Km genotype could be ascertained from whole blood, saliva and hair roots without DNA extraction. No genetic contradiction was found in the results of Km genotyping among parents and their children. The estimated gene frequency of 115 Japanese individuals living in Okayama Prefecture, Japan, was: Km*3 = 0.739 and Km*1,2 = 0.261.


Relationship between exposure to vector bites and antibody responses to mosquito salivary gland extracts.
Mosquito-borne diseases are major health problems worldwide. Serological responses to mosquito saliva proteins may be useful in estimating individual exposure to bites from mosquitoes transmitting these diseases. However, the relationships between the levels of these IgG responses and mosquito density as well as IgG response specificity at the genus and/or species level need to be clarified prior to develop new immunological markers to assess human/vector contact. To this end, a kinetic study of antibody levels against several mosquito salivary gland extracts from southeastern French individuals living in three areas with distinct ecological environments and, by implication, distinct Aedes caspius mosquito densities were compared using ELISA. A positive association was observed between the average levels of IgG responses against Ae. caspius salivary gland extracts and spatial Ae. caspius densities. Additionally, the average level of IgG responses increased significantly during the peak exposure to Ae. caspius at each site and returned to baseline four months later, suggesting short-lived IgG responses. The species-specificity of IgG antibody responses was determined by testing antibody responses to salivary gland extracts from Cx. pipiens, a mosquito that is present at these three sites at different density levels, and from two other Aedes species not present in the study area (Ae. aegypti and Ae. albopictus). The IgG responses observed against these mosquito salivary gland extracts contrasted with those observed against Ae. caspius salivary gland extracts, supporting the existence of species-specific serological responses. By considering different populations and densities of mosquitoes linked to environmental factors, this study shows, for the first time, that specific IgG antibody responses against Ae. caspius salivary gland extracts may be related to the seasonal and geographical variations in Ae. caspius density. Characterisation of such immunological-markers may allow the evaluation of the effectiveness of vector-control strategies or estimation of the risk of vector-borne disease transmission.


Influenza Virus: Small Molecule Therapeutics and Mechanisms of Antiviral Resistance.
Influenza viruses cause severe upper respiratory illness in children and the elderly during seasonal epidemics. Influenza viruses from zoonotic reservoirs can also cause pandemics with significant loss of life in all age groups. Although vaccination is one of the most effective methods to protect against seasonal epidemics, seasonal vaccines vary in efficacy, can be ineffective in the elderly population, and do not provide protection against novel strains. Small molecule therapeutics are a critical part of our antiviral strategies to control influenza virus epidemics and pandemics as well as to ameliorate disease in elderly and immunocompromised individuals. This review aims to summarize the existing antiviral strategies for combating influenza viruses, the mechanisms of antiviral resistance for available drugs, and novel therapeutics currently in development. We systematically evaluated and synthesized the published scientific literature for mechanistic detail into therapeutic strategies against influenza viruses. Current IAV strains have developed resistance to neuraminidase inhibitors and nearly complete resistance to M2 ion channel inhibitors, exacerbated by sub-therapeutic dosing used for treatment and chemoprophylaxis. New tactics include novel therapeutics targeting host components and combination therapy, which show potential for fighting influenza virus disease while minimizing viral resistance. Antiviral drugs are crucial for controlling influenza virus disease burden, but their efficacy is limited by human misuse and the capacity of influenza viruses to circumvent antiviral barriers. To relieve the public health hardship of influenza virus, emerging therapies must be selected for their capacity to impede not only influenza virus disease, but also the development of antiviral resistance.


A simple, ex vivo phagocytosis assay of Plasmodium vivax merozoites by flow cytometry.
As phagocytosis is the first line of defense against malaria, we developed a phagocytosis assay with Plasmodium vivax (P. vivax) merozoites that can be applied to evaluate vaccine candidates. Briefly, after leukocyte removal with loosely packed cellulose powder in a syringe, P. vivax trophozoites matured to the merozoite-rich schizont stages in the presence of the E64 protease inhibitor. The Percoll gradient-enriched schizonts were chemically disrupted to release merozoites that were submitted to merozoite opsonin-dependent phagocytosis in two phagocytic lines with human and mouse antibodies against the N- and C-terminus of P. vivax Merozoite Surface Protein-1 (Nterm-PvMSP1 and MSP119). The resulting assay is simple and efficient for use as a routine phagocytic assay for the evaluation of merozoite stage vaccine candidates.


Development of an Objective Model to Define Near-Term Risk of Ileocecal Resection in Patients with Terminal Ileal Crohn Disease.
The decision to either escalate medical therapy or proceed to ileocecal resection (ICR) in patients with terminal ileal Crohn disease (CD) remains largely subjective. We sought to develop a risk score for predicting ICR at 1 year from computed tomography or magnetic resonance enterography (CTE/MRE). We conducted a retrospective cohort study including all consecutive adult (> 18 years) patients with imaging findings of terminal ileal CD (Montreal classification: B1, inflammatory predominant; B2, stricturing; or B3, penetrating) on CTE/MRE between January 1, 2016, and December 31, 2016. The risk for ICR at 6 months and at 1 year of CTE/MRE and risk factors associated with ICR, including demographics, CD-specific immunosuppressive therapeutics, and disease presentation at the time of imaging, were determined. Of 559 patients, 121 (21.6%) underwent ICR during follow-up (1.4 years [IQR 0.21-1.64 years]); the risk for ICR at 6 months and at 1 year was 18.2% (95% CI 14.7%-21.6%) and 20.5% (95% CI 16.8%-24.1%), respectively. Multivariable analysis revealed Montreal classification (B2, hazard ratio [HR] 2.73, and B3, HR 6.80, both P < 0.0001), upstream bowel dilation (HR 3.06, P < 0.0001), and younger age (19-29 years reference, 30-44 years, HR 0.83 [P = 0.40]; 45-59 years, HR 0.58 [P = 0.04], and 60+ years, HR 0.45 [P = 0.01]) to significantly increase the likelihood of ICR. A predictive nomogram for interval ICR was developed based on these significant variables. The presence of CD strictures, penetrating complications, and upstream bowel dilation on CTE/MRE, combined with young age, significantly predict ICR. The suggested risk model may facilitate objective therapeutic decision-making.


A National Chinese Survey on Ultrasound Feature Interpretation and Risk Assessment of Breast Masses Under ACR BI-RADS.
Through this nationwide survey on ACR BI-RADS including ultrasound images of 10 selected breast lesions, we aimed to learn about consistency in feature interpretation and assessment categories and to identify factors that might contribute to inconsistencies, thereby promoting the application of BI-RADS in China. The survey was delivered through a self-developed website about blinded image interpretation and was released to the public through online platforms and social media. A total of 10 representative lesions were selected by an experienced radiologist to gather information about the general practice of BI-RADS lexicons and categories. The Kappa statistic, the chi-squared test, and descriptive statistics were used for data analysis. Nine hundred ultrasound workers completed the questionnaire, coming from all provinces and major cities in China. They had different positions, grades of work organization, and seniority. The interrater agreement of BI-RADS features was fair to substantial (kappa value: 0.37-0.66). For BI-RADS categories, the highest agreement was observed in the typical benign group (average constituent rate = 74.78%), and generally lower agreement was observed in the typical malignant (average constituent rate = 36.03%) and suspicious groups (average constituent rate = 39.02%). We found inconsistencies in BI-RADS applications, providing direction for image feature research using big data. Therefore, we call for more efforts to improve the consistency of BI-RADS application and provide an evidence-based basis for identifying benign and malignant lesions by sonographic features.


Information content of the kernel matrix for the phase function retrieval problem.
We investigate the information content of the radiation measurements to be used in the retrieval of the scattering properties of the atmosphere with the perturbation technique that we previously introduced. Applying this technique to different sets of data, we obtained solutions with varying accuracy. An analysis of these solutions shows that selecting linearly independent data in directions corresponding to small values of the scattering angle increases the number of pieces of information. (This result is in accord with conclusions reached by other researchers, based on a variety of criteria.) This information content should be largely independent of the method or methods employed to perform the inversion procedure.


Essential fatty acids in the management of impaired nerve function in diabetes.
Impaired conversion of linoleic acid to gamma-linolenic acid (GLA) has been demonstrated in animal diabetes and inferred from blood fatty acid profiles in human diabetes. This impairment could theoretically lead to defective nerve function because metabolites of GLA are known to be important in nerve membrane structure, nerve blood flow, and nerve conduction. Administration of GLA corrects the impaired nerve function in animal models of diabetes. Two multicenter, randomized, placebo-controlled trials in humans with diabetic neuropathy have shown significant benefits of GLA as compared with placebo in neurophysiological parameters, thermal thresholds, and clinical sensory evaluations. Further work is needed to define the place of this therapeutic approach and its interactions with other treatment modalities.


The double-edged sword: The role of empathy in military veterans' partners distress.
The existing literature has shown that war veterans' posttraumatic stress symptoms (PTSS) are associated with high levels of distress in their female partners. According to the literature, spouses' empathy for their spouses can be a risk factor for their own mental health. However, this subject has not been examined among veteran couples. The current study therefore investigated both the direct and moderating contribution of females' cognitive and affective empathy to their own PTSS and depression symptoms, above and beyond the preexisting traumatic events of the women's own lives and the veterans' PTSS. Participants were 300 Israeli men who had served in the 2006 Israel-Lebanon War and their female partners, all of whom completed survey questionnaires. Results revealed that although cognitive empathy can play a positive role for the female in the aftermath of a traumatic event, affective empathy can potentially make a negative contribution to her distress. Women's education, in number of years, and their own previous traumatic life events, as well as veterans' levels of PTSS, were all found to make a direct contribution to females' PTSS and depression symptoms. Findings support the theory that although higher empathy can play a positive role in military couples in which the male partner displays symptoms of PTSS symptoms, it can also contribute negatively to her distress. (PsycINFO Database Record


Isolated limb perfusion based anti-p21ras gene therapy in a rat rhabdomyosarcoma.
Inhibition of ras oncogene is a promising new strategy. Gene therapy against ras proved successful in human and murine tumour cell lines. Previously we demonstrated effective targeted transfection of tumour in a rat model by using an isolated limb perfusion (ILP) for the delivery of adenoviral vectors. This study explores the anti-tumour activity of an adenoviral construct encoding an intracellular single-chain antibody (scFv) against p21ras (Y28). In order to determine the influence of the ras status on the efficacy of the scFv, we used a wild-type rat rhabdomyosarcoma and its ras-oncogene transfectant, for in vitro studies. In vivo we used the ILP delivery method to study anti-tumour activity on established limb tumours. In vitro studies demonstrated an inhibition of growth caused by the Y28 construct. No significant difference between transfected and wild-type cell lines could be demonstrated. Upon ILP, homogeneous transduction was observed in 5% of tumour cells. Perfusion with the Y28 construct, however, did not result in any additional anti-tumour activity compared to controls. Despite in vitro activity and in vivo transfection, no significant tumour response could be detected using anti-p21ras gene therapy in this ILP-tumour model.


Tetramethylpyrazine suppresses interleukin-8 expression in LPS-stimulated human umbilical vein endothelial cell by blocking ERK, p38 and nulear factor-kappaB signaling pathways.
To determine the anti-inflammatory effects of Tetramethylpyrazine (TMP) and to investigate the inhibitory effect of TMP on IL-8 production in human umbilical vein endothelial cells (HUVECs) induced by LPS might be mediated by inhibiting p38, ERK and NF-kappaB signaling pathways. HUVECs were treated with or without TMP for 24h before exposure to LPS for 4h. IL-8 gene and protein expressions were determined by RT-PCR and ELISA. Cell viability was determined by methyl thiazoyltetrazolium (MTT) assay. Phosphorylation of ERK1/2 and p38 were examined by western blotting. TMP inhibits LPS-induced IL-8 production in HUVECs at both the protein and mRNA levels, suggesting that TMP has an antiinflammatory effect on endothelial cells. TMP also inhibited U937 monocyte adhesion to HUVECs stimulated by LPS. LPS-induced phosphorylation of ERK1/2 and p38 were inhibited by TMP. The inhibitory effect of TMP on NF-kappaB (p65) activity was mediated by blocking the consequent translocation of p65 into the nucleus. The inhibitory effect of TMP on the LPS-induced IL-8 production is mediated by the NF-kappaB-dependent pathway, and TMP also separately affects the ERK and p38 MAPK pathway. TMP may be beneficial in the treatment of cardiovascular disorders such as atherosclerosis.


Tournament ABC analysis of the western Palaearctic population history of an oak gall wasp, Synergus umbraculus.
Approximate Bayesian computation (ABC) is a powerful and widely used approach in inference of population history. However, the computational effort required to discriminate among alternative historical scenarios often limits the set that is compared to those considered more likely a priori. While often justifiable, this approach will fail to consider unexpected but well-supported population histories. We used a hierarchical tournament approach, in which subsets of scenarios are compared in a first round of ABC analyses and the winners are compared in a second analysis, to reconstruct the population history of an oak gall wasp, Synergus umbraculus (Hymenoptera, Cynipidae) across the Western Palaearctic. We used 4,233 bp of sequence data across seven loci to explore the relationships between four putative Pleistocene refuge populations in Iberia, Italy, the Balkans and Western Asia. We compared support for 148 alternative scenarios in eight pools, each pool comprising all possible rearrangements of four populations over a given topology of relationships, with or without founding of one population by admixture and with or without an unsampled "ghost" population. We found very little support for the directional "out of the east" scenario previously inferred for other gall wasp community members. Instead, the best-supported models identified Iberia as the first-regional population to diverge from the others in the late Pleistocene, followed by divergence between the Balkans and Western Asia, and founding of the Italian population through late Pleistocene admixture from Iberia and the Balkans. We compare these results with what is known for other members of the oak gall community, and consider the strengths and weaknesses of using a tournament approach to explore phylogeographic model space.


A randomized, controlled trial of Social Cognition and Interaction Training (SCIT) for outpatients with schizophrenia spectrum disorders.
In schizophrenia, the ability to adaptively infer the thoughts and feelings of others (i.e., social cognition) is strongly associated with community functioning. Researchers have designed psychosocial interventions to improve social cognition with the aim of improving downstream social functioning. Social Cognition and Interaction Training (SCIT) is one such intervention. Previous research on SCIT has been promising, but has consisted largely of smaller trials with insufficient experimental control. Randomized, controlled trial. The current article reports on a controlled trial of 66 adults with schizophrenia randomized to receive either SCIT (n = 33), delivered in weekly group sessions, or treatment as usual (n = 33) for 6 months. Participants completed assessments of social cognition, social functioning, neurocognition and symptoms at baseline, post-treatment, and 3-month follow-up. Primary analyses suggest that SCIT may improve social functioning, negative symptoms, and possibly hostile attributional bias. Post-hoc analyses suggest a dose-response effect. Findings are discussed in the context of continuing to refine and improve social cognitive interventions for schizophrenia. Social cognitive intervention is a feasible and promising approach to improving social functioning among individuals with schizophrenia-spectrum disorders. Dose-response findings suggest that delivering social cognitive interventions with greater frequency may maximize their benefit to patients. Research on social cognitive interventions is still young and effects from well-controlled trials have been inconsistent. It is not yet clear which components of social cognitive training may be the key active ingredients.


Exploring the Asymmetrical Relationship Between the Power of Finance Bias and Evidence.
Financial conflicts of interest can influence the design, conduct, and dissemination of medical trials. In attempting to resist "finance bias," critics and proponents of evidence-based medicine (EBM) and its precursors have largely focused on trying to improve evidence. These efforts have led to successes ranging from the 1962 Kefauver-Harris amendments to the US Federal Drug and Cosmetic Act of 1938 to recent recommendations that all trials be published. However, there are two problems with the strategy of trying to improve evidence as a buffer against finance bias. First, without political teeth, rules of evidence can be ignored with relative impunity. This is because, as sociologist Bent Flyvbjerg has pointed out, there is an asymmetry between power (of finance bias) and rationality (evidence), tending towards victory of power in an open confrontation. Second, by improving the way evidence is produced, the process has become more expensive, and thus more susceptible to influence by finance bias. Unless they address the powers behind finance bias directly, critics and proponents may be doomed to lose the war against finance bias, even if they win some battles. For EBM to be effective, the power of finance bias influencing the production and dissemination of evidence needs to be addressed as a priority. This is starting to happen, with initiatives such as the AllTrials campaign, which identifies and exposes unpublished trials. On the other hand, there are reasons to be less optimistic, as Cochrane, the most trusted source of evidence, has become more susceptible to stronger influences from industry.


[Clinical features of patients with Basedow Graves disease seen at a university hospital].
Basedow Graves disease (BGD) is the leading cause of hyperthyroidism. The characteristics of patients seen at a university hospital may differ from those described in the general population. To describe the clinical features of patients with BGD seen at a university hospital. Review of medical records of all patients seen at our hospital between 2009 and 2014 with the diagnosis of thyrotoxicosis, hyperthyroidism or BGD. Clinical features, laboratory results and treatments were recorded. We reviewed clinical records of 272 patients; 15 had to be excluded due to incomplete data. BGD was present in 77.9% (n = 212). The mean age of the latter was 42 years (range 10-81) and 76% were women. Ninety six percent were hyperthyroid at diagnosis and thyroid stimulating hormone was below 0.1 mIU/L in all patients. Median free thyroxin and triiodothyronine levels were 3.26 ng/dl and 3.16 ng/ml, respectively. Thyrotropin-receptor antibodies were positive in 98.5% and 85.7% had positive thyroid peroxidase antibodies. Graves orbitopathy (GO) was clinically present in 55% of patients. Of this group, 47% had an active GO, 26% had a moderate to severe disease and 7.8% had sight-threatening GO. As treatment, 26% received radioiodine, 44% anti-thyroid drugs exclusively, 28% underwent thyroidectomy and 2% did not require therapy. In this group of patients, we observed a greater frequency of severe eye disease and a high rate of surgical management. This finding could be explained by referral to highly qualified surgical and ophthalmological teams.


A mindfulness-based group intervention to reduce psychological distress and fatigue in patients with inflammatory rheumatic joint diseases: a randomised controlled trial.
To evaluate the effects of a mindfulness-based group intervention, the Vitality Training Programme (VTP), in adults with inflammatory rheumatic joint diseases. In a randomised controlled trial, the VTP-a 10-session mindfulness-based group intervention including a booster session after 6 months-was compared with a control group that received routine care plus a CD for voluntary use with mindfulness-based home exercises. The primary outcome was psychological distress measured by the General Health Questionnaire-20. Self-efficacy (pain and symptoms) and emotion-focused coping (emotional processing and expression) were used as co-primary outcomes. Secondary outcomes included pain, fatigue, patient global disease activity, self-care ability and well-being. Effects were estimated by mixed models repeated measures post-intervention and at 12-month follow-up. Of 73 participants randomised, 68 completed assessments post-intervention and 67 at 12 months. Significant treatment effects in favour of the VTP group were found post-treatment and maintained at 12 months in psychological distress (adjusted mean between-group difference -3.7, 95% CI -6.3 to -1.1), self-efficacy pain (9.1, 95% CI 3.4 to 14.8) and symptoms (13.1, 95% CI 6.7 to 19.3), emotional processing (0.3, 95% CI 0.02 to 0.5), fatigue (-1.1, 95% CI -1.8 to -0.4), self-care ability (1.0, 95% CI 0.5 to 1.6) and overall well-being (0.6, 95% CI 0.1 to 1.2). No significant group differences were found in emotional expression, pain or disease activity. The VTP improved most primary and secondary outcomes compared with individual use of CD exercises. Improvements were maintained at 12 months, suggesting that the VTP is a beneficial complement to existing treatments for patients with inflammatory rheumatic joint diseases.