Miracle-dz/UniFAR-FTUs huggingface dataset:
Defining the Effectiveness of Antimalarial Chemotherapy: Investigation of the Lag in Parasite Clearance Following Drug Administration.

BACKGROUND The emergence of drug-resistant malaria highlights the need for new agents. A desired characteristic of candidate antimalarials is rapid killing of parasites. This is typically measured by the rate of exponential clearance of parasitemia following treatment. However, this clearance rate excludes the highly variable lag phase, when the parasitemia level may increase, remain constant, or decrease. Understanding factors determining this lag phase is important for drug development. METHODS We assessed the kinetics of parasitemia in 112 volunteers infected with blood-stage Plasmodium falciparum and treated with 8 different antimalarials. The parasitemia level was measured by quantitative polymerase chain reaction. We analyzed the relationship between the timing of treatment in the parasite growth cycle, and whether the parasitemia level rose or fell in the first 12 or 24 hours after treatment. RESULTS The timing of treatment in the parasite life cycle predicted whether subjects experienced rises or falls in parasitemia level after treatment. Antimalarials were unable to prevent rises in the parasitemia level in the first 12 hours. However, in the first 24 hours after treatment, fast-acting but not slow-acting drugs reduced the parasitemia level independent of when treatment was administered. CONCLUSIONS The highly variable lag phase depends on the speed of action of an antimalarial and when in the periodic growth cycle it is administered.
Severity of Plasma Leakage Is Associated With High Levels of Interferon &ggr;–Inducible Protein 10, Hepatocyte Growth Factor, Matrix Metalloproteinase 2 (MMP-2), and MMP-9 During Dengue Virus Infection

Background. Dengue virus infection typically causes mild dengue fever, but, in severe cases, life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) occur. The pathophysiological hallmark of DHF and DSS is plasma leakage that leads to enhanced vascular permeability, likely due to a cytokine storm. Methods. Ninety patients with dengue during 2010–2012 in Singapore were prospectively recruited and stratified according to their disease phase, primary and secondary infection status, and disease severity, measured by plasma leakage. Clinical parameters were recorded throughout the disease progression. The levels of various immune mediators were quantified using comprehensive multiplex microbead-based immunoassays for 46 immune mediators. Results. Associations between clinical parameters and immune mediators were analyzed using various statistical methods. Potential immune markers, including interleukin 1 receptor antagonist, interferon &ggr;–inducible protein 10, hepatocyte growth factor, soluble p75 tumor necrosis factor &agr; receptor, vascular cell adhesion molecule 1, and matrix metalloproteinase 2, were significantly associated with significant plasma leakage. Secondary dengue virus infections were also shown to influence disease outcome in terms of disease severity. Conclusions. This study identified several key markers for exacerbated dengue pathogenesis, notably plasma leakage. This will allow a better understanding of the molecular mechanisms of DHF and DSS in patients with dengue.
Natural History and Tumor Volume Kinetics of Papillary Thyroid Cancers During Active Surveillance

Importance Active surveillance of low-risk papillary thyroid cancer (PTC) is now an accepted alternative to immediate surgery, but experience with this approach outside of Japan is limited. The kinetics (probability, rate, and magnitude) of PTC tumor growth under active surveillance have not been well defined. Objective To describe the kinetics of PTC tumor growth during active surveillance. Design, Setting, and Participants Cohort study of 291 patients undergoing active surveillance for low-risk PTC (intrathyroidal tumors ⩽1.5 cm) with serial tumor measurements via ultrasonography at a tertiary referral center in the United States. Intervention Active surveillance. Main Outcomes and Measures The cumulative incidence, rate, and magnitude of the change in tumor diameter or volume, as well as associations with patient and tumor characteristics. Results Of the 291 patients, 219 (75.3%) were women; mean (SD) age was 52 (15) years. During a median (range) active surveillance of 25 (6-166) months, growth in tumor diameter of 3 mm or more was observed in 11 of 291 (3.8%) patients, with a cumulative incidence of 2.5% (2 years) and 12.1% (5 years). No regional or distant metastases developed during active surveillance. In all cases, 3-dimensional measurements of tumor volume allowed for earlier identification of growth (median, 8.2 months; range, 3-46 months before increase in tumor diameter). In multivariable analysis, both younger age at diagnosis (hazard ratio per year, 0.92; 95% CI, 0.87-0.98; P = .006) and risk category at presentation (hazard ratio for inappropriate, 55.17; 95% CI, 9.4-323.19; P < .001) were independently associated with the likelihood of tumor growth. Of the tumors experiencing volume growth, kinetics demonstrated a classic exponential growth pattern, with a median doubling time of 2.2 years (range, 0.5-4.8 years; median r2 = 0.75; range, 0.42-0.99). Conclusions and Relevance The rates of tumor growth during active surveillance in a US cohort with PTCs measuring 1.5 cm or less were low. Serial measurement of tumor volumes may facilitate early identification of tumors that will continue to grow and thereby inform the timing of surveillance imaging and therapeutic interventions.
Targeting invasive properties of melanoma cells

Melanoma is a skin cancer notorious for its metastatic potential. As an initial step of the metastatic cascade, melanoma cells part from the primary tumour and invade the surrounding tissue, which is crucial for their dissemination and the formation of distant secondary tumours. Over the last two decades, our understanding of both, general and melanoma specific mechanisms of invasion has significantly improved, but to date no efficient therapeutic strategy tackling the invasive properties of melanoma cells has reached the clinic. In this review, we assess the major contributions towards the understanding of the molecular biology of melanoma cell invasion with a focus on melanoma specific traits. These traits are based on the neural crest origin of melanoma cells and explain their intrinsic invasive nature. A particular emphasis is given not only to lineage specific signalling mediated by TGFβ, and noncanonical and canonical WNT signalling, but also to the role of PDE5A and RHO‐GTPases in modulating modes of melanoma cell invasion. We discuss existing caveats in the current understanding of the metastatic properties of melanoma cells, as well as the relevance of the ‘phenotype switch’ model and ‘co‐operativity’ between different phenotypes in heterogeneous tumours. At the centre of these phenotypes is the lineage commitment factor microphthalmia‐associated transcription factor, one of the most crucial regulators of the balance between de‐differentiation (neural crest specific gene expression) and differentiation (melanocyte specific gene expression) that defines invasive and noninvasive melanoma cell phenotypes. Finally, we provide insight into the current evidence linking resistance to targeted therapies to invasive properties of melanoma cells.
Objectivation de l'impact qualitatif d'une infirmière référente en consultation d'urologie

Objectif : notre objectif a ete de demontrer la valeur ajoutee de l’infirmier(e) referent(e) dans une consultation generale en urologie.Methodes : notre etude prospective evaluative porte sur une population ambulatoire de 135 patients (40 femmes, 95 hommes) inclus. Les troubles de la fonction urinaire ont ete definis par la Classification internationale du fonctionnement, du handicap et de la sante (CIF) de l’Organisation mondiale de la sante (OMS). La composante activite – participation a ete analysee dans le domaine de la communication avant et apres la consultation chez l’urologue. Nous avons utilise les resultats obtenus sur base d’une echelle visuelle analogique (EVA). L’EVA a egalement determine un pourcentage qualifiant le facteur facilitateur de l’environnement cree par l’infirmiere specialisee. L’analyse statistique comporte une etude de la population ainsi qu’une comparaison par analyse de la variance (ANOVA) de la composante activite-participation.Resultats : la population etait âgee de 4 ans et 10 mois a 96 ans (m = 63,29 ; ecart-type (ET) = 19,71). Le code qualificatif median du trouble urologique observe etait de 2 (modere). L’analyse de la variance de la composante activite-participation a objective une difference significative avant et apres la consultation (F = 6,4172 ; p < 0,001). La troisieme question posee qualifiait le facteur facilitateur de l’environnement cree par l’infirmiere sur base d’une EVA avec une moyenne de 97,79 % (ET = 4,67). Conclusion : notre travail prospectif s’est porte sur l’evaluation de l’impact qualitatif d’une infirmiere specialisee dans le decours d’une consultation ambulatoire urologique a caractere general. Le caractere qualitatif d’environnement facilitateur d’un personnel paramedical specialise est important dans le cadre participatif de la communication et de la comprehension du message medical.
Textbook of rheumatology

Structure and Function of Joints, Connective Tissue, And Muscle. Immune and Inflammatory Responses. Evaluation of the Patient. Special Issues of the Rheumatic Diseases. Diagnostic Tests and Procedures for Rheumatic Diseases. Clinical Pharmacology in Rheumatic Diseases. Rheumatoid Arthritis. Spondyloarthropaties. Systemic Lupus Erythematosus and Related Syndromes. Vasculitic Syndromes. Connective Tissue Diseases Characterized By Fibrosis. Inflammatory Diseases of the Muscle. Rheumatic Diseases of Childhood. Syndromes of Impaired Immune Function. Crystal-Associated Synovitis. Osteoarthritis and Polychondritis. Infiltrative Disorders Associated with Rheumatic Diseases. Infectious Arthritis. Arthritis as a Manifestation of Other Systemic Diseases. Disorders of Bone and Structural Proteins. Tumors Involving Joints. Rehabilitation. Reconstructive Surgery for Rheumatic Diseases.
2‐Deoxy‐D‐glucose has distinct and cell line‐specific effects on the survival of different cancer cells upon antitumor drug treatment

The dependence of tumors on glycolysis for ATP generation offers a rationale for therapeutic strategies aimed at selective inhibition of the glycolytic pathway. Analysis of tumor cell responses to anticancer drugs revealed that inhibition of glycolysis by 2‐deoxy‐D‐glucose (2‐DG) generally augmented the apoptotic response; however, in HCT116 human colon carcinoma cells, apoptosis was suppressed. A comparison of neuroblastoma SK‐N‐BE(2) and HCT116 cells revealed, that in contrast to HCT116, in SK‐N‐BE(2) cells 2‐DG alone was able to induce cell death. In SK‐N‐BE(2) cells the decrease in ATP levels upon treatment with 2‐DG was more prominent because in HCT116 cells mitochondria compensated for the loss of ATP caused by glycolysis suppression. In both cells lines 2‐DG triggered endoplasmic reticulum (ER) stress, assessed by the accumulation of the marker protein GRP78/BiP. Suppression of ER stress by mannose attenuated the 2‐DG‐induced apoptotic response in SK‐N‐BE(2) cells, implying that apoptosis in these cells is a consequence of ER stress induction. In HCT116 cells, ER stress stimulated autophagy, assessed by the accumulation of the lipidated form of LC3. The inhibitor of ER stress mannose attenuated autophagy and reversed 2‐DG‐mediated suppression of cisplatin‐induced apoptosis. When autophagy in HCT116 cells was suppressed by bafilomycin, cisplatin‐induced apoptosis was decreased. At the same time, stimulation of autophagy in SK‐N‐BE(2) cells suppressed cell death. Thus, successful treatment of tumors with conventionally used anticancer drugs should be combined with targeting metabolic pathways involved in the regulation of apoptosis, autophagy, and cellular bioenergetics.
Cross‐species genetics converge to TLL2 for mouse avoidance behavior and human bipolar disorder

Interspecies genetic analysis of neurobehavioral traits is critical for identifying neurobiological mechanisms underlying psychiatric disorders, and for developing models for translational research. Recently, after screening a chromosome substitution strain panel in an automated home cage environment, chromosomes 15 and 19 were identified in female mice for carrying genetic loci that contribute to increased avoidance behavior (sheltering preference). Furthermore, we showed that the quantitative trait locus (QTL) for baseline avoidance behavior on chromosome 15 is homologous with a human linkage region for bipolar disorder (8q24). Similarly, we now performed comparative analysis on the QTL for avoidance behavior found on chromosome 19 and correspondingly revealed an overlap of the mouse interval and human homologous region 10q23‐24, which has been previously linked to bipolar disorders. By means of a comparative genetic strategy within the human homologous region, we describe an association for TLL2 with bipolar disorder using the genome‐wide association study (GWAS) data set generated by the Wellcome Trust Case Control Consortium (WTCCC). On the basis of genetic homology and mood stabilizer sensitivity, our data indicate the intriguing possibility that mouse home cage avoidance behavior may translate to a common biochemical mechanisms underlying bipolar disorder susceptibility. These findings pave new roads for the identification of the molecular mechanisms and novel treatment possibilities for this psychiatric disorder, as well as for the validity of translational research of associated psychiatric endophenotypes.
Association of antibiotics in infancy with early childhood obesity.

IMPORTANCE Obesity in children and adults is associated with significant health burdens, making prevention a public health imperative. Infancy may be a critical period when environmental factors exert a lasting effect on the risk for obesity; identifying modifiable factors may help to reduce this risk. OBJECTIVE To assess the impact of antibiotics prescribed in infancy (ages 0-23 months) on obesity in early childhood (ages 24-59 months). DESIGN, SETTING, AND PARTICIPANTS We conducted a cohort study spanning 2001-2013 using electronic health records. Cox proportional hazard models were used to adjust for demographic, practice, and clinical covariates. The study spanned a network of primary care practices affiliated with the Children's Hospital of Philadelphia including both teaching clinics and private practices in urban Philadelphia, Pennsylvania, and the surrounding region. All children with annual visits at ages 0 to 23 months, as well 1 or more visits at ages 24 to 59 months, were enrolled. The cohort comprised 64,580 children. EXPOSURES Treatment episodes for prescribed antibiotics were ascertained up to 23 months of age. MAIN OUTCOMES AND MEASURES Obesity outcomes were determined directly from anthropometric measurements using National Health and Nutrition Examination Survey 2000 body mass index norms. RESULTS Sixty-nine percent of children were exposed to antibiotics before age 24 months, with a mean (SD) of 2.3 (1.5) episodes per child. Cumulative exposure to antibiotics was associated with later obesity (rate ratio [RR], 1.11; 95% CI, 1.02-1.21 for ≥ 4 episodes); this effect was stronger for broad-spectrum antibiotics (RR, 1.16; 95% CI, 1.06-1.29). Early exposure to broad-spectrum antibiotics was also associated with obesity (RR, 1.11; 95% CI, 1.03-1.19 at 0-5 months of age and RR, 1.09; 95% CI, 1.04-1.14 at 6-11 months of age) but narrow-spectrum drugs were not at any age or frequency. Steroid use, male sex, urban practice, public insurance, Hispanic ethnicity, and diagnosed asthma or wheezing were also predictors of obesity; common infectious diagnoses and antireflux medications were not. CONCLUSIONS AND RELEVANCE Repeated exposure to broad-spectrum antibiotics at ages 0 to 23 months is associated with early childhood obesity. Because common childhood infections were the most frequent diagnoses co-occurring with broad-spectrum antibiotic prescription, narrowing antibiotic selection is potentially a modifiable risk factor for childhood obesity.
Norepinephrine transporter heterozygous knockout mice exhibit altered transport and behavior

The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET+/−), demonstrating that they display an approximately 50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface‐resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET+/− mouse establishes an activated state of existing surface NET proteins. The NET+/− mice exhibit increased anxiety in the open field and light–dark box and display deficits in reversal learning in the Morris water maze. These data suggest that recovery of near basal activity in NET+/− mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET+/− mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders.
Primary T-cell Non – Hodgkin lymphoma of the Urinary Bladder Presenting as Haematuria and Bilateral Hydronephrosis: Report of a Rare Case

Introduction: Primary T cell lymphoma of the urinary bladder is extremely rare disease. Most of the lymphomas of urinary bladder are B-cell lymphomas. We encountered a case of T-cell lymphoma of the urinary bladder presenting as haematuria and bilateral hydronephrosis. Presentation of Case: A 42-year-old man was admitted to our hospital because of intermittent painful gross haematuria associated with bilateral loin pain and vomiting lasting for 3-4 weeks. Results of his general examination were normal. An ultrasonographic study and Computed Tomography (CT) of his abdomen and pelvis revealed bilateral gross hydro-ureteronephrosis with significantly thickened urinary bladder wall with large circumferential growth involving the entire bladder occluding both ureteric orifices with internal calcification. A cystoscopy procedure with Trans Urethral Resection of Bladder Tumour (TURBT) was performed. Postoperative microscopic examination and immunohistochemistry showed medium to large lymphocytes with hyperchromatic nuclei and strong expression of CD3 in the tumour cells and negativity for CD20 and cytokeratin. A diagnosis of T-cell non Hodgkin Lymphoma was entertained. Conclusion : Presentation of bilateral hydronephrosis with primary T cell lymphoma has not been reported previously. This sort of presentation can mimic other bladder malignancy and present a diagnostic challenge. An ancillary technique, Immunohistochemistry in our case, helped us arrive at the correct diagnosis and subsequent appropriate management.
Enkephalin knockout male mice are resistant to chronic mild stress

Enhanced stress reactivity or sensitivity to chronic stress increases the susceptibility to mood pathologies such as major depression. The opioid peptide enkephalin is an important modulator of the stress response. Previous studies using preproenkephalin knockout (PENK KO) mice showed that these animals exhibit abnormal stress reactivity and show increased anxiety behavior in acute stress situations. However, the consequence of enkephalin deficiency in the reactivity to chronic stress conditions is not known. In this study, we therefore submitted wild‐type (WT) and PENK KO male mice to chronic stress conditions, using the chronic mild stress (CMS) protocol. Subsequently, we studied the CMS effects on the behavioral and hormonal level and also performed gene expression analyses. In WT animals, CMS increased the expression of the enkephalin gene in the paraventricular nucleus (PVN) of the hypothalamus and elevated the corticosterone levels. In addition, WT mice exhibited enhanced anxiety in the zero‐maze test and depression‐related behaviors in the sucrose preference and forced swim tests. Surprisingly, in PENK KO mice, we did not detect anxiety and depression‐related behavioral changes after the CMS procedure, and even measured a decreased hormonal stress response. These results indicate that PENK KO mice are resistant to the CMS effects, suggesting that enkephalin enhances the reactivity to chronic stress.
Human Metapneumovirus Infection in Chronic Obstructive Pulmonary Disease: Impact of Glucocorticosteroids and Interferon

Background Human metapneumovirus (hMPV) infection is implicated in exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Research into the pathogenesis of infection is restricted to animal models, and information about hMPV replication and inflammatory and immune responses in human disease is limited. Methods Human primary bronchial epithelial cells (PBECs) from healthy and asthmatic subjects and those with COPD were infected with hMPV, with or without glucocorticosteroid (GCS) exposure. Viral replication, inflammatory and immune responses, and apoptosis were analyzed. We also determined whether adjuvant interferon (IFN) can blunt hMPV infection in vitro and in a murine model. Results hMPV infected human PBECs and viral replication was enhanced in cells from patients with COPD. The virus induced gene expression of IFN-stimulated gene 56 (ISG56) and IFN-β, as well as IFN-γ-inducible protein 10 (IP-10) and regulated on activation, normal T cell expressed and secreted (RANTES), and more so in cells from patients with COPD. GCS exposure enhanced hMPV replication despite increased IFN expression. Augmented virus replication associated with GCS was mediated by reduced apoptosis via induction of antiapoptotic genes. Adjuvant IFN treatment suppressed hMPV replication in PBECs and reduced hMPV viral titers and inflammation in vivo. Conclusions hMPV infects human PBECs, eliciting innate and inflammatory responses. Replication is enhanced by GCS and adjuvant IFN is an effective treatment, restricting virus replication and proinflammatory consequences of hMPV infections.