Severe drug-associated colitis with Crohn's features in setting of ixekizumab therapy for chronic plaque psoriasis.
Ixekizumab is monoclonal antibody targeted against interleukin-17 (IL-17) and has been approved for use in chronic plaque psoriasis. Despite its efficacy in treating psoriasis, concerns have been raised regarding Ixekizumab's potential to induce and exacerbate inflammatory bowel disease (IBD). Here we report the new onset of severe drug-associated colitis with surgical complications in a 45-year-old male patient who was receiving Ixekizumab therapy for chronic plaque psoriasis. Review of the patient's colonic pathology demonstrated acute inflammatory changes with features of Crohn's disease. The patient remained disease-free 9-months following his hospitalization and cessation of Ixekizumab. This case raises suspicion for an association between Ixekizumab and IBD and calls on clinicians to have heightened awareness of potential risks before prescribing anti-IL-17 agents.


Drug export and allosteric coupling in a multidrug transporter revealed by molecular simulations.
Multidrug resistance is a serious problem in current chemotherapy. The efflux system largely responsible for resistance in Escherichia coli contains the drug transporter, AcrB. The structures of AcrB were solved in 2002 as the symmetric homo-trimer, and then in 2006 as the asymmetric homo-trimer. The latter suggested a functionally rotating mechanism. Here, by molecular simulations of the AcrB porter domain, we uncovered allosteric coupling and the drug export mechanism in the AcrB trimer. Allosteric coupling stabilized the asymmetric structure with one drug molecule bound, which validated the modelling. Drug dissociation caused a conformational change and stabilized the symmetric structure, providing a unified view of the structures reported in 2002 and 2006. A dynamic study suggested that, among the three potential driving processes, only protonation of the drug-bound protomer can drive the functional rotation and simultaneously export the drug.


Poly(rA).poly(rU) with Ni(2+) ions at different temperatures: infrared absorption and vibrational circular dichroism spectroscopy.
Phase transitions were studied of the sodium salt of poly(rA).poly(rU) induced by elevated temperature without Ni(2+) and with Ni(2+) in 0.07 M concentration in D(2)O (approximately 0.4 [Ni]/[P]). The temperature was varied from 20 degrees C to 90 degrees C. The double-stranded conformation of poly(rA).poly(rU) was observed at room temperature (20 degrees C-23 degrees C) with and without Ni(2+) ions. In the absence of Ni(2+) ions, partial double- to triple-strand transition of poly(rA).poly(rU) occurred at 58 degrees C, whereas only single- stranded molecules existed at 70 degrees C. While poly(rU) did not display significant helical structure, poly(rA) still maintained some helicity at this temperature. Ni(2+) ions significantly stabilized the triple-helical structure. The temperature range of the stable triple-helix was between 45 degrees C and 70 degrees C with maximum stability around 53 degrees C. Triple- to single-stranded transition of poly(rA).poly(rU) occurred around 72 degrees C with loss of base stacking in single-stranded molecules. Stacked or aggregated structures of poly(rA) formed around 86 degrees C. Hysteresis took place in the presence of Ni(2+) during the reverse transition from the triple-stranded to the double-stranded form upon cooling. Reverse Hoogsteen type of hydrogen-bonding of the third strand in the triplex was suggested to be the most probable model for the triple-helical structure. VCD spectroscopy demonstrated significant advantages over infrared absorption or the related electronic CD spectroscopy.


Corticospinal excitability enhancement with simultaneous transcranial near-infrared stimulation and anodal direct current stimulation of motor cortex.
Non-invasive brain stimulation (NIBS) is beneficial to many neurological and psychiatric disorders by modulating neuroplasticity and cortical excitability. However, recent studies evidence that single type of NIBS such as transcranial direct current stimulation (tDCS) does not have meaningful clinical therapeutic responses due to their small effect size. Transcranial near-infrared stimulation (tNIRS) is a novel form of NIBS. Both tNIRS and tDCS implement its therapeutic effects by modulating cortical excitability but with different mechanisms. We hypothesized that simultaneous tNIRS and tDCS is superior to single stimulation, leading to a greater cortical excitability. Sixteen healthy subjects participated in a double-blind, sham-controlled, cross-over designed study. Motor evoked potentials (MEPs) were used to measure motor cortex excitability. The changes of MEP were calculated and compared in the sham condition, tDCS stimulation condition, tNIRS condition and the simultaneous tNIRS and anodal tDCS condition. tDCS alone and tNIRS alone both elicited higher MEP after stimulation, while the MEP amplitude in the simultaneous tNIRS and tDCS condition was significantly higher than either tNIRS alone or tDCS alone. The enhancement lasted up to at least 30 minutes after stimulation, indicating simultaneous 820 nm tNIRS with 2 mA anodal tDCS have a synergistic effect on cortical plasticity. Simultaneous application of tNIRS with tDCS produces a stronger cortical excitability effect. The simultaneous tNIRS and tDCS is a promising technology with exciting potential as a means of treatment, neuro-enhancement, or neuro-protection.


Natural disasters and mass-casualty events affecting children and families: a description of emergency preparedness and the role of the primary care physician.
To determine the compliance of a select number of families with national recommendations for disaster preparedness. A questionnaire focusing on knowledge of community evacuation plans and the presence of a family emergency response plan was distributed simultaneously in Dauphin County, Pennsylvania, and Bronx County, New York. A total of 1024 questionnaires were analyzed, and it was found that 35% (95% confidence interval [CI] = 32-38) of families were familiar with community evacuation plans, and 43% (95% CI = 40-46) had a family emergency response plan. Also, 17% (95% CI = 15-19) of respondents had discussed preparedness with their primary care physician; this subset of respondents was more likely to be familiar with community evacuation plans and was more likely to have a family emergency response plan. These data show that families are, for the most part, not in compliance with national recommendations for preparedness. Families who discussed preparedness with their primary care physician were more likely to be compliant.


Relationship between diabetes mellitus and atrial fibrillation prevalence in the Polish population: a report from the Non-invasive Monitoring for Early Detection of Atrial Fibrillation (NOMED-AF) prospective cross-sectional observational study.
The global burden of atrial fibrillation (AF) and diabetes mellitus (DM) is constantly rising, leading to an increasing healthcare burden of stroke. AF often remains undiagnosed due to the occurrence in an asymptomatic, silent form, i.e., silent AF (SAF). The study aims to evaluate the relationships between DM and AF prevalence using a mobile long-term continuous ECG telemonitoring vest in a representative Polish and European population ≥ 65 years for detection of AF, symptomatic or silent. A representative sample of 3014 participants from the cross-sectional NOMED-AF study was enrolled in the analyses (mean age 77.5, 49.1% female): 881 (29.2%) were diagnosed with DM. AF was screened using a telemonitoring vest for a mean of 21.9 ± 9.1days. Overall, AF was reported in 680 (22.6%) of the whole study population. AF prevalence was higher among subjects with concomitant DM (DM+) versus those without DM (DM-) [25%, 95% CI 22.5-27.8% vs 17%; 95% CI 15.4-18.5% respectively, p < 0.001]. DM patients were commonly associated with SAF [9%; 95% CI 7.9-11.4 vs 7%; 95% CI 5.6-7.5 respectively, p < 0.001], and persistent/permanent AF [12.2%; 95% CI 10.3-14.3 vs 6.9%; 95% CI 5.9-8.1 respectively, p < 0.001] compared to subjects without DM. The prolonged screening was associated with a higher percentage of newly established AF diagnosis in DM+ vs DM- patients (5% vs 4.5% respectively, p < 0.001). In addition to shared risk factors, DM+ subjects were associated with different AF and SAF independent risk factors compared to DM- individuals, including thyroid disease, peripheral/systemic thromboembolism, hypertension, physical activity and prior percutaneous coronary intervention/coronary artery bypass graft surgery. AF affects 1 out of 4 subjects with concomitant DM. The higher prevalence of AF and SAF among DM subjects than those without DM highlights the necessity of active AF screening specific AF risk factors assessment amongst the diabetic population. NCT03243474.


HIV infection and community midwives: experience and practice.
To assess the effects of HIV infection on the work of community midwives, a postal survey of 1 in 5 in Scotland and England was carried out. The 907 respondents represent an 83% response rate. While only 1% of respondents had experience of patients with AIDS, 8% had been involved with known asymptomatic HIV infection and 32% had encountered those that they considered to be 'at high risk'. While the workload generated by HIV-infected patients for individual midwives at this time was small, almost all midwives themselves considered that they had a role to play in the prevention of HIV infection through health education and in counselling. While less than a quarter of those who had encountered HIV-positive patients had provided health education, more than half had done so to those worried about HIV infection and almost a quarter had counselled them. However, confidence to provide these aspects of practice was low, even among those who had received in-service education, although higher than among those who had not done so. A minority of community midwives had read policies or guidelines about aspects of practice and service provision, except for infection control where two thirds had read what they considered an adequate policy.


Reexpansion pulmonary edema after treatment of primary spontaneous pneumothorax.
A 24-year-old male patient, without further symptoms or comorbidities presented to the emergency room with acute dyspnea after heavy lifting two days before. On auscultation an attenuated vesicular breath was noticed on the right lung. In the initial chest radiograph a right-sided primary spontaneous pneumothorax with minor mediastinal shift was diagnosed. After insertion of a 12-French chest tube the patient's clinical condition deteriorated. The following chest radiograph and computed tomography of the thorax showed a reexpansion pulmonary edema in the right lung. The patient was admitted to the ICU and supportive treatment was initiated. Pulmonary reexpansion edema after drainage of a pneumothorax is a very rare complication with mortality rates reaching up to 20%. The exact pathophysiology remains unknown. Typical Symptoms include dyspnea, hypotension, and tachycardia. To minimize the risk of a pulmonary reexpansion edema, not more than 1200-1800 ml of air should be drained at once and the drainage should be stopped when the patient starts coughing.


Mental health court outcomes by offense type at admission.
Using a statewide database of mental health court (MHC) defendants, this study examines criminal justice outcomes by target arrest offense type. Findings suggest that defendants with a felony are less likely to complete MHC but those who do are at no greater risk of recidivism post-exit than those with a misdemeanor. In terms of jail days, both completers and noncompleters with a felony had reductions in jail days; however, misdemeanor defendants, especially those who did not complete MHC, had increases. We discuss why MHC supervision may sometimes have a negative effect and offer recommendations on how courts might modify supervision.


On the analogy in the structure of the spleen green heme protein and granulocyte myeloperoxidase.
The molecular structure of the spleen green heme protein was reinvestigated by gel-permeation, SDS-polyacrylamide gel electrophoresis, and amino acid analysis. The results showed that the enzyme is a tetramer (Mr 1.5 X 10(5)) with two heavy subunits (Mr 6 X 10(4) with a single prosthetic group per subunit) and two light subunits (Mr 1.5 X 10(4)), and that the tetramer structure is maintained by disulfide bond(s). The amino acid composition of the spleen green heme protein is similar to that of granulocyte myeloperoxidase. The present results contradict the data of Davis and Averill [(1981) J. Biol. Chem. 256, 5992-5996], who reported the enzyme as a monomeric peroxidase with an Mr of 57 000.


A pilot study testing the effect of different levels of financial incentives on weight loss among overweight employees.
To test the ability of two levels of modest financial incentives to encourage weight loss among overweight employees. This study used a randomized design with measurements at baseline, 3, and 6 months and two levels of financial incentives ($7 and $14 per percentage point of weight lost). Payments were structured so that all participants had equal ability to obtain the incentives during the study period. At 3 months, participants with no financial incentive lost 2 pounds, those in the $7 group lost approximately 3 pounds, and those in the $14 group lost 4.7 pounds. Between baseline and 6 months, when the financial gains were equalized, weight losses were similar across groups. This study revealed that modest financial incentives can be effective in motivating overweight employees to lose weight.


A reassessment of suicide measurement.
Concern with suicide measurement is a positive, albeit relatively recent, development. A concern with "the social loss from suicide" requires careful attention to appropriately measuring the phenomenon. This paper applies two different methods of measuring suicide data: the conventional age-standardized suicide (count) rate; and the alternative rate, the potential years of life lost (PYLL) rate. The purpose of applying these two measures is to place suicide in Queensland in a historical and comparative (relative to other causes of death) perspective. Both measures are applied to suicide data for Queensland since 1920. These measures are applied also to two "largish" causes of death and two "smaller" causes of death, i.e., circulatory diseases, cancers, motor vehicle accidents, suicide. The two measures generate quite different pictures of suicide in Queensland: Using the PYLL measure, suicide is a quantitatively larger issue than is indicated by the count measure. The PYLL measure is the more appropriate measure for evaluation exercise of public health prevention strategies. This is because the PYLL measure is weighted by years of life lost and, thus, it incorporates more information than the count measure which implicitly weights each death with a somewhat partial value, viz. unity.


Individual and population screening of varices needing treatment by a simple, safe and accurate test.
Several tests have been developed to screen varices needing treatment (VNT) in different screening settings. We aimed to develop simple estimators to quantify VNT risk and spare endoscopy while missing <5% of VNT, adapted to different screenings in the main etiologies. 2,368 patients with chronic liver disease were included. The main VNT predictors were platelets, prothrombin index (PI) and LSM. Their interactions led to score construction, LIP: (LSM*45)/(PI*platelets), and BLIP: BMI-adjusted LIP in NAFLD. Scores were categorized either for population (VNT sensitivity ≥95%) or individual (negative predictive value ≥95%) VNT screening. 1) Scores diagnosing VNT. AUROCs were, PLER: 0.767 Anticipate: 0.773 (p=0.059 vs previous), LIP: 0.779 (p=0.136), PLEASE: 0.789 (p=0.196). 2) Population screening performance was in increasing order (with missed VNT rate), Baveno6 criteria: 23.9% (2.5%), Anticipate: 24.5%, p=0.367 vs previous (3.3%), PLER: 27.3%, p<0.001 (3.6%), LIP: 33.4%, p<0.001 (4.2%), PLEASE: 35.2%, p=0.006 (3.6%). In NAFLD, LIP: 38.6%, BLIP: 40.8%, p=0.038. 3) Individual screening performance was, expanded Baveno6 criteria: 42.7%, LIP: 54.1%, p<0.001. In NAFLD, performance was, NAFLD-cirrhosis criteria: 66.7%, BLIP: 74.6%, p<0.001. LIP combined simplicity, performance and safety in each etiology. In NAFLD, BMI-adjusted LIP outperformed other tests.


Molecular identification and function characterization of four finTRIM genes from the immortal fish cell line, EPC.
In mammals, tripartite motif (TRIM)-containing proteins are involved in interferon (IFN)-mediated antiviral response as pivotal players endowed with antiviral effects and modulatory capacity. Teleost fish have a unique subfamily of TRIM, called finTRIM (fish novel TRIM, FTR) generated by genus- or species-specific duplication of TRIM genes. Herein, four TRIM genes are identified from Epithelioma papulosum cyprini (EPC) cells, and phylogenetically close to the members of finTRIM, thus named FTREPC1, FTREPC2, FTREPC3 and FTREPC4. Despite high similarity in nucleotide sequence, FTREPC1/2 genes encode two proteins with a typically consecutive tripartite motif followed by a C-terminal B30.2 domain, while FTREPC3/4-encoding proteins retain only a RING domain due to early termination of translation. They are induced by poly(I:C), GCRV and SVCV as IFN-stimulated genes (ISGs), and this induction is severely impaired by blockade of STAT1 pathway and is dependent on a typical ISRE motif within the 5' untranslated regions (5'UTRs) of FTREPC1/2/3/4 genes. Whereas overexpression of FTREPC1/2/3/4 alone does not activate fish IFN promoters, overexpression of FTREPC1 or FTREPC2, rather than FTREPC3 and FTREPC4, significantly impairs intracellular poly(I:C)-triggered activation of fish IFN promoters. Consistently, FTREPC1/2 promote virus replication through negatively regulating IFN response. Our results provide evidence for the involvement of EPC finTRIM proteins in IFN antiviral response and insights into genus- or species-specific regulation of fish innate immune pathways.


Neurobiological signatures of anxiety and depression in resting-state functional magnetic resonance imaging.
There is increasing interest in using neurobiological measures to inform psychiatric nosology. It is unclear at the present time whether anxiety and depression are neurobiologically distinct or similar processes. It is also unknown if the best way to examine these disorders neurobiologically is by contrasting categorical definitions or by examining symptom dimensions. A cross-sectional neuroimaging study was conducted of patients with generalized anxiety disorder (GAD), major depressive disorder (MDD), comorbid GAD and MDD (GAD/MDD), or neither GAD nor MDD (control subjects). There were 90 participants, all medication-free (17 GAD, 12 MDD, 23 GAD/MDD, and 38 control subjects). Diagnosis/category and dimensions/symptoms were assessed to determine the best fit for neurobiological data. Symptoms included general distress, common to anxiety and depression, and anxiety-specific (anxious arousal) or depression-specific (anhedonia) symptoms. Low-frequency (.008-.1 Hz) signal amplitude and functional connectivity analyses of resting-state functional magnetic resonance imaging data focused on a priori cortical and subcortical regions of interest. Support was found for effects of diagnosis above and beyond effects related to symptom levels as well as for effects of symptom levels above and beyond effects of diagnostic categories. The specific dimensional factors of general distress and anxious arousal as well as a diagnosis of MDD explained unique proportions of variance in signal amplitude or functional connectivity. Using resting-state functional magnetic resonance imaging, our data show that a single conceptual model alone (i.e., categorical diagnoses or symptom dimensions) provides an incomplete mapping of psychopathology to neurobiology. Instead, the data support an additive model that best captures abnormal neural patterns in patients with anxiety and depression.


Preoperative duplex on admission prevents unnecessary carotid surgery.
Our unit policy is to duplex on admission all patients undergoing carotid endarterectomy to confirm patency. The aim of this study was to evaluate whether this had led to avoidance of unnecessary carotid surgery in a significant number of patients. Over a 7-year period from January 1997 to December 2003, a total of 475 patients were scheduled for carotid endarterectomy. Of these, 439 patients subsequently underwent carotid endarterectomy. These data were obtained from prospectively collected vascular departmental records and we also hand searched notes of the 36 cancelled patients. There were a total of 36 cancellations for various reasons. Of these, 8 were clearly occluded on duplex. A further 16 were highly suspicious of occlusion on duplex and thus surgery was deferred and selective angiography was undertaken. Of these 9 were confirmed to be occluded on angiogram and a further 4 had severe stenoses or virtual occlusion, 3 patients had a distal internal carotid artery occlusion. Thus a total of 24 patients had an occlusion either diagnosed directly on duplex or because of suspicion on duplex. Unnecessary carotid surgery was avoided in 24 of 475 (5%) of patients. This study shows that a preoperative duplex on admission for surgery results in 1 of 20 patients avoiding unnecessary carotid surgery.


Norepinephrine enhances stimulus-evoked calcium and potassium concentration changes in dentate granule cell layer.
Changes in extracellular Ca2+ and K+ concentrations were measured in the dentate gyrus with ion-selective/reference electrodes during high-frequency perforant path stimulation. Bath application of norepinephrine (NE, 50 microM) markedly enhanced both evoked decreases in extracellular calcium and increases in extracellular potassium concentration. These effects of NE were observed in the granule cell layer (stratum granulosum), but not 200 microns away in the dendritic layer (stratum moleculare). The beta-antagonist propranolol (1 microM) completely blocked the NE-induced enhancement of Ca2+ signals in the dentate. In contrast to the dentate, NE did not enhance evoked Ca2+ of K+ concentration changes in the CA1 pyramidal cell layer. These results indicate that NE markedly enhanced both Ca2+ and K+ fluxes, probably by a beta-receptor-mediated mechanism, in the dentate gyrus during high-frequency stimulation of a type able to elicit long-term potentiation (LTP). These increases may underly the action of NE in modulating LTP in the dentate gyrus.


Trans fatty acids and birth outcome: some first results of the MEFAB and ABCD cohorts.
Using data from two longitudinal pregnancy and birth cohorts in the Netherlands, the potential influence of trans fatty acids (TFA) on fetal development was investigated by multiple regression analysis. After adjustment for a large number of potential confounders, birth length (BL) and head circumference (HC) were significantly and negatively related to the C18:1trans concentration in phospholipids isolated from umbilical plasma (HC), umbilical arterial walls (HC and BL), or umbilical venous walls (BL). A significant and negative relationship was also observed between birth weight and the C18:1trans concentration in maternal plasma phospholipids at early pregnancy, but this attenuated upon correction for potential confounders. These results indicate that TFA may compromise fetal development.


Cyclic reactions-mediated self-supply of H2O2 and O2 for cooperative chemodynamic/starvation cancer therapy.
Hydroxyl radical (·OH)-mediated chemodynamic therapy (CDT) and glucose oxidase (GOx)-based starvation therapy (ST) are two emerging antitumor strategies, limited by acid/H2O2 deficiency and tumor hypoxia, respectively. Herein, we developed a liposomal nanoplatform co-delivering Fe(OH)3-doped CaO2 nanocomposites and GOx molecules for synergistic CDT/ST with a complementary effect. Based on Fenton reactions initiated by iron ions, CaO2-supplied H2O2 could not only generate ·OH for H2O2-sufficient CDT, but also produce O2 to promote the catalytic efficiency of GOx under hypoxia. In return, the enhanced ST generated gluconic acid and H2O2, further amplifying CDT. Through in vitro and in vivo experiments, we demonstrated that such a mutually reinforced modality based on the cyclic Fenton/starvation reactions provided a novel and potent anticancer mechanism for the effective treatment of hypoxic cancers.


An attempt to extend the donor criteria for successful living-related kidney transplantation from a donor with membranous nephropathy.
Marginally appropriate donors may be considered to extend the donor criteria for renal transplantation because of the donor shortage. We have reported a successful outcome after kidney transplantation from a living-related donor diagnosed with membranous nephropathy. A 38-year-old man began continuous ambulatory peritoneal dialysis (CAPD) at the age of 37. His 63-year-old father showed mild proteinuria, diagnosed as membranous nephropathy by needle biopsy. However, the father had normal renal function on preoperative examination, except for mild proteinuria. After adequate informed consent, we transplanted a kidney from the father who was diagnosed with membranous nephropathy into his son using a cyclosporine (CsA)-based immunosuppressive regimen. The postoperative course was good in both the recipient and the donor without rejection or infection. At 57 months after transplantation, the serum creatinine level was 1.7 mg/dL in the recipient and 1.2 mg/dL in the donor. An allograft needle biopsy at 39 months after transplantation showed mild spike formation with partial thickening of the glomerular basement membrane (GBM). Electron microscopy showed decreased electron-dense deposits and electron-lucent washout lesions with thickening of the GBM. This was diagnosed as stage IV membranous nephropathy, resulting from clearance of immune complexes and histological repair of the GBM. For the present donor, graft donation did not affect his residual renal function. Preexisting membranous nephropathy itself may show remission after transplantation into the recipient to achieve successful results, however, long-term careful observation of both the donor and recipient is required.


omega-haloalkyl esters of 5'-adenosine monophosphate as potential active-site-directed reagents for dehydrogenases.
A series of esters of adenosine 5'-monophosphate with ethyl, propyl, or hexyl moieties substituted at the omega-position with chlorine or bromine were prepared. The compounds were competitive inhibitors of horse liver alcohol dehydrogenase with respect to coenzyme, NAD+, and had inhibition (dissociation) constants in the range of 40 to 260 microM at pH 8.0, 25 degrees C. The bromoalkyl esters were designed to be active-site-directed inactivators and were chemically reactive as tested with the model compound 4-(p-nitrobenzyl)pyridine. Yeast alcohol dehydrogenase was inactivated by the bromohexyl analog by an active-site-directed mechanism, with a Ki = 1.5 mM and a pseudo-bimolecular rate constant of 0.03 M-1 S-1, which is 150 times larger than the bimolecular rate constant for inactivation by 2-bromoethanol. However, the rates of inactivation of other dehydrogenases treated with 10 mM concentrations of these compounds were generally slower than with the simpler reagent, 2-bromoethanol. Thus, the reactive functional group attached to the AMP moiety may not be properly oriented for affinity labeling of these dehydrogenases. The bromoalkyl esters may be useful for inactivating other enzymes.


Déjà Vu: Recurrent Sudden Cardiac Arrests in a Child With an Anomalous Left Coronary Artery.
Sudden cardiac arrest from anomalous coronary artery from the opposite sinus of Valsalva is rarely observed in children under 10 years of age. We report a 7-week-old infant with a brief resolved unexplained event from left anomalous aortic origin of a coronary artery who underwent unroofing and again developed syncope at 8 years of age. Ischemia was detected by stress echocardiography both times. (Level of Difficulty: Advanced.).


Time-restricted feeding during embryonic development leads to metabolic dysfunction in adult rat offspring.
Maternal circadian eating time and frequency are associated with altered glucose metabolism during pregnancy in humans. Research on long maternal fasting intervals is inconclusive, and little is known about the effect of maternal time feeding on offspring health. Therefore, the aim of the present study is to determine whether maternal time feeding influences the metabolic status of both male and female offspring. Pregnant rats were provided ad libitum access to chow diet or fed during either the light phase (LP) or dark phase (DP) during embryonic development. At the age of 150 days, glucose tolerance, lipid concentrations, and insulin secretion were determined in adult male and female offspring. Both male and female offspring of LP and DP dams exhibited alterations in the lipid profile, and female offspring were glucose intolerant. Glucose-stimulated insulin secretion decreased in male and female offspring of LP and DP dams. Acetylcholine increased insulin secretion in male and female offspring. Islets from male and female offspring of DP dams exhibited less pronounced inhibition of insulin secretion by epinephrine, suggesting alterations in the cholinergic and adrenergic pathways in these animals. Our data suggest that a time-restricted feeding regimen during embryonic development could program rat offspring for metabolic dysfunction during adulthood.


Effectiveness of clozapine, olanzapine, quetiapine, risperidone, and haloperidol monotherapy in reducing hostile and aggressive behavior in outpatients treated for schizophrenia: a prospective naturalistic study (IC-SOHO).
Antipsychotic medications may reduce hostile and aggressive behavior in schizophrenia. This study compared the effectiveness of antipsychotics in the treatment of aggression. The Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study compares the effectiveness of antipsychotic treatments in practice setting. Schizophrenia outpatients who initiated or changed to a new antipsychotic are followed in this non-interventional, prospective observational study for up to 3 years, with 6-months data now available on the entire cohort (N=7655). The presence or absence of verbal or physical hostility/aggression was assessed retrospectively for the period of 6 months before enrollment, and prospectively in the period of 6 months after enrollment (the study treatment period). At baseline, patients in five monotherapy treatment groups (combined N=3135) were prescribed one of the treatments: clozapine, olanzapine, quetiapine, risperidone, or haloperidol, and had complete data. Hostile/aggressive behavior was reduced during the treatment period. Olanzapine and risperidone were significantly superior to haloperidol and to clozapine in this respect. These results remained essentially unchanged when adjusting for baseline imbalances in age, gender, age of onset, and substance abuse. As monotherapy, both olanzapine and risperidone were superior to haloperidol and clozapine in reducing aggression. The relative lack of effectiveness of clozapine may be specific to this study population.


Serum ferritin levels in small cell lung cancer.
Serum ferritin levels were measured before treatment, using an immunoradiometric method, in 39 patients with small cell lung cancer. In 11 patients serial estimations were also made. The median serum ferritin level for male patients was 660 micrograms/l (range 13-1329) and for females 306 (range 134-5300), the normal range being 32-501. This increase is significant (P less than 0.001). Serum ferritin levels were not related to metastatic, haematological or iron status. Serial ferritin levels did not reflect the clinical course of the disease. Patients with a pre-treatment serum ferritin of less than 600 micrograms/l had a significant prolongation of median survival compared to those with an initial serum ferritin of greater than 600 micrograms/l (P less than 0.02). Serum ferritin levels are not of value in staging small cell lung cancer nor in monitoring its progress. However, the initial serum ferritin is of prognostic significance.


Polymyxin resistance in carbapenem-resistant Enterobacteriaceae isolates from patients without polymyxin exposure: a multicentre study in China.
Polymyxins were recently approved for the clinical treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections in China. The aim of this study was to determine the prevalence and molecular mechanisms of polymyxin-resistant CRE prior to the clinical application of polymyxin and to evaluate the potential for emerging polymyxin resistance in China. A total of 504 unique CRE isolates were collected from six tertiary-care hospitals in China between October 2016 and September 2017. All isolates underwent antimicrobial susceptibility testing. Clinical, demographic, antimicrobial exposure and infection data were collected from patients' medical charts. PCR detection, Sanger sequencing and reverse transcription real-time fluorescence quantitative PCR (RT-qPCR) were used to investigate the molecular mechanism of polymyxin resistance. A total 19 (3.8%) polymyxin-resistant isolates were identified, including Klebsiella pneumoniae, Escherichia coli, Klebsiella aerogenes and Enterobacter cloacae. Genetic analysis in K. pneumoniae strains identified insertion sequence (IS) elements (n = 3), a stop codon (n = 1) and gene deletion (n = 2) in mgrB and a pmrB missense mutation (T157P) (n = 1). Two E. coli isolates contained mcr-1 and an E. cloacae strain harboured a frameshift in mgrB. Further transcriptional analysis showed that pmrA, pmrB, pmrC and pmrK were significantly upregulated in polymyxin-resistant isolates. Despite the lack of polymyxin exposure, 3.8% of CRE were resistant to polymyxin in China. Both chromosomal and plasmid-encoded mechanisms were identified. Our study suggests that clinical practice should be alert to pre-existing polymyxin resistance among CRE isolates to avoid further dissemination of polymyxin resistance.


Diverse chemical space of indoleamine-2,3-dioxygenase 1 (Ido1) inhibitors.
Indoleamine-2,3-dioxygenase 1 (IDO1) catalyses the first and rate limiting step of kynurenine pathway accounting for the major contributor of L-Tryptophan degradation. The Kynurenine metabolites are identified as essential cofactors, antagonists, neurotoxins, immunomodulators, antioxidants as well as carcinogens. The catalytic active site of IDO1 enzyme consists of hydrophobic Pocket-A positioned in the distal heme site and remains connected to a second hydrophobic Pocket-B towards the entrance of the active site. IDO1 enzyme also relates directly to the modulation of the innate and adaptive immune system. Various studies proved that the over expression of IDO1 enzyme play a predominant role in the escape of immunity during cancer progression. Recently, there has been considerable interest in evaluating the potential of IDO1 inhibitors to mobilize the body's immune system against solid tumours. In the last two decades, enormous attempts to advance new IDO1 inhibitors are on-going both in pharmaceutical industries and in academia which resulted in the discovery of a diverse range of selective and potent IDO1 inhibitors. The IDO1 inhibitors have therapeutic utility in various diseases and in the near future, it may have utility in the treatment of COVID-19. Despite various reviews on IDO1 inhibitors in last five years, none of the reviews provide a complete overview of diverse chemical space including naturally occurring and synthetic IDO1 inhibitors with detailed structure activity relationship studies. The present work provides a complete overview on the IDO1 inhibitors known in the literature so far along with the Structure-Activity Relationship (SAR) in each class of compounds.


An Unsupervised Approach for Extraction of Blood Vessels from Fundus Images.
Pathological disorders may happen due to small changes in retinal blood vessels which may later turn into blindness. Hence, the accurate segmentation of blood vessels is becoming a challenging task for pathological analysis. This paper offers an unsupervised recursive method for extraction of blood vessels from ophthalmoscope images. First, a vessel-enhanced image is generated with the help of gamma correction and contrast-limited adaptive histogram equalization (CLAHE). Next, the vessels are extracted iteratively by applying an adaptive thresholding technique. At last, a final vessel segmented image is produced by applying a morphological cleaning operation. Evaluations are accompanied on the publicly available digital retinal images for vessel extraction (DRIVE) and Child Heart And Health Study in England (CHASE_DB1) databases using nine different measurements. The proposed method achieves average accuracies of 0.957 and 0.952 on DRIVE and CHASE_DB1 databases respectively.


Multiple unit activity recording in the corticotropic area of the deafferented hypothalamus and corticosteronemia in the pigeon.
10 Diurnal variations in both multiple unit activity and plasma corticosterone level were suppressed after complete neural isolation of the basal hypothalamus in the pigeon. 20 It is suggested that the circadian activity of the hypothalamic pituitary corticotropic unit partially depends upon the inhibiting influence from the hippocampic-septal structures.


Colorectal cancer in a small rural hospital.
Over a 20-year period, 168 cases of colorectal cancer were treated in a 50-bed rural hospital by 1 surgeon. The majority of the patients were older than 70 years of age. The stage of disease was comparatively advanced, with 71% of the patients having nodal or distant metastases, 19% with bowel obstruction, and 8% with perforation. The operability and resectability rates were 100% and 96%, respectively. The crude 5-year survival was 50% for the entire series. The 5-year survival after curative operations in which there was no gross residual tumor at the end of the operation was 63%, and the 5-year survival for resection of localized node-negative disease was 81%. The wound infection rate was 2%, and the operative mortality rate was 1% for combined elective and emergency operations. The results of treatment of colorectal cancer in small rural hospitals are infrequently reported, and this series may be compared with the published results from large teaching institutions.


Non-rigid-registration-based positioning and labelling of triaxial OPMs on a flexible cap for wearable magnetoencephalography.
Recent advances in highly sensitive miniaturized optically pumped magnetometers (OPMs) have enabled the development of wearable magnetoencephalography (MEG) offering great flexibility in experimental setting. The OPM array for wearable MEG is typically attached to a flexible cap and exhibits a variable spatial layout across different subjects, which imposes challenges concerning the efficient positioning and labelling of OPMs. A pair of reflective markers are affixed to each triaxial OPM sensor above its cable to determine its location and sensitive axes. A non-rigid registration of optically digitized marker locations with a pre-labelled template of marker locations is performed to map newly digitized markers to OPMs. The positioning and labelling of 66 OPM sensors could be completed within 35 s. Across ten experiments, all OPMs were accurately labelled, and the mean test-retest errors were 0.48 mm for sensor locations and 0.20 degree for sensitive axes. By combining six OPMs' positions with their respective recordings, magnetic dipoles inside a phantom were located with a mean error of 5.5 mm, and the best fitted dipole for MEG with auditory stimuli presented was located on a subject's primary auditory cortex. The proposed method reduces the reliance on error-prone and laborious manual operations inherent in existing methods, therefore significantly improving the efficiency of OPM positioning and labelling on a flexible cap. We developed a method for the precise and rapid positioning and labelling triaxial OPMs on a flexible cap, thereby facilitating the practical implementation of wearable OPM-MEG.


A Deep Learning Approach for Automated Bone Removal from Computed Tomography Angiography of the Brain.
Advanced visualization techniques such as maximum intensity projection (MIP) and volume rendering (VR) are useful for evaluating neurovascular anatomy on CT angiography (CTA) of the brain; however, interference from surrounding osseous anatomy is common. Existing methods for removing bone from CTA images are limited in scope and/or accuracy, particularly at the skull base. We present a new brain CTA bone removal tool, which addresses many of these limitations. A deep convolutional neural network was designed and trained for bone removal using 72 brain CTAs. The model was tested on 15 CTAs from the same data source and 17 CTAs from an independent external dataset. Bone removal accuracy was assessed quantitatively, by comparing automated segmentation results to manual segmentations, and qualitatively by evaluating VR visualization of the carotid siphons compared to an existing method for automated bone removal. Average Dice overlap between automated and manual segmentations from the internal and external test datasets were 0.986 and 0.979 respectively. This was superior compared to a publicly available noncontrast head CT bone removal algorithm which had a Dice overlap of 0.947 (internal dataset) and 0.938 (external dataset). Our algorithm yielded better VR visualization of the carotid siphons than the publicly available bone removal tool in 14 out of 15 CTAs (93%, chi-square statistic of 22.5, p-value of < 0.00001) from the internal test dataset and 15 out of 17 CTAs (88%, chi-square statistic of 23.1, p-value of < 0.00001) from the external test dataset. Bone removal allowed subjectively superior MIP and VR visualization of vascular anatomy/pathology. The proposed brain CTA bone removal algorithm is rapid, accurate, and allows superior visualization of vascular anatomy and pathology compared to other available techniques and was validated on an independent external dataset.


A familial tetraphocomelia syndrome involving limb deformities, cleft lip, cleft palate, and associated anomalies--a new syndrome.
This paper reports a rare malformation syndrome which is observed in two sibs (brother and sister) of a family. It consists of nearly symmetric reductive defects of the limbs, flexon contractures of various joints, cleft lip and cleft palate, multiple minor abnormalities including capillary hemangioma of the forehead, hypoplastic cartilages of ears and nose, micrognathia, intrauterine growth retardation, and possibly mental retardation. Chromosomes of both parents and propositi are normal. Genetic data suggest autosomal recessive inheritance.


Tendon-grasping strength of various suture configurations for rotator cuff repair.
The purpose of the present study is to evaluate the mechanical performance and initial strength of the arthroscopic Mason-Allen, double mattress, inclined Mason-Allen, and lasso loop stitch configurations. Using 36 sheep infraspinatus tendons, tendon widths and thicknesses were measured with a digital caliper to confirm standardization of the tendons. Four different stitch configurations (Mason-Allen, inclined Mason-Allen, double mattress, and lasso loop) were biomechanically tested with cyclic loading followed by load to failure testing. The cyclic elongation, peak-to-peak displacement, ultimate tensile strength, stiffness, and mode of failure were recorded. Mean tendon widths and thicknesses were statistically the same. The lasso loop (0.7 ± 0.1 mm) demonstrated a mean cyclic elongation greater than the Mason-Allen (0.5 ± 0.3 mm) and double mattress (0.5 ± 0.3 mm) groups (P = 0.011; P = 0.013). No differences were found in ultimate failure load, stiffness, and peak-to-peak displacement for the Mason-Allen (mean 99 ± 42 N, 39 ± 9 N/mm, 0.6 ± 0,1 mm), inclined Mason-Allen (113 ± 52 N, 44 ± 14 N/mm, 0.5 ± 0.1 mm), double mattress stitch (119 ± 68 N, 45 ± 10 N/mm, 0.5 ± 0.1 mm), or lasso loop (100 ± 38 N, 42 ± 7 N/mm, 0.5 ± 0.1 mm) groups (n.s.). Each specimen failed at the suture-tendon interface. Three specimens (two Mason-Allen and one inclined Mason-Allen) failed during cyclic testing. Conventional Mason-Allen configuration can be applied with double-loaded suture anchor safely. Recent modifications of the configurations offer no biomechanical advantage.


Further studies on the formation of oxygen radicals by potassium superoxide in aqueous medium for biochemical investigations.
Potassium superoxide (KO2) forms superoxide anion (O2-) in aqueous medium as measured by the superoxide dismutase (SOD)-inhibitable cytochrome c reduction assay of McCord and Fridovich. The reduction of cytochrome c by O2- formed by KO2 was observed only above pH 7.0 and demonstrated a pH optimum at pH 9.6. SOD was an effective inhibitor of the cytochrome c reduction produced by KO2. Hydroxyl radical scavengers and singlet oxygen quenchers did not interfere with the reduction of cytochrome c by KO2. These data demonstrate that addition of KO2 to aqueous medium is an easy chemical method for the production of O2- in controlled amounts.


Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML.
Occurrence of the BCR-ABL(T315I) gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL(T315I). To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL(T315I) CML cells on c-Myc through nonobvious off targets.


Estimating persistent oil contamination in tropical region using vegetation indices and random forest regression.
The persistence of soil contamination after cessation of oil activities remains a major environmental issue in tropical regions. The assessment of the contamination is particularly difficult on vegetated sites, but promising advances in reflectance spectroscopy have recently emerged for this purpose. This study aimed to exploit vegetation reflectance for estimating low concentrations of Total Petroleum Hydrocarbons (TPH) in soils. A greenhouse experiment was carried out for 42 days on Cenchrus alopecuroides (L.) under realistic tropical conditions. The species was grown on oil-contaminated mud pit soils from industrial sites, with various concentrations of TPH. After 42 days, a significant decrease in plant growth and leaf chlorophyll and carotenoid contents was observed for plants exposed to 5-19 g kg-1 TPH in comparison to the controls (p < 0.05). Conversely, pigment contents were higher for plants exposed to 1 g kg-1 TPH (hormesis phenomenon). These modifications proportionally affected the reflectance of C. alopecuroides at leaf and plant scales, especially in the visible region around 550 and 700 nm. 33 vegetation indices were used for linking the biochemical and spectral responses of the species to oil using elastic net regressions. The established models indicated that chlorophylls a and b and β-carotene were the main pigments involved in the modifications of reflectance (R2 > 0.7). The same indices also succeeded in estimating the concentrations of TPH using random forest regression, at leaf and plant scales (RMSE = 1.46 and 1.63 g kg-1 and RPD = 5.09 and 4.44, respectively). Four out of the 33 indices contributed the most to the models (>75%). This study opens up encouraging perspectives for monitoring the cessation of oil activities in tropical regions. Further researches will focus on the application of our approach at larger scale, on airborne and satellite imagery.


Total Hip Arthroplasty in Patients Who Have Marfan Syndrome: Adverse Events and 5-Year Revision Rates.
Marfan syndrome is a rare inherited connective tissue disease, which may be present in patients who have advanced hip pathologies that may require total hip arthroplasty (THA). The postoperative course of patients who have Marfan syndrome following THA has not yet been defined. Adult patients who have and do not have Marfan syndrome and underwent THA were identified in a national database. Patients diagnosed who had infection, trauma, or neoplasms within the 90 days prior to surgery were excluded. Those who have versus those who did not have Marfan syndrome were matched 1:10 based on age, sex, and a comorbidity index. After matching, 144 patients who have Marfan syndrome and 1,440 who do not have Marfan syndrome were identified. The 90-day postoperative adverse events and 5-year revisions were assessed and compared with multivariable analyses and log rank tests, respectively. Multivariable analyses demonstrated that Marfan syndrome was independently associated with greater odds of 90-day adverse events: venous thromboembolic events (odds ratio [OR]: 2.9, P = .001), cardiac events (OR: 4.5, P = .034), pneumonia (OR: 3.5, P < .001), and urinary tract infections (OR: 5.2, P < .001). There was no significant difference in 5-year rates of revision. Following THA, Marfan syndrome was independently associated with greater rates of several 90-day adverse events, but not higher 5-year rates of revision. The identified at-risk adverse events may help guide surgeons to improve perioperative care pathways, while having confidence regarding joint survival of THA in this rare disease population.


Routine knee MRI: how common are peripheral nerve abnormalities, and why does it matter?
To evaluate the frequency, MRI appearance, and clinical significance of peripheral nerve abnormalities encountered on routine knee MRI. A retrospective review was performed to identify consecutive patients who underwent routine knee MRI from March 2015-2018 and had peripheral nerve abnormalities. MRIs were reviewed for the presence of tibial (TN) and common peroneal nerve (CPN) abnormalities (including hyperintensity, bulbous enlargement, discontinuity, architectural distortion, skeletal muscle denervation). The presence or absence of concomitant meniscal, cruciate, and collateral ligament tears was documented. Patient demographics and clinical outcomes were recorded. Descriptive statistics were reported. The search yielded 8125 MRIs, of which 50 knee MRIs (patient age (years): 44 + 19) had peripheral nerve abnormalities (hyperintensity (TN: 30%(15/50), CPN: 80%(40/50)), bulbous enlargement (TN: 10%(5/50), CPN: 30%(15/50)), discontinuity (TN: 0, CPN: 4%(2/50)), architectural distortion (TN: 4%(2/50), CPN: 18%(9/50)), and skeletal muscle denervation (TN: 14%(7/50), CPN: 28%(14/50)). Medial meniscus (TN: 12% (6/50), CPN: 36%(18/50)), ACL (TN: 4%(2/50), CPN: 32%(16/50)), PCL (TN: 2%(1/50), CPN: 20%(10/50)), and lateral meniscus (TN: 12%(6/50), CPN: 24%(12/50)) tears were frequently present. Of these, 32% (16/50) were treated for peripheral nerve injury (PNI), characterized as high-grade (n = 7/16) or low-grade (n = 9/16). Nerve discontinuity, architectural distortion, and denervation were encountered more in high-grade PNI than low-grade PNI. Five patients were recalled for follow-up imaging and operative management was performed in 36% of cases (18/50). Although uncommon (frequency = 0.6%), peripheral nerve abnormalities (CPN more common than TN) are encountered on routine knee MRI and affect patient management, with 36% requiring surgical treatment.


Complete mimicry: Rhabdomyosarcoma with FUS::TFCP2 fusion masquerading as carcinoma-diagnostic challenge and report of two cases.
Rhabdomyosarcomas (RMS) are malignant mesenchymal tumors with skeletal muscle differentiation which are classified into alveolar, embryonal, pleomorphic, and spindle cell/sclerosing RMS. Within the spindle cell/sclerosing RMS tumor type there is a recently recognized sub-type categorized as intraosseous spindle cell RMS with TFCP2/NCOA2 gene fusion. This rare tumor is highly aggressive with predominant involvement of the craniofacial and pelvic bones with approximately 30 cases reported to date. Histopathologic features include spindle cell and epithelioid morphology with a characteristic co-expression of epithelial markers, myogenic markers, and ALK1 expression. We report two cases of gnathic spindle cell/sclerosing RMS with FUS::TFCP2 gene fusion that were initially interpreted as carcinomas by referring institutions and later reclassified when encountered in our practice after additional work-up and molecular characterization.


Cyclotron Resonance Study of Monolayer Graphene under Double Moiré Potentials.
We report the first cyclotron resonance study of monolayer graphene under double-moiré potentials in which the crystal axis of graphene is nearly aligned to those of both the top and bottom hexagonal boron nitride (h-BN) layers. Under mid-infrared light irradiation, we observe cyclotron resonance absorption with the following unique features: (1) cyclotron resonance magnetic field BCR is entirely different from that of nonaligned monolayer graphene, (2) BCR exhibits strong electron-hole asymmetry, and (3) splitting of BCR is observed for |ν| < 1, with the split maximum at |ν| = 1, resulting in eyeglass-shaped trajectories. These features are well explained by considering the large bandgap induced by the double moiré potentials, the electron-hole asymmetry in the Fermi velocity, and the Fermi-level-dependent enhancement of spin gaps, which suggests a large electron-electron correlation contribution in this system.


Localization of D-amino acid oxidase mRNA in the mouse kidney and the effect of testosterone treatment.
D-Amino acid oxidase (DAO), which catalyzes oxidative deamination of D-amino acids, is known to be highly expressed in the kidney. This study was designed to examine the localization of DAO mRNA in the mouse kidney using in situ hybridization histochemistry (ISH). For comparison, ISH for mRNA of ornithine decarboxylase (ODC), which is also highly expressed in the mouse kidney, was simultaneously performed. Adult, male mice which received 1 mg of testosterone propionate or vehicle injection, were sacrificed 14 h after injection and their kidneys were removed and processed for ISH. Hybridization signals for both mRNAs were exclusively located over the epithelial cells of the proximal tubule in the vehicle-treated animals. Signals for the DAO mRNA were observed at nearly the same hybridization intensity throughout the proximal tubule, whereas hybridization signals for the ODC mRNA were observed exclusively in the pars convoluta. Following testosterone treatment, ODC mRNA in the pars convoluta was expressed with a stronger intensity than that in the vehicle-injected animals. ODC mRNA was also expressed in the pars recta with a weaker intensity than in the pars convoluta. On the other hand, DAO mRNA expression was little affected by testosterone treatment. These results indicate that, although both genes are possibly expressed in the same cells, the expression of these genes is regulated by different mechanisms.


Lack of weight gain and relapse risk in a large tuberculosis treatment trial.
Readily identified markers of tuberculosis relapse risk are needed, particularly in resource-limited settings. The association between weight gain or loss during antituberculosis therapy and relapse has not been well studied. Subjects in the Tuberculosis Trials Consortium Study 22 were studied. Underweight was defined as 10% or more below ideal body weight at diagnosis. Weight change was assessed between (1) diagnosis and completion of induction phase therapy, (2) diagnosis and end of continuation phase therapy, and (3) completion of induction to completion of continuation phase therapy. A total of 857 subjects were monitored for 2 yr, and 61 of 857 (7.1%) relapsed. Relapse risk was high among persons who were underweight at diagnosis (19.1 vs. 4.8%; p < 0.001) or who had a body mass index of less than 18.5 kg/m(2) (19.5 vs. 5.8%; p < 0.001). Among persons who were underweight at diagnosis, weight gain of 5% or less between diagnosis and completion of 2-mo intensive phase therapy was moderately associated with an increased relapse risk (18.4 vs. 10.3%; relative risk, 1.79, 95% confidence interval, 0.96-3.32; p = 0.06). In a multivariate logistic regression model that was adjusted for other risk factors, a weight gain of 5% or less between diagnosis and completion of 2-mo intensive phase therapy among persons underweight at diagnosis was significantly associated with relapse risk (odds ratio, 2.4; p = 0.03). Among persons underweight at diagnosis, weight gain of 5% or less during the first 2 mo of treatment is associated with an increased relapse risk. Such high-risk patients can be easily identified, even in resource-poor settings. Additional studies are warranted to identify interventions to decrease risk of relapse in such patients.


A study of phosphoenolpyruvate carboxykinase from Moniliformis dubius (Acanthocephala).
Procedures have been developed for the extraction and subsequent purification of the enzyme phosphoenolpyruvate carboxykinase (GTP) (PEPCK) from Moniliformis dubius (Acanthocephala), a parasite of the rat small intestine. This is believed to be the first purification of PEPCK from an invertebrate animal. The enzyme, when purified to homogeneity as indicated by electrophoretic criteria, has a molecular weight of 73 700. Kinetic studies indicated that the enzyme had a pH optimum of 5.5 and required Mn2+ as the divalent cation. The apparent Km values determined for the substrates of the carboxylation reaction were low compared with the published values for purified PEPCK from vertebrate sources. Several competitive inhibitors were found and their Ki values determined. The possible regulation of PEPCK activity in M. dubius is discussed with reference to the observed kinetic parameters.


Study of the dissolved organic matter (DOM) of the Auzon cut-off meander (Allier River, France) by spectral and photoreactivity approaches.
Wetlands are recognized for the importance of their hydrological function and biodiversity, and there is now a consensus to protect and restore them as well as to complete the knowledge on their functioning. Here, we studied the dissolved organic matter (DOM) of a wetland composed of the Auzon cut-off meander, the Allier River, the alluvial fluvial flow, and watershed aquifer. Water was sampled at different locations, in spring, summer, and autumn. For each sample, DOM was characterized for its chemical and optical properties and its photooxidant capacity through its ability to generate DOM triplet excited states (3DOM*) and singlet oxygen upon simulated solar light exposure. UV-visible and fluorescence indices revealed that DOM was mainly microbial-derived whatever the sampling sites with spatial and temporal variations in terms of aromaticity (5.5-22%), specific UV absorbance at 254 nm (0.28-2.82 L m-1mgC-1), ratio of the absorbance at 254 and 365 nm (4.6-10.8), fluorescence index (1.35-166), and biological index (0.812-2.25). All the samples generated 3DOM* and singlet oxygen, rates of formation of which showed parallel variations. Using principal component analysis (PCA), we found positive correlations between the sensitizing properties of DOM samples and parameters associated to the abundance of low molecular weight and low absorbing chromophores. Moreover, the parameter variation across the wetland reinforced the hydrological movements observed in a previous study, suggesting that these parameters could be used as water connection tracers.


Targeting androgen receptor for prostate cancer therapy: From small molecules to PROTACs.
Prostate cancer (PCa) remains a serious type of cancer for men worldwide. The majority of new PCa cases are associated with androgen receptor (AR) hyperactivity. Various AR-targeting molecules that suppress its activity have been discovered. In this review, we present the already marketed antiandrogens and a selection of structurally and chemically interesting AR-targeting compounds, from a pharmacochemical perspective. Focus has been placed on the applied design approaches, structural evolution and structure-activity relationships of the most prominent compound classes. Passing from the traditional steroidal AR antagonists to the modern AR-targeting proteolysis targeting chimeras (PROTACs), we intend to provide a comprehensive overview on AR-targeting molecules for PCa treatment.


On the importance of population-based serological surveys of SARS-CoV-2 without overlooking their inherent uncertainties.
The SARS-CoV-2 epidemic has caused an unprecedented public health situation and more than ever it is important to be well informed on methods to monitor and analyse the progression of the epidemic. This brief note aims to explain the scope in conducting large-scale serological surveys of SARS-CoV-2 to define the landscape of population immunity, without overlooking the inherent uncertainty steaming from sampling design and diagnostic validity. The note completes with a succinct appendix of simple statistical methods for estimating prevalence from random population samples using imperfect diagnostic tests.


Scenarios of intermittent E. coli contamination from sewer overflows to shellfish growing waters: The Dart Estuary case study.
Sewage overflows (SOs) and Combined Sewer Overflows (CSOs) significantly contribute to the bacterial contamination of coastal waters, which is of especial concern for aquaculture, a growing industry worldwide. Hydrodynamic and water quality models were used to investigate impacts of CSO discharge frequency and duration, river discharge and tides on Escherichia coli levels at shellfish farming sites in the Dart Estuary (UK), being the employed methodology generally applicable. High E. coli contamination occurred during neap tides and high river discharges due to higher retention and lower bacterial decay. Synchronicity of CSO spills affected the duration of the pollution episodes rather than peak concentrations, more influenced by discharges of the neighbouring CSOs. During peak discharges, E. coli concentrations could be 10 times higher than during average flows. CSO spills were more frequent when rainfall was >20 mm. Model outputs combined with rainfall forecasts can indicate microbiological contamination risk in the aquaculture sites.


Portable colorimetric enzymatic disposable biosensor for histamine and simultaneous histamine/tyramine determination using a smartphone.
Tyramine oxidase (TAO), peroxidase (HRP), and Amplex Red (AR) have been immobilized on cellulose to obtain disposable biosensors for the determination of histamine. During the enzymatic reaction, AR is oxidized and a pink spot is obtained. Using a smartphone and measuring the G (green) color coordinate, histamine can be determined in the presence of other biogenic amines (putrescine and cadaverine) in concentrations ranging from 2·10-5 M to 5·10-4 M with a 7.5·10-6 M limit of detection (LoD). Despite tyramine interference, experimental conditions are provided which allow rapid and simple histamine and simultaneous histamine/tyramine (semi)quantitative determination in mixtures. Finally, tyramine and histamine were determined in a tuna extract with good results (compared to the reference HPLC-MS method). The methodology can also be applied in solution allowing histamine (and simultaneous histamine/tyramine) determination with a lower LoD (1.8·10-7 M) and a similar selectivity.


Immunomodulatory changes in patients with colorectal cancer.
Solid tumors are frequently accompanied by a depressed cellular and humoral immunity. This study analyzed changes these factors in colorectal cancer patients. We compared cellular (leukocytes, lymphocytes, HLA-DR expression on monocytes) and humoral immune parameters (interleukin-6, interleukin-10, tumor necrosis factor alpha) in 40 patients with colorectal cancer and in 18 healthy controls. Leukocytes were in the normal range in patients and controls. However, tumor patients showed significant lymphopenia in comparison to controls. HLA-DR antigen expression on CD14+ monocytes was reduced in the cancer patients while IL-6 and IL-10 plasma levels were increased. Patients with UICC stage III had IL-6 and IL-10 concentrations were significantly increased as well. These findings suggest that colorectal tumor establishment and progression results in a malfunction of the immune system, and underline the importance of elucidating in detail the mechanisms of immune modulation in cancer patients.


Juxtamembrane tryptophans have distinct roles in defining the OmpX barrel-micelle boundary and facilitating protein-micelle association.
Defining the span of the transmembrane region, a key requirement to ensure correct folding, stability and function of bacterial outer membrane β-barrels, is assisted by the amphipathic property of tryptophan. We demonstrate the unique and distinctive properties of the interface Trp76 and Trp140 of outer membrane protein X, and map their positional relevance to the refolding process, barrel formation and the resulting stability in dodecylphosphocholine micelles. The solvent-exposed Trp76 displays a rigid interfacial localization, whereas Trp140 is relatively micelle-solvated and contributes to barrel folding and global OmpX stability. Kinetic contribution to OmpX stability is influenced by the two tryptophans. Differential associations of the indoles with the detergent milieu therefore contribute to micelle-assisted β-barrel folding and concomitant OmpX stability.


[Psychological symptoms in a group of climacteric women, before and after a psychotherapeutic process].
Two of each three women in their menopause present climacterical syndrome, showing frequently psychological symptoms, which is translated in diminution of the personal satisfaction, which generates the necessity of specialized attention. To know the presence and frequency of psychological symptoms, before and after a psychotherapeutic process with a psychodynamic approach, in a group of women in their menopause. The sample consisted of 41 women divided in two groups, with pre and post application of the survey of symptoms, group 1 received psychotherapy and group 2 did not, although it required it, for this reason it was considered the control. The psychotherapy consisted of 17 sessions and the used techniques most frequently were: confrontation, clarification and interpretation. Differences in the diminution as in the absence of symptoms were observed as much after the psychotherapeutic process. The psychoanalytic psychotherapy is functional in this type of patients for the diminution and in some cases the disappearance of psychological symptoms.


Special Issue on "Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis".
This Special issue contains 48 contributions highlighting novel findings and current concepts in basic and clinical liver fibrosis research. These articles emphasize issues on pathogenesis, cellular mediators, modulators, molecular pathways, disease-specific therapies, scoring systems, as well as novel preclinical animal models for the study of liver fibrogenesis. This editorial aims to briefly summarize the content of these papers.


Unusual Presentation of Systemic Lupus Erythematosus in a Young Male: A Case Report.
Hepatic involvement in systemic lupus erythematosus (SLE) is common but described infrequently. Liver is usually never the primary organ to be affected in lupus. Again hepatic involvement probably does not carry much prognostic importance though it may correlate with lupus activity. We here report a case of 21-year-old man with no prior comorbidity or addiction who presented to us with acute hepatic illness with jaundice. He also had malar rash and arthralgia. Viral markers were negative. Antinuclear antibody and anti-double-stranded DNA (dsDNA) were strongly positive. Liver biopsy was consistent with autoimmune hepatitis, whereas skin biopsy was suggestive of SLE. He had a brisk and complete recovery with prompt use of immunosuppressive agents (corticosteroids and azathioprine). Cyclophosphamide was started latter in view of lupus nephritis. This is probably the fourth reported case of SLE presenting as acute hepatic illness with jaundice.


Exchange transfusion in cerebral malaria complicated by disseminated intravascular coagulation.
A patient with cerebral malaria complicated by full-blown DIC, after failing to respond to other forms of treatment, was successfully treated by exchange transfusion. To the best of the authors' knowledge, this may be first reported case of full-blown DIC in malaria successfully treated by exchange transfusion.


The effectiveness of the hair-restorer "Dabao" in males with alopecia androgenetica. A clinical experiment.
In a randomized, double-blind trial the effectiveness of 6 months' use of a Chinese herb extract (Dabao) as a hair-restorer was studied on 396 males with alopecia androgenetica. The effect was evaluated by nonvellus hair counts, participants' opinions and a panel's judgement of a photo-report. Twenty-three participants withdrew prematurely from the study. In both the Dabao and placebo groups an increase in the amount of hair was observed; 133 and 109 hairs on a 5 cm2 marked area, a difference of 24 hairs (p = 0.03, one-sided). Participants as well as the panel reached a similar conclusion. Regarding cosmetic effect, 42% of the participants in the Dabao group and 37% in the placebo group reported positive results. The average panel score for the cosmetic result on a scale of -10 to +10 was 0.46 in the Dabao and 0.21 in the placebo group, a difference of 0.24 (p = 0.04, one-sided). It appears from our study that, although the cosmetic effect over 6 months is modest, Dabao does have a certain effect on the growth of nonvellus hair.


Hyperbranched polyglycerol-modified graphene oxide as an efficient drug carrier with good biocompatibility.
As a promising drug carrier, graphene oxide (GO) has been studied widely in drug delivery due to its excellent loading ability to aromatic drugs. However, its biocompatibility, such as stability and blood compatibility, is now the biggest obstacle for its further application. Herein, the hyperbranched polyglycerol (HPG)-modified GO was prepared through the anionic ring-opening polymerization using GO as the initiator directly, and then the doxorubicin hydrochloride was loaded and showed obvious cytotoxicity to tumor cells. The obtained HPG-GO displayed good stability in the aqueous solution, as well showed low toxicity in vitro and in vivo. As an injectable drug carrier, HPG-GO showed good blood compatibility with negligible effect on the hemolysis and blood coagulation. Such a stable and blood-compatible GO derivative may be applied widely in drug delivery in the future.


Positive Emotions Experienced on Days of Stress are Associated with Less Same Day and Next Day Negative Emotion.
Positive emotions help us during times of stress. They serve to replenish resources and provide relief from stressful experiences. Positive emotions may be particularly beneficial during times of stress by dampening negative emotional reactivity and quickening recovery from stressful events. In this study, we used a daily diary design to examine how positive emotions experienced on days with minor stressful events are associated with same day and next day stressor-related negative emotions. We combined data from the National Study of Daily Experiences II (NSDE II) and the Midlife in the United States survey (MIDUS II), resulting in 1,588 participants who answered questions about daily stressors and emotion across 8 consecutive days. On days when people experienced a stressor and had higher than their average level of positive emotion, they experienced less of a same day increase in negative emotion. Additionally, they experienced less subsequent negative emotion the following day and were less likely to experience a stressor the next day. Results held when adjusting for trait measures of positive and negative emotion. These results suggest that daily positive emotions experienced on days of stress help regulate our negative emotion during times of stress.


[Regression on order statistics and its application in estimating nondetects for food exposure assessment].
To explore the application of regression on order statistics (ROS) in estimating nondetects for food exposure assessment. Regression on order statistics was adopted in analysis of cadmium residual data set from global food contaminant monitoring, the mean residual was estimated basing SAS programming and compared with the results from substitution methods. The results show that ROS method performs better obviously than substitution methods for being robust and convenient for posterior analysis. Regression on order statistics is worth to adopt,but more efforts should be make for details of application of this method.


Bioorthogonal Hydroamination of Push-Pull-Activated Linear Alkynes.
A bioorthogonal reaction between N,N-dialkylhydroxylamines and push-pull-activated halogenated alkynes is described. We explore the use of rehybridization effects in activating alkynes, and we show that electronic effects, when competing stereoelectronic and inductive factors are properly balanced, sufficiently activate a linear alkyne in the uncatalyzed conjugative retro-Cope elimination reaction while adequately protecting it against cellular nucleophiles. This design preserves the low steric profile of an alkyne and pairs it with a comparably unobtrusive hydroxylamine. The kinetics are on par with those of the fastest strain-promoted azide-alkyne cycloaddition reactions, the products regioselectively formed, the components sufficiently stable and easily installed, and the reaction suitable for cellular labeling.


Use of serum concentrations of interleukin-18 and monocyte chemoattractant protein-1 as prognostic indicators in primary immune-mediated hemolytic anemia in dogs.
The cytokine response in immune-mediated hemolytic anemia (IMHA) is poorly characterized and correlation with outcome is unknown. To determine if cytokine activity is correlated with outcome in dogs with IMHA. Twenty dogs with primary IMHA and 6 control dogs. Prospective study on dogs with IMHA with blood sampling at admission. Serum activity of interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, monocyte chemoattractant protein-1 (MCP-1), granulocyte-macrophage colony stimulating factor (GM-CSF), interferon-inducible protein-10, interferon-gamma, and keratinocyte chemoattractant (KC) was assessed. Thirty-day case fatality rate was 25% (5/20 dogs). Increased concentrations (median [range]) of IL-2 (45.5 ng/L [0;830] versus 0 ng/L [0;46.8]), IL-10 (8.2 ng/L [0;60.6] versus 0 ng/L [0;88.2]), KC (1.7 μg/L [0.3;4.7] versus 0.5 μg/L [0.2;1.1]), and MCP-1 (162 ng/L [97.6;438] versus 124 ng/L [90.2;168]) were observed in dogs with IMHA compared with controls. The cytokine profile was indicative of a mixture of pro- and anti-inflammatory cytokines of various cellular origins. Cytokines/chemokines strongly associated with macrophage/monocyte activation and recruitment were significantly increased in nonsurvivors compared with survivors; IL-15 (179 ng/L [48.0;570] versus 21.3 ng/L [0;193]), IL-18 (199 ng/L [58.7;915] versus 37.4 ng/L [0;128]), GM-CSF (134 ng/L [70.0;863] versus 57.6 ng/L [0;164]), and MCP-1 (219 ng/L [135;438] versus 159 ng/L [97.6;274]), respectively. Logistic regression suggested increased IL-18 and MCP-1 concentrations were independently associated with mortality in this population (P<.05, Wald's type 3). A mixed cytokine response is present in dogs with IMHA and mediators of macrophage activation and recruitment might serve as prognostic indicators.


Evaluation of the efficiency of extraction of ultraviolet-absorbing pollen allergens and organic pollutants from airborne dust samples by capillary electromigration methods.
Capillary electromigration methods, zone electrophoresis (CZE) and micellar electrokinetic chromatography (MEKC), have been used for evaluation of the efficiency of different extraction agents applied to the extraction of pollen allergens and organic pollutants from dust samples collected during different periods (before, during and after pollen seasons) and in different locations in air-filtration devices (car-traffic tunnel in Prague and a metro station in Paris). Water and acetic acid extracts were analyzed by CZE using acetic acid as background electrolyte (BGE). Water and alkaline water-SDS-buffer extracts were analyzed by MEKC in Tris-phosphate BGE with anionic detergent sodium dodecylsulfate (SDS) micellar pseudophase. More material was extracted and more components were found in the water-buffer extracts than in the water extracts, and better resolution of the components was achieved by MEKC than by CZE. Significant differences have been found in the analyses of dust extracts of different origin. More material and more components have been found in the extracts of the dust collected in the pollen-rich period (March, April) than in the pollen-free period (December, January).


Association Between Changes in Depressive Symptoms and Hazardous Drinking: Findings From the Korea Welfare Panel Study (2013-2018).
Objective: This study aimed to evaluate the longitudinal association between changes in depressive symptoms and hazardous drinking among South Korean adults. Participants/Methods: This study was conducted using a sample drawn from participants enrolled in the Korea Welfare Panel Study (KoWePS) from 2013 to 2018. Hazardous drinking was defined as a score of 11 points for men and seven points for women on the Korean version of the Alcohol Use Disorders Identification Test. Depressive symptoms were evaluated using an 11-item version of the Center for Epidemiologic Studies Depression Scale. A generalized estimating equation model was used to analyze the association between changes in depressive symptoms and hazardous drinking. Results: Of the 12,878 people registered with KoWePS and without follow-up losses from 2013 to 2018, a total of 2,341 were included in this study, excluding those under the age of 19 and those with missing data. Persistent depressive symptoms (men, odds ratio [OR]: 2.20, 95% confidence interval [CI]: 1.48-3.21; women, OR: 2.64, 95% CI: 1.66-4.22) and the changes from non-depressive symptoms to depressive symptoms (men, adjusted OR: 2.18, 95% CI: 1.80-2.64; women, OR: 1.71, 95% CI: 1.27-2.29) increased the likelihood of hazardous drinking. Conclusions: Persistent depressive symptoms and changes from non-depressive to depressive symptoms are associated with increased prevalence of hazardous drinking. This suggests that an evaluation of the underlying mental illness or emotion should be made when counseling for abstaining from alcohol for chronic drinkers or the general public.


Sex-dependent control of murine emotional-affective behaviour in health and colitis by peptide YY and neuropeptide Y.
Peptide YY (PYY) and neuropeptide Y (NPY) are involved in regulating gut and brain function. Because gastrointestinal inflammation is known to enhance anxiety, we explored whether experimental colitis interacts with genetic deletion (knockout) of PYY and NPY to alter emotional-affective behaviour. Male and female wild-type, NPY (NPY(-/-) ), PYY (PYY(-/-) ) and NPY(-/-) ; PYY(-/-) double knockout mice were studied in the absence and presence of mild colitis induced by ingestion of dextran sulphate sodium (2%) in drinking water. Anxiety-like behaviour was tested on the elevated plus maze and open field, and depression-like behaviour assessed by the forced swim test. In the absence of colitis, anxiety-like behaviour was increased by deletion of NPY but not PYY in a test- and sex-dependent manner, while depression-like behaviour was enhanced in NPY(-/-) and PYY(-/-) mice of either sex. The severity of DSS-induced colitis, assessed by colonic myeloperoxidase content, was attenuated in NPY(-/-) but not PYY(-/-) mice. Colitis modified anxiety- and depression-related behaviour in a sex-, genotype- and test-related manner, and knockout experiments indicated that NPY and PYY were involved in some of these behavioural effects of colitis. These data demonstrate sex-dependent roles of NPY and PYY in regulation of anxiety- and depression-like behaviour in the absence and presence of colitis. Like NPY, the gut hormone PYY has the potential to attenuate depression-like behaviour but does not share the ability of NPY to reduce anxiety-like behaviour.


DNA methylation in thoracic neoplasms.
Thoracic neoplasms, which include lung cancers, esophageal carcinoma, and thymic epithelial tumors, are the leading causes of tumor-related death and a major health concern worldwide. The development of neoplasms is a multistep process involving both genetic and epigenetic alterations. A growing body of research provides evidence that aberrant DNA methylation, including DNA hypermethylation in promoter regions, global DNA hypomethylation and the overexpression of DNA methyltransferases, plays an important role in tumorigenesis. In this review, we summarize published observations of methylation pattern disruptions in thoracic tumors, and discuss how these abnormalities contribute to the development of cancers. We review recent findings showing that suppressing the activity of the DNA methylating enzymes DNMTs can have potent anti-cancer effects, and discuss the possibility of developing novel therapies for thoracic tumors based on DNMT inhibition.


The Complete Mitochondrial Genomes of Four Species in the Subfamily Limenitidinae (Lepidoptera, Nymphalidae) and a Phylogenetic Analysis.
The complete mitogenomes of four species, Neptis thisbe, Neptis obscurior, Athyma zeroca, and Aldania raddei, were sequenced with sizes ranging from 15,172 bp (N. obscurior) to 16,348 bp (Al. raddei). All four mitogenomes display similar nucleotide content and codon usage of protein-coding genes (PCGs). Typical cloverleaf secondary structures are identified in 21 tRNA genes, while trnS1 (AGN) lacks the dihydrouridine (DHC) arm. The gene orientation and arrangement of the four mitogenomes are similar to that of other typical mitogenomes of Lepidoptera. The Ka/Ks ratio of 13 PCGs among 58 Limenitidinae species reveals that cox1 had the slowest evolutionary rate, while atp8 and nad6 exhibited a higher evolutionary rate. The phylogenetic analysis reveals that tribe-levels are well-supported monophyletic groups. Additionally, Maximum Likelihood analysis recovered the relationship (Parthenini + ((Chalingini + (Cymothoini + Neptini)) + (Adoliadini + Limenitidini))). However, a Bayesian analysis based on the same dataset recovered the relationship (Parthenini + (Adoliadini + ((Cymothoini + Neptini) + (Chalingini + Limenitidini)))). These results will offer valuable data for the future study of the phylogenetic relationships for Limenitidinae.


Executive Function and BMI Trajectories Among Rural, Poor Youth at High Risk for Obesity.
The aim of this study was to identify longitudinal trajectories of conjoint development of executive function (EF) and obesity among a diverse sample of poor, rural youth and to evaluate individual differences in infant growth, parental BMI, and cumulative risk. Participants included 948 youth from the Family Life Project. Child anthropometrics were measured at 2 and 6 months and at 2, 3, 4, 5, 7, and 12 years. EF tasks were administered at 3, 4, and 5 years. Mothers reported youth birth weight, parental height and weight, and cumulative risk indicators. Multidimensional growth mixture modeling identified three classes: "High EF - High Obesity Resilience"; "Low EF - Delayed-Onset Severe Obesity"; and "Low EF - Early-Onset Severe Obesity." Youth in the low-EF, early-onset class displayed higher birth weight and BMI at 6 months, whereas the low-EF, delayed-onset class had rapid weight gain during infancy, parents with class II obesity, and greater cumulative risk and was more likely to be Black and female. Despite increased obesity risk among this sample, the majority of youth exhibited higher EF and some degree of obesity resilience. Youth with EF deficits displayed the greatest risk for severe obesity but had differing BMI trajectories and obesity risk profiles, which has implications for obesity intervention.


Microbiome-miRNA interactions in the progress from undifferentiated arthritis to rheumatoid arthritis: evidence, hypotheses, and opportunities.
The human microbiome has attracted attention for its potential utility in precision medicine. Increasingly, more researchers are recognizing changes in intestinal microbiome can upset the balance between pro- and anti-inflammatory factors of host immune system, potentially contributing to arthritis immunopathogenesis. Patients who develop rheumatoid arthritis from undifferentiated arthritis can face multiple irreversible joint lesions and even deformities. Strategies for identifying undifferentiated arthritis patients who have a tendency to develop rheumatoid arthritis and interventions to prevent rheumatoid arthritis development are urgently needed. Intestinal microbiome dysbiosis and shifts in the miRNA profile affect undifferentiated arthritis progression, and may play an important role in rheumatoid arthritis pathophysiologic process via stimulating inflammatory cytokines and disturbing host and microbial metabolic functions. However, a causal relationship between microbiome-miRNA interactions and rheumatoid arthritis development from undifferentiated arthritis has not been uncovered yet. Changes in the intestinal microbiome and miRNA profiles of undifferentiated arthritis patients with different disease outcomes should be studied together to uncover the role of the intestinal microbiome in rheumatoid arthritis development and to identify potential prognostic indicators of rheumatoid arthritis in undifferentiated arthritis patients. Herein, we discuss the possibility of microbiome-miRNA interactions contributing to rheumatoid arthritis development and describe the gaps in knowledge regarding their influence on undifferentiated arthritis prognosis that should be addressed by future studies.


Serial intravascular ultrasound analysis comparing double kissing and classical crush stenting for coronary bifurcation lesions.
Compared with the classical crush, double kissing (DK) crush improved outcomes in patients with coronary bifurcation lesions. However, there is no serial intravascular ultrasound (IVUS) comparisons between these two techniques. This study aimed to analyze the mechanisms of the two crush stenting techniques using serial IVUS imaging. A total of 54 patients with IVUS images at baseline, post-stenting and eight-month follow-up were classified into classical (n = 16) and DK (n = 38) groups. All patients underwent final kissing balloon inflation (FKBI). Unsatisfactory kissing (KUS) was defined as the presence of wrist or >20% stenosis during FKBI at the side branch (SB) ostium. The vessels at bifurcation lesions were divided into the proximal main vessel (MV) stent, the crushed segment, the distal MV stent, the SB ostium and the SB stent body. KUS and incomplete crushing were commonly observed in the classical group (62.5%, 81.3%), compared with DK group (18.0%, 39.5%, P < 0.001 and P = 0.004). The post-stenting stent symmetry in the classical group was 71.85 ± 7.69% relative to 85.93 ± 6.09% in DK group (P = 0.022), resulting in significant differences in neointimal hyperplasia (NIH, 1.60 ± 0.21 mm(2) vs. 0.85 ± 0.23 mm(2) , P = 0.005), late lumen loss (1.31 ± 0.81 mm(2) vs. 0.55 ± 0.70 mm(2) , P = 0.013), and minimal lumen area (MLA, 3.57 ± 1.52 mm(2) vs. 4.52 ± 1.40 mm(2,) P = 0.042) at the SB ostium between two groups. KUS was positively correlated with the incomplete crush and was the only predictor of in-stent-restenosis (ISR) at the SB ostium. DK crush was associated with improved quality of the FKBI and larger MLA. KUS predicted the occurrence of ISR.


Pharmacotherapy of juvenile rheumatoid arthritis.
Salicylate is the drug of first choice in the initial treatment of juvenile rheumatoid arthritis. In therapeutic dosage it will adequately control joint symptoms in the majority of patients. For children who do not respond to or are intolerant of salicylate, a change to one of the other nonsteroidal anti-inflammatory agents is appropriate. In progressive polyarthritis unresponsive to the above agents, the addition of gold, antimalarials, or penicillamine is indicated, preferably in that order. Corticosteroid therapy should be reserved for selected patients meeting specific criteria. Pharmacotherapy of juvenile rheumatoid arthritis should always be individualized. For optimal treatment of the whole child it must be combined with both physical and educational measures.


Bio-Inspired Active Self-Cleaning Surfaces via Filament-Like Sweepers Array.
Hydrodynamic forces from moving fluids can be utilized to remove contaminants which is an ideal fouling-release strategy for underwater surfaces. However, the hydrodynamic forces in the viscous sublayer are greatly reduced owing to the no-slip condition, which restricts their practical applications. Here, inspired by sweeper tentacles of corals, an active self-cleaning surface with flexible filament-like sweepers are reported. The sweepers can penetrate the viscous sublayer by utilizing energy from outer turbulent flows and remove contaminants with adhesion strength of >30 kPa. Under an oscillating flow, the removal rate of the single sweeper can reach up to 99.5% due to dynamic buckling movements. In addition, the sweepers array can completely clean its coverage area within 10 s through coordinated movements as symplectic waves. The active self-cleaning surface depends on the fluid-structure coupling between sweepers and flows, which breaks the concept of conventional self-cleaning.


Search for Higgs bosons decaying into bb and produced in association with a vector boson in pp collisions at square root of s = 1.8 TeV.
We present a new search for H0V production, where H0 is a scalar Higgs boson decaying into bb with branching ratio beta, and V is a Z0 boson decaying into e+e-, mu+mu-, or nunu. This search is then combined with previous searches for H0V where V is a W+/- boson or a hadronically decaying Z0. The data sample consists of 106 +/- 4 pb(-1) of pp collisions at square root of s = 1.8 TeV accumulated by the Collider Detector at Fermilab. Observing no evidence of a signal, we set 95% Bayesian credibility level upper limits on sigma(pp --> H0V) x beta. For H0 masses of 90, 110, and 130 GeV/c2, the limits are 7.8, 7.2, and 6.6 pb, respectively.


Urinary leukotriene E₄ levels identify children with tobacco smoke exposure at risk for asthma exacerbation.
Children with asthma exposed to secondhand smoke (SHS) might be at higher risk for severe exacerbations, but biomarkers of susceptibility to SHS exposure have not been previously reported. We sought to assess the usefulness of urinary leukotriene E(4) (uLTE₄) levels in the prediction of increased risk of severe asthma exacerbations requiring emergency department (ED) or urgent care (UC) visits. Forty-four schoolchildren with moderate-to-severe asthma receiving inhaled corticosteroids were followed for 5 months with repeated measurements of uLTE₄ and monitoring of ED and UC visits. SHS exposure status was determined by using prestudy questionnaires and repeated measurements of urinary cotinine during the study. Nine (45%) of 20 children with SHS exposure experienced a severe exacerbation requiring an ED or UC visit compared with 3 (12.5%) of 24 children without significant SHS exposure (relative risk, 3.6; 95% CI, 1.1-11.5; P = .02). The uLTE₄ level was a significant predictor of exacerbation risk in children exposed to SHS (area under the curve, 0.85; P = .003). Other predictors, such as nighttime symptom frequency, prebronchodilator and postbronchodilator lung function, and exhaled nitric oxide levels, were not related to exacerbations in this group. uLTE₄ levels at or greater than 106 pg/mg achieved 67% (6/9) sensitivity and 100% (11/11) specificity for predicting children with SHS exposure who required an ED or UC visit. Children exposed to SHS are at increased risk for severe asthma exacerbations, despite use of inhaled corticosteroids. uLTE₄ levels identify children exposed to SHS at high risk for asthma exacerbations.


Interval length and time-use by children with AD/HD: a comparison of four models.
Predictions made by 4 competing models of time use by children with AD/HD were tested using a computerized version of the Matching Familiar Figures Test in 2 studies. In Study 1 teacher-identified AD/HD children (N = 10) and non-AD/HD controls (N = 10) completed the task under 3 different trial duration conditions (5, 10, and 15 s). In Study 2 the same task was completed by a group of children with a diagnosis of Hyperkinetic Disorder (N = 12) and controls (N = 12). In both studies AD/HD children performed poorly on trials of both 5- and 15-s duration but as well as controls on the 10-s trials. This quadratic function provided support for the State Regulation Deficit model of time use in AD/HD. The value of tailoring the temporal features of learning contexts to the conceptual style of AD/HD children is discussed.


Cancer chemoprevention through Frizzled receptors and EMT.
Frizzled (FZD) transmembrane receptors are well known for their role in β-catenin signaling and development and now understanding of their role in the context of cancer is growing. FZDs are often associated with the process of epithelial to mesenchymal transition (EMT) through β-catenin, but some also influence EMT through non-canonical pathways. With ten different FZDs, there is a wide range of activity from oncogenic to tumor suppressive depending on the tissue context. Alterations in FZD signaling can occur during development of premalignant lesions, supporting their potential as targets of chemoprevention agents. Agonizing or antagonizing FZD activity may affect EMT, which is a key process in lesion progression often targeted by chemoprevention agents. Recent studies identified a specific FZD as important for activity of an EMT inhibiting chemopreventive agent and other studies have highlighted the previously unrecognized potential for targeting small molecules to FZD receptors. This work demonstrates the value of investigating FZDs in chemoprevention and here we provide a review of FZDs in cancer EMT and their potential as chemoprevention targets.


Calcium dependency of excitatory chemical synaptic transmission in the frog cerebellum in vitro.
Chemical synaptic transmission was studied with microelectrode techniques in isolated frog cerebella maintained in vitro. Purkinje cell (PC) EPSPs, elicited by selective monosynaptic electrical stimulation of both the parallel fiber (PF) and climbing fiber (CF) inputs, could be inverted by depolarizing (outward) current injections. Evoked synaptic transmission at both junctions was reduced by lowering the extracellular concentration of calcium ions ([Ca2+]) below 2 mM. Raising [Ca2+] above 2 mM to 8 mM did not further increase synaptic transmission. Mg2+, Sr2+, and Ba2+ did not substitute for Ca2+ in the transmission process.


Intracoronary beta-irradiation with a rhenium-188-filled balloon catheter: a randomized trial in patients with de novo and restenotic lesions.
Restenosis requiring reintervention is the main limitation of coronary angioplasty. Intracoronary irradiation reduces neointimal proliferation. We studied the efficacy of a self-centering liquid rhenium-188-filled balloon catheter for coronary beta-brachytherapy. After successful coronary angioplasty with or without stenting, 225 patients (71% de novo lesions) were randomly assigned to receive 22.5 Gy intravascular beta-irradiation in 0.5-mm tissue depth (n=113) or to receive no additional intervention (n=112). Clinical and procedural data did not differ between the groups except a higher rate of stenting in the control group (63%) compared with the rhenium-188 group (45%, P<0.02). After 6 months of follow-up, late loss was significantly lower in the irradiated group compared with the control group, both of the target lesion (0.11+/-0.54 versus 0.69+/-0.81 mm, P<0.0001) and of the total segment (0.22+/-0.67 versus 0.70+/-0.82 mm, P<0.0001). This was also evident in the subgroup of patients with de novo lesions and independent from stenting. Binary restenosis rates were significantly lower at the target lesion (6.3% versus 27.5%, P<0.0001) and of the total segment (12.6% versus 28.6%, P<0.007) after rhenium-188 brachytherapy compared with the control group. Target vessel revascularization rate was significantly lower in the rhenium-188 (6.3%) compared with the control group (19.8%, P=0.006). Intracoronary beta-brachytherapy with a rhenium-188 liquid-filled balloon is safe and efficiently reduces restenosis and revascularization rates after coronary angioplasty.


Self-removing passive drain to facilitate postoperative care via telehealth during the COVID-19 pandemic.
Telehealth postoperative visits are an attractive strategy to minimize exposure, especially during the SARS-CoV-2 (COVID-19) pandemic. The use of a surgical drain often prevents this minimal-exposure approach in that patients return to the outpatient clinic for drain removal. Following unilateral neck dissection, the customary closed-suction drain was replaced with a self-removing, passive drain dressing to facilitate same-day discharge and telehealth postoperative follow-up. The patient removed the dressing and drain at home during a telehealth visit on postoperative day 4 and she healed favorably without any signs of infection or seroma. When thoughtfully applied in the appropriate clinical context, small practice adaptations like this can facilitate telehealth solutions that diminish unnecessary exposure for patients, their caregivers, and health care staff.