Spectrum and antibiotic resistance of uropathogens isolated from hospital and community patients with urinary tract infections in two large hospitals in Kuwait.
To determine the spectrum of microbial etiology and antibiotic resistance pattern of the uropathogens that cause urinary tract infections in 2 large teaching hospitals in Kuwait over a period of 1 year. The Vitek identification card system was used to identify the uropathogens. Susceptibility of the isolates against 18 antibiotics was performed by the microbroth dilution method using the Vitek automated system. In addition, gram-positive bacteria were tested in parallel by the disk diffusion technique. The six overall most common isolates were: Escherichia coli, accounting for 47% of isolates in both hospitals, followed by Candida spp. (10.8%), Klebsiella pneumoniae (9.6%), Streptococcus agalactiae (GBS; 9.5%), Enterococcus faecalis (4.2%) and Pseudomonas aeruginosa (4.1%). Amikacin provided the widest coverage amongst all the antibiotics tested followed by ciprofloxacin, gentamicin and piperacillin-tazobactam. For the gram-negatives, high resistance (26-63%) to the beta-lactam antibiotics was noted, especially to ampicillin, amoxicillin-clavulanic acid, cephalothin and cefuroxime. Resistance to trimethoprim-sulfamethoxazole was also high. None of the enterococci was resistant to the glycopeptides, but 38-60% of the Staphylococcus haemolyticus were resistant to vancomycin or teicoplanin. These data show the high level of antimicrobial resistance amongst the uropathogens causing urinary tract infection in the two hospitals studied.


Complex chromosomal rearrangements in a secondary acute myeloblastic leukemia after chemotherapy in TRAPS.
We report on the cytogenetic findings from a patient with a de novo TNF-receptor-associated periodic syndrome (TRAPS), who showed first symptoms at the age of four months. Thus, he obtained a long-term therapy with cortisone, chlorambucile, methotrexate and cyclophosphamide. At the age of 14 he developed a secondary acute myeloblastic leukemia. Highly complex chromosomal rearrangements were detected after banding analysis. The exact definition of karyotype and the involved breakpoints could only be resolved after application of sophisticated multicolor-FISH techniques: 44,XY,-5,der(6)t(6;7)(6pter right curved arrow 6q12::7p22.2 right curved arrow 7pter or 7pter right curved arrow 7p22.2), dic(7;19)t(6;19;6;7;19;7;19)(19qter right curved arrow 19q12::7p13 right curved arrow 7p11.1::19q12 right curved arrow 19p12 or 19p12 right curved arrow 19q12::7p11.1 right curved arrow 7q21.3::6q12 right curved arrow 6q26::19p13.3 right curved arrow 19p12::6q26-6qter),dic(12;13)(13qter right curved arrow 13p11.2::12p13.1 right curved arrow 12qter),ace(12;13)(13pter right curved arrow 13p11.2::12p13.1 right curved arrow 12pter), -19. The simultaneous presence of two dicentric chromosomes has not been reported previously and is striking, as such chromosomes are suggested to be instable. However, such chromosomes are observed frequently after chemo- or radiotherapy and in secondary, i.e. therapy related AML (tAML). Thus, AML in this case may result from a long-term therapy of TRAPS with methotrexate, cyclophosphamide, chlorambucile and cortisone.


24- and 26-homo-1,25-dihydroxyvitamin D3: preferential activity in inducing differentiation of human leukemia cells HL-60 in vitro.
1,25-Dihydroxyvitamin D3, the hormonal form of vitamin D3, promotes the differentiation of HL-60 human promyelocytic leukemia cells into monocytes. Differentiation changes include the induction of phagocytosis, the initiation of nitroblue tetrazolium-reducing activity, and the appearance of nonspecific acid esterase. We have found that the 24-homo- and 26-homo-1,25-dihydroxyvitamin D3 and their delta 22 analogues are 10-fold more potent than 1,25-dihydroxyvitamin D3 in inducing differentiation of HL-60 cells in vitro. In vivo, these analogues show activity similar to 1,25-dihydroxyvitamin D3 in stimulating intestinal calcium transport in vitamin D-deficient rats. The 24-homoanalogues are significantly less active, whereas the 26-homo derivatives are more active than the natural hormone in mobilizing calcium from bone. This unusual activity pattern cannot be explained on the basis of the affinity of these analogues for the 1,25-dihydroxyvitamin D3 intracellular receptor: both 24-homo- and 26-homo-1,25-dihydroxyvitamin D3 have the same effectiveness as 1,25-dihydroxyvitamin D3 in displacing the tritiated hormone from its receptor in rat intestine or HL-60 cells. These analogues of 1,25-dihydroxyvitamin D3 may be of some interest as possible therapeutic substances, or as tools in understanding the action of 1,25-dihydroxyvitamin D3 in inducing differentiation.


A Distributed Optimization Problem Subject to Partial-Impact Cost Functions.
This article focuses on a distributed optimization problem subject to partial-impact cost functions that relates to two decision variable vectors. To this end, two algorithms are presented with the aim of solving the considered optimization problem in a structure fashion and in a gradient fashion, respectively. Furthermore, a connection between the equilibrium of the induced algorithm and the involved optimization problem is established, with the aid of the tools from nonsmooth analysis and change of coordinate theorem. Two numerical examples with practical significance are given to demonstrate the efficiency of the designed algorithm.


Morphometric image analysis of vascular endothelial growth factor receptor-3 in preeclamptic, HIV infected women.
To ascertain the expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in placental conducting and exchange villi from normotensive, preeclamptic (PE) and antiretroviral treated pregnant women, using morphometric image analysis. This study utilizes retrospectively collected, paraffin wax-embedded, placental samples (n = 90) that were immuno-stained for VEGFR-3. During selection of the retrospective study, women with chronic illnesses were filtered out, to exclusively allow for the examination of VEGFR-3 immuno-expression in HIV and preeclamptic women. The study population consisted of normotensive (n = 30) and preeclamptic (n = 60) groups which were further divided on the basis of HIV status (negative - and positive +), and early and late onset preeclampsia (EOPE and LOPE respectively). The resulting groups were as follows; N- (n = 15), N+ (n = 15), EOPE- (n = 15), EOPE+ (n = 15), LOPE- (n = 15) and LOPE+ (n = 15). Microscopic examination and morphometric image analysis were performed on the immuno-stained placental tissue samples. Analysis on HIV status did not yield a significant difference in conducting (p = 0.3015) or exchange (p = 0.4535) villi, regardless of pregnancy type. The N vs. PE analysis showed a reduced immuno-expression of VEGFR-3 in both conducting (p = 0.0107) and exchange (p < 0.0001) villi. Results from a multiple group comparative analysis of N vs. EOPE vs. LOPE VEGFR-3 immuno-expression, showed a significant difference between the N vs. EOPE groups. The results presented provide compelling evidence that HIV infection does not significantly alter angiogenesis in placental villi. PE however, has caused angiogenic dysregulation and trophoblast pathology was observed. We report a severe downregulation of VEGFR-3 in placental villi from EOPE woman, regardless of HIV status. Hence we suggest a future investigation into EOPE's aetiology and its downstream effects on pregnancy.


Velocity vector imaging in the measurement of left ventricular myocardial mechanics on cardiac magnetic resonance imaging: correlations with echocardiographically derived strain values.
Regional and global function can be measured by echocardiography using speckle-tracking, a technique that has previously been validated against crystal sonomicrometry. However, the application of Velocity Vector Imaging (VVI) to images obtained from cardiac magnetic resonance (CMR) imaging has never been validated against those values derived from VVI applied to two-dimensional echocardiographic images in the same patient group. The aim of this study was to validate for the first time the application of VVI to retrospectively acquired CMR data sets for the assessment of left ventricular strain and rotation, using echocardiographic strain assessment by VVI as the reference technique. Cine steady-state free precession CMR data sets and two-dimensional echocardiographic images obtained on the same day in 36 adult patients with hypertrophic cardiomyopathy were analyzed retrospectively using VVI to quantify global longitudinal and circumferential strain and rotation parameters. The absolute differences in longitudinal strain between the two imaging modalities were -1.1 ± 3.3% (endocardial) and -2.2 ± 3.6% (full thickness). The absolute differences in circumferential strain were -4.7 ± 5.3% (endocardial) and -3.4 ± 3.8% (full thickness). CMR consistently resulted in higher strain values than echocardiography. The absolute differences in twist were -0.2 ± 5.6% (endocardial) and 0.1 ± 5.8% (full thickness). The application of VVI to CMR data sets allows a feasible and reproducible method for strain analysis in HCM, demonstrating excellent agreement with two-dimensional echocardiography-derived values. Given the superior image quality obtained with CMR in a significant proportion of patients, this technique provides a method for strain assessment without the need for dedicated CMR acquisition and analytic techniques.


Heparinase II from Flavobacterium heparinum. Role of histidine residues in enzymatic activity as probed by chemical modification and site-directed mutagenesis.
The three heparinases derived from Flavobacterium heparinum are powerful tools for studying heparin-like glycosaminoglycans in major biological processes, including angiogenesis and development. Heparinase II is unique among the three enzymes because it is able to catalytically cleave both heparin and heparan sulfate-like regions of heparin-like glycosaminoglycans. Toward understanding the catalytic mechanism of heparin-like glycosaminoglycan degradation by heparinase II, we set out to investigate the role of the histidines of heparinase II in catalysis. We observe concentration-dependent inactivation of heparinase II in the presence of the reversible histidine-modifying reagent diethylpyrocarbonate (DEPC). With heparin as the substrate, the rate constant of inactivation was found to be 0.16 min-1 mM-1; with heparan sulfate as the substrate, the rate constant was determined to be 0.24 min-1 mM-1. Heparinase II activity is restored following hydroxylamine treatment. This, along with other experiments, strongly suggests that the inactivation of heparinase II by DEPC is specific for histidine residues and that three histidines are modified by DEPC. Substrate protection experiments show that heparinase II preincubation with heparin followed by the addition of DEPC resulted in a loss of enzymatic activity toward heparan sulfate but not heparin. However, heparinase II preincubation with heparan sulfate was unable to protect heparinase II from DEPC inactivation for either of the substrates. Proteolytic mapping studies with Lys-C were consistent with the chemical modification experiments and identified histidines 238, 451, and 579 as being important for heparinase II activity. Further mapping studies identified histidine 451 as being essential for heparin degradation. Site-directed mutagenesis experiments on the 13 histidines of heparinase II corroborated the chemical modification and the peptide mapping studies, establishing the importance of histidines 238, 451 and 579 in heparinase II activity.


Indexing UMLS Semantic Types for Medical Question-Answering.
Open-domain Question-Answering (QA) systems heavily rely on named entities, a set of general-purpose semantic types which generally cover names of persons, organizations and locations, dates and amounts, etc. If we are to build medical QA systems, a set of medically relevant named entities must be used. In this paper, we explore the use of the UMLS (Unified Medical Language System) Semantic Network semantic types for this purpose. We present an experiment where the French part of the UMLS Metathesaurus, together with the associated semantic types, is used as a resource for a medically-specific named entity tagger. We also explore the detection of Semantic Network relations for answering specific types of medical questions. We present results and evaluations on a corpus of French-language medical documents that was used in the EQueR Question-Answering evaluation forum. We show, using statistical studies, that strategies for using these new tags in a QA context are to take in account the individual origin of documents.


Sirtuin-activating compounds (STACs) alleviate D-galactosamine/lipopolysaccharide-induced hepatotoxicity in rats: involvement of sirtuin 1 and heme oxygenase 1.
Sirtuin activating compounds (STACs) attenuate various type of liver insults through mechanisms which are not fully understood. In the present study, we investigated the ameliorative potential of quercetin (natural polyphenol) and SRT1720 (synthetic SIRT1 activator) against D-galactosamine/lipopolysaccharide-induced hepatotoxicity (an experimental model of acute liver failure). Moreover, we compared and contrasted the roles of stress responsive enzymes, sirtuin 1 (SIRT1) and heme oxygenase 1 (HO-1) in hepatoprotection/ hepatotoxicity. Liver injury was induced in male Wistar rats by intraperitoneal injection of D-galactosamine (400 mg/kg) and lipopolysaccharide (10 microg/kg). Some animals were pretreated with quercetin (50 mg/kg i.p.) or SRT1720 (5 mg/kg i.p.). Twenty-four hours later, the effects of these treatments were evaluated by biochemical studies and Western blot. D-GalN/LPS treatment upregulated HO-1 expression, downregulated SIRT1 expression, decreased AST: ALT ratio and markedly increased bilirubin, catalase and conjugated diene levels. Pretreatment of D-GalN/LPS rats with either quercetin or SRT1720 returned SIRT1 expression, HO-1 expression and all the aforementioned markers towards normal. Collectively, these findings suggest that elevated HO-1 and low SIRT1 expressions are involved in the pathogenesis of D-GalN/LPS-induced hepatotoxicity. Drugs that downregulate HO-1 and/or upregulate SIRT1 seem to have antihepatotoxic effects and need further exploration.


Steady-state versus chemotherapy-based hematopoietic cell mobilization after anti-CD38-based induction therapy in newly diagnosed multiple myeloma.
The incorporation of anti-CD38 monoclonal antibodies (mAb) in induction regimens of newly diagnosed transplant-eligible multiple myeloma (MM) patients has been established as a new standard. However, the optimal strategy of stem cell mobilization in this context is not yet clear. From May 2020 till September 2022, we retrospectively reviewed patients receiving anti-CD38 mAb-based induction therapy followed by stem cell mobilization either in a steady-state protocol (SSM) using 10 μg/kg granulocyte colony-stimulating factor (G-CSF) for 5 days or in a chemotherapy-based protocol (CM) using 1-4 g/m2 cyclophosphamide and G-CSF. Overall, 85 patients (median age 61 years) were included in the analysis. In total, 90 mobilization attempts were performed, 42 with SSM and 48 with CM. There was no significant difference in the median concentration of CD34+ cells in peripheral blood (PB) prior to apheresis between SSM and CM (61/μL vs. 55.4/μL; p = .60). Cumulative CD34+ yields did not differ between the groups with median of 6.68 and 6.75 × 106 /kg body weight, respectively (p = .35). The target yield (≥4 × 106 CD34+ cells/kg body weight) was reached in 88% (CM) and 86% (SSM), with a high proportion even after a single apheresis session (76% vs. 75%). Plerixafor was found to be more frequently used in SSM (52%) than in CM (23%; p < .01). A total of 83 patients underwent autologous transplantation and all were engrafted. Stem cell collection in patients undergoing anti-CD38-based induction therapy is feasible with either CM or SSM, although SSM more frequently requires plerixafor.


Poliomyelitis in India: prospects and problems of control.
Based on many surveys of residual paralysis and limited surveillance, the incidence of acute paralytic poliomyelitis in India has been calculated to be 20-40 per 100,000 population per year; thus greater than 200,000 cases occur annually, or 500 every day. Although oral polio vaccine ( OPV ) has been highly effective in controlling outbreaks, its introduction in routine immunization programs has not succeeded in controlling poliomyelitis in India. This failure is the result of inappropriate immunization strategy and low rates of antibody response to vaccine virus. Injectable polio vaccine, although found to be highly effective in routine immunization programs, is very costly and in short supply. The annual immunization of the susceptible age group with OPV during a short period (pulse immunization) has been found to be highly effective; this strategy is recommended for national control of poliomyelitis.


Comparison of tissue-selective proinflammatory gene induction in mice infected with wild-type, DNA adenine methylase-deficient, and flagellin-deficient Salmonella enterica.
Mutants of Salmonella enterica serovar Typhimurium deficient in DNA adenine methylase (Dam) are attenuated for virulence in mice and confer heightened immunity in vaccinated animals. In contrast, infection of mice with wild-type (WT) strains or flagellin-deficient mutants of Salmonella causes typhoid fever. Here we examined the bacterial load and spatiotemporal kinetics of expression of several classes of host genes in Peyer's patches, the liver, and the spleen following oral infection of mice with WT, dam mutant, or flagellin-deficient (flhC) Salmonella. The genes evaluated included inflammatory (interleukin-1beta [IL-1beta], tumor necrosis factor alpha), chemokine (macrophage inflammatory protein 2), Th1/Th2 indicator (IL-12p40, IL-4), and interferon system (beta interferon [IFN-beta], IFN-gamma, protein Mx1 GTPase, RNA-dependent protein kinase, inducible nitric oxide synthase, suppressor of cytokine signaling 1) beacons. We showed that maximal interferon system and proinflammatory gene induction occurred by 5 days after infection and that the levels were comparable for the WT and flhC strains but were significantly lower for the dam mutant. Additionally, host gene expression in systemic tissues of individual animals was dependent on the bacterial load in the Peyer's patches for mice infected with WT, dam mutant, or flhC mutant Salmonella as early as 8 h after infection. Moreover, a bacterial load threshold in the Peyer's patches was necessary to stimulate the host gene induction in the liver and spleen. Taken together, these results suggest that bacterial load and the accompanying strain-specific cytokine signature are important determinants of the host innate immune response and associated disease manifestations observed in dam mutant Salmonella-infected animals compared to the immune response and disease manifestations observed in WT and flhC mutant Salmonella-infected animals.


The Absence of Endothelial Sodium Channel α (αENaC) Reduces Renal Ischemia/Reperfusion Injury.
The epithelial sodium channel (ENaC) has a key role in modulating endothelial cell stiffness and this in turn regulates nitric oxide (NO) synthesis. The physiological relevance of endothelial ENaC in pathological conditions where reduced NO bioavailability plays an essential role remains largely unexplored. Renal ischemia/reperfusion (IR) injury is characterized by vasoconstriction and sustained decrease in renal perfusion that is partially explained by a reduction in NO bioavailability. Therefore, we aimed to explore if an endothelial ENaC deficiency has an impact on the severity of renal injury induced by IR. Male mice with a specific endothelial sodium channel α (αENaC) subunit gene inactivation in the endothelium (endo-αENaCKO) and control littermates were subjected to bilateral renal ischemia of 22 min and were studied after 24 h of reperfusion. In control littermates, renal ischemia induced an increase in plasma creatinine and urea, augmented the kidney injury molecule-1 (Kim-1) and neutrophil gelatinase associated lipocalin-2 (NGAL) mRNA levels, and produced severe tubular injury. The absence of endothelial αENaC expression prevented renal tubular injury and renal dysfunction. Moreover, endo-αENaCKO mice recovered faster from renal hypoxia after the ischemia episode as compared to littermates. In human endothelial cells, pharmacological ENaC inhibition promoted endothelial nitric oxide synthase (eNOS) coupling and activation. Altogether, these data suggest an important role for endothelial αENaC in kidney IR injury through improving eNOS activation and kidney perfusion, thus, preventing ischemic injury.


Trying for a BRAF Slam Dunk.
The first basket clinical trial testing the BRAF inhibitor vemurafenib resulted in evidence of activity in 13 unique cancer types with BRAF V600 mutations, but the response rates were variable. Therefore, different cancer histologies with the same driver oncogene display different degrees of oncogenic pathway addiction.See related article by Subbiah et al., p. 657.


Optimization of a Digital Medicine System in Psychiatry.
Nonadherence to medication compromises the effectiveness of psychiatric treatments in patients with serious mental illness (SMI). A newly developed digital medicine system (DMS) offers an opportunity to objectively assess and report patient medication adherence. DMS includes a wearable sensor that receives a data signal from a medication tablet with an embedded ingestible sensor after ingestion of the medication and transmits that data to the patient's mobile device to display health care information for the patient and treatment team. Development of a DMS requires a program that investigates safety, tolerability, and usability of the system in patients with SMI. It necessitates rapid design adaptation of the individual components and the integrated system and human factors studies with the intended users. This article describes the program's methodology and shows results from 3 early studies, conducted in 2013 and 2014, to illustrate diversity of the programs' methodology. First, a standard 28-day study showed minimal skin irritation and demonstrated acceptable wearability of the wearable sensor. Second, a 16-week study provided usability feedback from patients with SMI and caregivers to improve the mobile application. Third, end-to-end bench-level integrated system testing led to multiple substudies of a master protocol (ClinicalTrials.gov identifier: NCT02091882) to investigate various aspects of the system (eg, ingestible sensor detection and latency). To develop a DMS in psychiatry, the system's multiple components must be considered simultaneously using various methodologies. A focus on usability, along with agile evaluation and feedback across studies, provides an optimal strategy for ensuring patient acceptance and successful regulatory review.


Health care or health trade? A historic moment of choice.
During the 20th century, medical care evolved from a notional economy of trying to a real economy of doing. Care systems can therefore usefully be measured and evaluated as production systems. Whether they will succumb to the pattern of competitive commodity production for profit in the market, or will succeed in developing their own new gift economy for human needs, will become a dominant political and economic issue in the 21st century. Health care is now becoming industrialized in essentially the same way as textile manufacture was industrialized in the 19th century, with corresponding loss of control by skilled workers over their work processes. The outcome of the struggle between skilled handloom weavers and their industrializing employers was determined by the huge rise in productivity associated with machines. The outcome of current struggles between public service and state-subsidized corporate care for profit will be decided likewise by superior productivity. Evidence suggests that in terms of health outcome, democratized public care with a much expanded and diversified workforce could be far more productive than industrialization.


The dual effect of background music on creativity: perspectives of music preference and cognitive interference.
Music, an influential environmental factor, significantly shapes cognitive processing and everyday experiences, thus rendering its effects on creativity a dynamic topic within the field of cognitive science. However, debates continue about whether music bolsters, obstructs, or exerts a dual influence on individual creativity. Among the points of contention is the impact of contrasting musical emotions-both positive and negative-on creative tasks. In this study, we focused on traditional Chinese music, drawn from a culture known for its 'preference for sadness,' as our selected emotional stimulus and background music. This choice, underrepresented in previous research, was based on its uniqueness. We examined the effects of differing music genres (including vocal and instrumental), each characterized by a distinct emotional valence (positive or negative), on performance in the Alternative Uses Task (AUT). To conduct this study, we utilized an affective arousal paradigm, with a quiet background serving as a neutral control setting. A total of 114 participants were randomly assigned to three distinct groups after completing a music preference questionnaire: instrumental, vocal, and silent. Our findings showed that when compared to a quiet environment, both instrumental and vocal music as background stimuli significantly affected AUT performance. Notably, music with a negative emotional charge bolstered individual originality in creative performance. These results lend support to the dual role of background music in creativity, with instrumental music appearing to enhance creativity through factors such as emotional arousal, cognitive interference, music preference, and psychological restoration. This study challenges conventional understanding that only positive background music boosts creativity and provides empirical validation for the two-path model (positive and negative) of emotional influence on creativity.


Effect of Selected Mercapto Flavor Compounds on Acrylamide Elimination in a Model System.
The effect of four mercapto flavor compounds (1,2-ethanedithiol, 1-butanethiol, 2-methyl-3-furanthiol, and 2-furanmethanethiol) on acrylamide elimination were investigated in model systems. The obtained results showed that mercaptans assayed were effective in elimination arylamide in a model system. Their reactivities for decreasing acrylamide content depended on mercaptan's molecular structure and acrylamide disappearance decreased in the following order: 1,2-ethanedithiol > 2-methyl-3-furanthiol > 1-butanethiol > 2-furanmethanethiol. Mercaptans were added to acrylamide to produce the corresponding 3-(alkylthio) propionamides. This reaction was irreversible and only trace amounts of acrylamide were formed by thermal heating of 3-(alkylthio) propanamide. Although a large amount disappeared, only part of the acrylamide conversed into 3-(alkylthio) propionamides. All of these results constitute a fundamental proof of the complexity of the reactions involved in the removal of free acrylamide in foods. This implies mercapto flavor/aroma may directly or indirectly reduce the level of acrylamide in food processing. This study could be regarded as a pioneer contribution on acrylamide elimination in a model system by the addition of mercapto flavor compounds.


[Vitronectin and fibronectin receptors in proliferative retinal diseases].
Integrins are membrane receptors which, together with their corresponding adhesion proteins, constitute a versatile recognition system and provide cells with information for position, anchorage, differentiation, migration, and growth. Vitronectin and fibronectin are two potent mediators of cell adhesion which, together with their receptors, represent a highly sophisticated system of communication in proliferative intraocular disorders. Using an immunofluorescence technique, we demonstrate a similar pattern of partial colocalization of vitronectin and fibronectin in proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). Furthermore, we show the expression of the corresponding cell surface receptors for vitronectin and fibronectin in membranes from patients with traumatic PVR (n = 8), idiopathic PVR (n = 8), and PDR (n = 6). At this time, it seems that further studies on integrins and their significance in proliferative retinal disorders are necessary before pharmacological approaches based on receptor antagonism can prove themselves to be possible and clinically applicable.


Endothelin-1 and macrophage colony-stimulating factor are co-localized in human amnion membrane cells and secreted into amniotic fluid.
We have examined the cellular localization and human amniotic fluid content of endothelin-1 (ET-1) and macrophage colony-stimulating factor (M-CSF). The study material consisted of amniotic fluid from 20 patients referred for amniocentesis, and placental samples from normal deliveries. ET-1 and M-CSF were analysed by radioimmunoassay and enzyme-linked immunosorbent assay respectively. The cellular localization of ET-1 and M-CSF in the amnion membranes was analysed by double-labelling immunocytochemistry using fluorescein isothiocyanate- and Cy3-labelled secondary antibodies. Release of ET-1 and M-CSF was studied in cultured amniocytes. We found that the mean +/- SD concentrations of ET-1 and M-CSF in fetal amniotic fluid were 45.6 +/- 17.3 pmol/l (range 16.8-85.5) and 7323 +/- 3415 ng/l (range 2640-12 110) respectively. Double-labelling immunocytochemistry showed that both M-CSF and ET-1 were co-localized in the same cells to a high extent. Further analysis revealed that levels of M-CSF, but not ET-1, were significantly correlated with pregnancy length. Both M-CSF and ET-1 were released from cultured amniocytes in response to interleukin-1. These findings show that ET-1 and M-CSF are partly co-localized to specific cells in the human amniotic membrane. As both M-CSF and ET-1 were released from cultured amniocytes in vitro, this suggests that they both may be secreted into fetal amniotic fluid in vivo as well.


Activation of (His)6-Raf-1 in vitro by partially purified plasma membranes from v-Ras-transformed and serum-stimulated fibroblasts.
The serine-threonine protein kinase Raf-1 is an important signal transducer in mitogenesis, phosphorylating and activating mitogen-activated protein (MAP) kinase kinase. Raf-1 activation in vivo is dependent on Ras, but the mechanism of Raf activation is unknown. The ability of preparations of plasma membranes to activate exogenous (His)6-Raf-1 was studied. Plasma membranes of v-Ras-transformed NIH 3T3 cells, but not parental cells, enhanced MAP kinase kinase kinase (MAPKKK) activity dependent on addition of (His)6-Raf-1 and ATP/Mg. Treatment of membranes with concentrations of Bacillus cereus phosphatidylcholine-specific phospholipase C that activated Raf-1 in vivo failed to enhance MAPKKK activity in vitro. Activation of (His)6-Raf-1 in vitro by membranes was dependent on binding to Ras. Membranes from v-Src-transformed cells also activated (His)6-Raf-1 and synergized with v-Ras membranes. Serum-treatment of NIH 3T3 cells stimulated the ability of membranes to activate (His)6-Raf-1. Activated (His)6-Raf-1 could be recovered on Ni(2+)-agarose, and this methodology was used to demonstrate that activation by membranes was ATP dependent. These findings demonstrate Ras- and ATP-dependent step(s) for Raf-1 activation by plasma membranes in vitro.


Male obesity effects on sperm and next-generation cord blood DNA methylation.
The prevalence of metabolic disorders, in particular obesity has dramatically increased worldwide. Genetic variants explain only a minor part of the obesity epidemic induced by physical inactivity and over-nutrition. Epidemiological studies in humans and animal models indicate that epigenetic changes associated with adverse parental and/or intrauterine factors may contribute to the missing heritability of metabolic disorders. Possible adverse paternal effects are likely transmitted by sperm to the next-generation. To investigate this hypothesis, we have systematically analyzed the effects of male body mass index (BMI) on sperm epigenome and its association with next-generation fetal cord blood (FCB) DNA methylation. Methylation levels of maternally imprinted (PEG1, PEG4, PEG5, and PEG10), paternally imprinted (H19-IG DMR, IGF2-DMR0, and MEG3-IG DMR) regions, and obesity-related non-imprinted HIF3A gene were quantified by bisulphite pyrosequencing in sperm samples of 294 human donors undergoing in vitro fertilization or intracytoplasmic sperm injection, and in 113 FCBs of the resulting offspring. Multivariable regression analyses revealed that MEG3 intergenic differentially methylated region (IG DMR) showed positive correlation between sperm methylation and donor's BMI. A gender-specific correlation between paternal BMI and FCB methylation was observed for MEG3-IG DMR, HIF3A, and IGF2-DMR0. The former two genes displayed same directional nominal association (as sperm) between paternal BMI and FCB methylation in male offspring. Hypomethylation of IGF2-DMR0 with increased paternal BMI was observed in FCBs from female offsprings. Our results suggest that male obesity is nominally associated with modification of sperm DNA methylome in humans, which may affect the epigenome of the next-generation. Nevertheless, it is important to note that none of the associated p-values survived multiple testing adjustments. Future work should test the effect of associated methylation aberrations in the offspring as DNA methylation was shown to control expression and/or imprint establishment across the studied genes.


Cloning, sequence analysis, and functional expression of the acetyl coenzyme A synthetase gene from Methanothrix soehngenii in Escherichia coli.
In the acetoclastic methanogen Methanothrix soehngenii, acetate is activated to acetyl coenzyme A by acetyl coenzyme A synthetase (Acs). The acs gene, coding for the single Acs subunit, was isolated from a genomic library of M. soehngenii DNA in Escherichia coli by using antiserum raised against the purified Acs. After introduction in E. coli, the acs gene was expressed, resulting in the production of an immunoreactive protein of 68 kDa, which is approximately 5 kDa smaller than the known size of purified Acs. In spite of this difference in size, the Acs enzymes are produced in similar quantities in E. coli and M. soehngenii and show comparable specific activities. Upstream from the acs gene, consensus archaeal expression signals were identified. Immediately downstream from the acs gene there was a putative transcriptional stop signal. The amino acid sequence deduced from the nucleotide sequence of the acs gene showed homology with those of functionally related proteins, i.e., proteins involved in the binding of coenzyme A, ATP, or both.


Recent advances in MXene-based nanocomposites for supercapacitors.
MXene materials have become a competitive candidate for electrochemical energy storage due to their unique two-dimensional layered structure, high density, metal-like conductivity, fast ion intercalation, tunable surface terminal groups, and good mechanical flexibilities, showing unique application advantages in the field of supercapacitors. With widely research of MXene in energy storage applications, plenty of studies in synthesis strategies of MXene, including etching, intercalation and exfoliation processes, and its charge storage mechanism in supercapacitors have been conducted. However, the restacking of two-dimensional MXene nanosheets severely affects their electrochemical performance. To prevent the stacking of MXene, MXene-based nanocomposite electrode materials have been developed with remarkable electrochemical performance by incorporating conventional active capacitive materials, including metal oxides/sulfides and conductive polymers, with MXene. This review summarizes the etching strategies of MXenes and selection of intercalants, also discusses the charge storage mechanism of MXenes in aqueous and nonaqueous electrolytes. It mainly expounds the preparation strategies and applications of MXene-based nanocomposites in supercapacitors, including MXene/metal oxide, MXene/metal sulfide, MXene/conducting polymer, and MXene/carbon-based composites. Additionally, the advantages of combining MXene with other active materials in supercapacitor applications, which support its promising prospects, are discussed. Finally, the critical challenges faced by MXene-based nanocomposites in long-term research are mentioned.


Hematologic effects of interleukin-1 beta, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor in tumor-bearing mice treated with fluorouracil.
Myelosuppression following intensive chemotherapy in cancer patients is associated with increased morbidity and mortality. Hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), alone or in combination with interleukin-1 (IL-1), have been shown to counteract myelosuppression resulting from some, but not all, chemotherapeutic regimens. In an attempt to apply these findings to intensive therapy with proliferation-dependent chemotherapeutic drugs such as fluorouracil (5-FU), we investigated combination biochemotherapy in a murine model. Female CD8F1 [(BALB/c X DBA/8)F1] mice bearing first-passage transplants of spontaneous CD8F1 breast tumors were treated intraperitoneally once a week for 3 successive weeks with a course of 5-FU alone or with a course of 5-FU in combination with recombinant human interleukin-1 beta (rHuIL-1 beta) alone or in combination with CSFs. rHuIL-1 beta alone or in combination with rHuG-CSF or recombinant murine GM-CSF significantly improved tumor growth inhibition (60% vs. 90%) and survival (20% vs. 90%-100%), increased the maximally tolerated dose of 5-FU, accelerated recovery of neutrophil counts in peripheral blood, and reduced duration of significant neutropenia and loss of body weight (29% vs. 10% loss). Clinical trials of IL-1 have been initiated in patients with advanced cancer receiving multiple courses of high-dose 5-FU.


[Phenylephrine 10% eye drop action in the eyelid position in healthy subjects].
To determine the upper and lower eyelid position with a single drop of 10% phenylephrine in normal individuals and observe positional lid changes in upper and lower lids of the opposite eye. Prospective observational study including 24 healthy subjects of both genders (age range: 20-39 yrs) submitted to instillation of a single drop of 10% phenylephrine in the upper fornix of one randomly chosen eye. A video camera recorded the images of both eyes before and after eye drop application at 3, 10, 15, 30, 45 and 60 minutes. The images were digitally processed and edited to analyze lid measurements (upper lid height: distance between the highest upper margin lid point and a horizontal line traced from the medial to the lateral canthus; lower lid height: distance between the lowest margin lid point and the above-mentioned line). Before and after drug instillation, upper lid height was significantly different (p<0.001) at all moments with a mean elevation of 0.79 mm. The lower lid height changed too with a mean retraction of 0.37 mm. In the fellow eye upper lid drop was observed at almost all moments with the lowest value at 3 minutes (mean reduction of 0.68 mm) and elevation (0.37 mm) of lower lid. This experiment showed that a single drop of 10% phenylephrine acted not only on the upper eyelid but also on lower lid of the tested eye. Control mechanism of lid opening and closing changed upper and lower lid positioning of the opposite eye in healthy subjects.


Twelve tips for designing and running longitudinal integrated clerkships.
Longitudinal integrated clerkships (LICs) involve learners spending an extended time in a clinical setting (or a variety of interlinked clinical settings) where their clinical learning opportunities are interwoven through continuities of patient contact and care, continuities of assessment and supervision, and continuities of clinical and cultural learning. Our twelve tips are grounded in the lived experiences of designing, implementing, maintaining, and evaluating LICs, and in the extant literature on LICs. We consider: general issues (anticipated benefits and challenges associated with starting and running an LIC); logistical issues (how long each longitudinal experience should last, where it will take place, the number of learners who can be accommodated); and integration issues (how the LIC interfaces with the rest of the program, and the need for evaluation that aligns with the dynamics of the LIC model). Although this paper is primarily aimed at those who are considering setting up an LIC in their own institutions or who are already running an LIC we also offer our recommendations as a reflection on the broader dynamics of medical education and on the priorities and issues we all face in designing and running educational programs.


Identification of interleukin-1 beta as a key mediator in the upregulation of Cav3.2-USP5 interactions in the pain pathway.
We recently reported that nerve injury or peripheral inflammation triggers an upregulation of the deubiquitinase, USP5 in mouse dorsal root ganglion and spinal dorsal horn. This leads to dysregulated ubiquitination of Cav3.2 T-type calcium channels, thus increasing Cav3.2 channel plasma membrane expression and nociceptive signaling in the primary afferent pain pathway. This phenomenon could be recapitulated by noninvasive, optogenetic activation of transient receptor potential vanilloid-1–expressing nociceptors, indicating that neuronal activity is a key player in this process. Given the relevance of the pro-inflammatory cytokine interleukin-1 beta in many forms of pathological pain, we hypothesized that interleukin-1 beta may be a critical cofactor required to drive upregulation of interactions between USP5 and Cav3.2 channels. Here, we report that gene expression, as well as protein levels for interleukin-1 beta and the endogenous interleukin-1 receptor-I antagonist, IL-1Ra are unaltered following conditioning stimulation of optogenetically targeted cutaneous nociceptors, indicating that neuronal activity is not a driver of interleukin-1 beta signaling. In contrast, co-immunoprecipitation experiments revealed that intrathecal administration of interleukin-1 beta in wild-type mice led to an increase in the interaction between USP5 and Cav3.2 in the spinal dorsal horn. Moreover, disruption of the interaction between USP5 and Cav3.2 with TAT peptides suppressed acute nocifensive responses produced by interleukin-1 beta, which was similar to that achieved by elimination of T-type channel activity with the channel blockers, mibefradil, or TTA-A2. Finally, this upregulation could be maintained in dorsal root ganglion neuron cultures exposed overnight to interleukin-1 beta, while the copresence of interleukin-1 receptor antagonist or the dampening of neuronal cell activity with tetrodotoxin attenuated this response. Altogether, our findings identify interleukin-1 beta as an upstream trigger for the upregulation of interactions between USP5 and Cav3.2 channels in the pain pathway, presumably by triggering increased firing activity in afferent fibers.


Separation anxiety: Splitting PD-L1 from CD80 suppresses autoimmunity.
A monoclonal antibody targeting CD80 on antigen presenting cells disrupts cis-interactions with PD-L1, reviving T cell inhibitory checkpoint signaling to suppress autoimmunity.


Positive selection of major histocompatibility complex-restricted suppressor T cells bearing the predominant idiotype in the immune response to lysozyme.
The lysozyme system provides an excellent model for studying the role of multiple major histocompatibility complex (MHC) genes in the induction and regulation of Ir-gene controlled immune responses. Immunization of H-2b mice leads to concomitant activation of helper and suppressor activities by different epitopes on hen egg-white lysozyme (HEL) and thus phenotype unresponsiveness to native HEL. HEL-specific suppressor T cells in C57BL/10 nonresponder mice show MHC restriction, because their enrichment on antigen-pulsed macrophage monolayers requires syngeneic macrophages as well as HEL. The expression of the selected suppressor function requires interaction between the restricted suppressor precursor cell and an HEL-triggered, suppressor-inducer T cell. The MHC-restricted suppressor precursors bear the predominant idiotype found on anti-HEL antibodies, whereas MHC-restricted helpers do not.


Heterogeneity in Survival with Immune Checkpoint Inhibitors and Its Implications for Survival Extrapolations: A Case Study in Advanced Melanoma.
Survival heterogeneity and limited trial follow-up present challenges for estimating lifetime benefits of oncology therapies. This study used CheckMate 067 (NCT01844505) extended follow-up data to assess the predictive accuracy of standard parametric and flexible models in estimating the long-term overall survival benefit of nivolumab plus ipilimumab (an immune checkpoint inhibitor combination) in advanced melanoma. Six sets of survival models (standard parametric, piecewise, cubic spline, mixture cure, parametric mixture, and landmark response models) were independently fitted to overall survival data for treatments in CheckMate 067 (nivolumab plus ipilimumab, nivolumab, and ipilimumab) using successive data cuts (28, 40, 52, and 60 mo). Standard parametric models allow survival extrapolation in the absence of a complex hazard. Piecewise and cubic spline models allow additional flexibility in fitting the hazard function. Mixture cure, parametric mixture, and landmark response models provide flexibility by explicitly incorporating survival heterogeneity. Sixty-month follow-up data, external ipilimumab data, and clinical expert opinion were used to evaluate model estimation accuracy. Lifetime survival projections were compared using a 5% discount rate. Standard parametric, piecewise, and cubic spline models underestimated overall survival at 60 mo for the 28-mo data cut. Compared with other models, mixture cure, parametric mixture, and landmark response models provided more accurate long-term overall survival estimates versus external data, higher mean survival benefit over 20 y for the 28-mo data cut, and more consistent 20-y mean overall survival estimates across data cuts. This case study demonstrates that survival models explicitly incorporating survival heterogeneity showed greater accuracy for early data cuts than standard parametric models did, consistent with similar immune checkpoint inhibitor survival validation studies in advanced melanoma. Research is required to assess generalizability to other tumors and disease stages. Given that short clinical trial follow-up periods and survival heterogeneity introduce uncertainty in the health technology assessment of oncology therapies, this study evaluated the suitability of conventional parametric survival modeling approaches as compared with more flexible models in the context of immune checkpoint inhibitors that have the potential to provide lasting survival benefits.This study used extended follow-up data from the phase III CheckMate 067 trial (NCT01844505) to assess the predictive accuracy of standard parametric models in comparison with more flexible methods for estimating the long-term survival benefit of the immune checkpoint inhibitor combination of nivolumab plus ipilimumab in advanced melanoma.Mixture cure, parametric mixture, and landmark response models provided more accurate estimates of long-term overall survival versus external data than other models tested.In this case study with immune checkpoint inhibitor therapies in advanced melanoma, extrapolation models that explicitly incorporate differences in cancer survival between observed or latent subgroups showed greater accuracy with both early and later data cuts than other approaches did.


Preparation and efficacy of Newcastle disease virus DNA vaccine encapsulated in PLGA nanoparticles.
Although the Newcastle disease virus (NDV) inactivated vaccines and attenuated live vaccines have been used to prevent and control Newcastle disease (ND) for years, there are some disadvantages. Recently, newly developed DNA vaccines have the potential to overcome these disadvantages. The low delivery efficiency, however, hindered the application of DNA vaccines for ND in practice. The eukaryotic expression plasmid pVAX1-F (o) DNA that expressed the F gene of NDV encapsulated in PLGA nanoparticles (pFNDV-PLGA-NPs) were prepared by a double emulsion-solvent evaporation method and optimal preparation conditions of the pFNDV-PLGA-NPs were determined. Under the optimal conditions, the pFNDV-PLGA-NPs were produced in good morphology and had high stability with a mean diameter of 433.5 ± 7.5 nm, with encapsulation efficiency of 91.8 ± 0.3% and a Zeta potential of +2.7 mV. Release assay in vitro showed that the fusion gene plasmid DNA could be sustainably released from the pFNDV-PLGA-NPs up to 93.14% of the total amount. Cell transfection test indicated that the vaccine expressed and maintained its bioactivity. Immunization results showed that better immune responses of SPF chickens immunized with the pFNDV-PLGA-NPs were induced compared to the chickens immunized with the DNA vaccine alone. In addition, the safety of mucosal immunity delivery system of the pFNDV-PLGA-NPs was also tested in an in vitro cytotoxicity assay. The pFNDV-PLGA-NPs could induce stronger cellular, humoral, and mucosal immune responses and reached the sustained release effect. These results laid a foundation for further development of vaccines and drugs in PLGA nanoparticles.


Additive clinical impact of epidermal growth factor receptor and podocalyxin-like protein expression in pancreatic and periampullary adenocarcinomas.
The outcome of periampullary adenocarcinomas remains poor with few treatment options. Podocalyxin-like protein (PODXL) is an anti-adhesive protein, the high expression of which has been shown to confer a poor prognosis in numerous malignancies. A correlation and adverse prognostic synergy between PODXL and the epidermal growth factor receptor (EGFR) has been observed in colorectal cancer. Here, we investigated whether this also applies to periampullary adenocarcinomas. We analyzed the immunohistochemical expression of PODXL and EGFR in tissue microarrays with tumors from two patient cohorts; (Cohort 1, n = 175) and (Cohort 2, n = 189). The effect of TGF-β-induced expression and siRNA-mediated knockdown of PODXL and EGFR, were investigated in pancreatic cancer cells (PANC-1) in vitro. We found a correlation between PODXL and EGFR in these cancers, and a synergistic adverse effect on survival. Furthermore, silencing PODXL in pancreatic cancer cells resulted in the down-regulation of EGFR, but not vice versa. Consequently, these findings suggest a functional link between PODXL and EGFR, and the potential combined utility as biomarkers possibly improving patient stratification. Further studies examining the mechanistic basis underlying these observations may open new avenues of targeted treatment options for subsets of patients affected by these particularly aggressive cancers.


A systematic review and meta-analysis of myelosuppression in pediatric patients treated with linezolid for Gram-positive bacterial infections.
The incidence of linezolid-induced myelosuppression in pediatric patients was reported at large difference among prospective studies, with a range of 0-24%. Additionally, there is little study which evaluated the impact of linezolid administration period on myelosuppression in pediatric patients, while it is one of the most frequent reason that linezolid therapy has to be discontinued in adult patients. Here, we performed a systematic review and meta-analysis to reveal the incidence of linezolid-induced thrombocytopenia and anemia, and impact of the administration period of linezolid on myelosuppression based on individual data analysis of pediatric patients. We systematically searched the Scopus, EMBASE, Cochrane Central Register of Controlled Trials, PubMed, and CINAHL until April 2020. We investigated the incidence of linezolid-induced thrombocytopenia and anemia using pooled analysis, and evaluated the impact of linezolid administration period on myelosuppression using meta-analysis. Thirteen studies with 969 pediatric patients were identified. The pooled incidences of thrombocytopenia and anemia were 9% (95% confidence interval (CI), 3-18%) and 4% (95% CI, 0-12%), respectively. Our meta-analysis showed the extension of linezolid administration period (more than 14 days) resulted in higher incidence of thrombocytopenia (OR 4.86, 95% CI 1.10-21.55) and anemia (OR 4.57, 95% CI 0.13-160.49). The incidence of linezolid-induced myelosuppression in pediatric patients was less than 10%. However, our meta-analysis revealed linezolid administration period for more than 14 days was one of risk factors associated with linezolid-induced myelosuppression. Therefore, especially for pediatric patients treated with linezolid for more than 14 days, careful monitoring of myelosuppression is required.


Numerical study of reflectance imaging using a parallel Monte Carlo method.
Reflectance imaging of biological tissues with visible and near-infrared light has the significant potential to provide a noninvasive and safe imaging modality for diagnosis of dysplastic and malignant lesions in the superficial tissue layers. The difficulty in the extraction of optical and structural parameters lies in the lack of efficient methods for accurate modeling of light scattering in biological tissues of turbid nature. We present a parallel Monte Carlo method for accurate and efficient modeling of reflectance images from turbid tissue phantoms. A parallel Monte Carlo code has been developed with the message passing interface and evaluated on a computing cluster with 16 processing elements. The code was validated against the solutions of the radiative transfer equation on the bidirectional reflection and transmission functions. With this code we investigated numerically the dependence of reflectance image on the imaging system and phantom parameters. The contrasts of reflectance images were found to be nearly independent of the numerical aperture (NA) of the imaging camera despite the fact that reflectance depends on the NA. This enables efficient simulations of the reflectance images using an NA at 1.00. Using heterogeneous tissue phantoms with an embedded region simulating a lesion, we investigated the correlation between the reflectance image profile or contrast and the phantom parameters. It has been shown that the image contrast approaches 0 when the single-scattering albedos of the two regions in the heterogeneous phantoms become matched. Furthermore, a zone of detection has been demonstrated for determination of the thickness of the embedded region and optical parameters from the reflectance image profile and contrast. Therefore, the utility of the reflectance imaging method with visible and near-infrared light has been firmly established. We conclude from these results that the optical parameters of the embedded region can be determined inversely from reflectance images acquired with full-field illumination at multiple incident angles or multiple wavelengths.


Rates of carpal tunnel syndrome, epicondylitis, and rotator cuff claims in Ontario workers during 1997.
The primary objective of this research was the calculation of crude and specific rates of first-allowed, lost-time carpal tunnel syndrome (CTS), epicondylitis, and rotator cuff syndrome/tear (RCS/RCT) claims in Ontario workers during 1997. A secondary objective was to determine if results related to these diagnoses were consistent with findings for all cumulative trauma disorders affecting the specific part of upper extremity region. Rates were calculated by combining claim counts and population "at-risk" estimates derived from the Ontario Workplace Safety and Insurance Board databases and Canadian Labour Force Survey, respectively. The prevention index was used to prioritize occupations for intervention. Gender-specific rates declined as one moved proximally along the upper extremity. Similarly, female to male claim rate ratios declined from 1.61 for CTS to 0.47 for RCS/RCT. Frequently occurring highest rate and prevention index occupational categories across gender and diagnoses included "textiles, furs & leathergoods" and "other machining occupations". Diagnosis-specific findings were consistent with previously reported part of upper extremity findings.


Decoupling Geometrical and Kinematic Contributions to the Silo Clogging Process.
Based on the implementation of a novel silo discharge procedure, we are able to control the grains velocities regardless of the outlet size. This allows isolating the geometrical and kinematic contributions to the clogging process. We find that, for a given outlet size, reducing the grains velocities to extremely low values leads to a clogging probability increment of almost two orders of magnitude, hence revealing the importance of particle kinematics in the silo clogging process. Then, we explore the contribution of both variables, outlet size and grains velocity, and we find that our results agree with an already known exponential expression that relates clogging probability with outlet size. We propose a modification of such expression revealing that only two parameters are necessary to fit all the data: one is related with the geometry of the problem, and the other with the grains kinematics.


Ethics: problems of clinical conduct.
The study provides a framework for ethical medical conduct. A number of articles of International Law, the Italian Constitution, the Penal Code and the Medical Code of Conduct have therefore been taken into consideration. Art. 32 of the Italian Constitution, relating to the ''right to health'' is examined, paying particular attention to certain parts, and is related to Art. 35 of the European Union Charter of Fundamental Rights. In considering Art. 43 of the Penal Code, which addresses the psychological element of criminal acts, reference is made to the Medical Code of Conduct and to the Hippocratic Oath. The considerations made point up the importance of a relationship of trust and esteem between doctor and patient in clinical practice, and that this approach must be cultivated starting from the first year of university studies.


Mutualism is only a part of human morality.
Baumard et al. mischaracterize our model of individual and social choice behavior. We model individuals who maximize preferences given their beliefs, and subject to their informational and material constraints (Fehr & Gintis 2007). Individuals thus must make trade-offs among self-regarding, other-regarding, and character virtue goals. Two genetic predispositions are particularly crucial. The first is strong reciprocity. The second is the capacity to internalize norms through the socialization process. Our model includes the authors' model as a subset.


Calprotectin and neutrophil gelatinase-associated lipocalin in the differentiation of pre-renal and intrinsic acute kidney injury.
Urinary calprotectin has recently been identified as a promising biomarker for the differentiation of pre-renal and intrinsic acute kidney injury (AKI). This study compares the diagnostic performance of calprotectin and neutrophil gelatinase-associated lipocalin (NGAL) in this differential diagnosis. Urinary calprotectin and NGAL concentrations were assessed in a study population of 87 subjects including 38 cases of intrinsic AKI, 24 cases of pre-renal AKI and 25 healthy controls. Urinary tract obstruction, renal transplantation and metastatic cancer were defined as exclusion criteria. Mean calprotectin concentrations were significantly lower in pre-renal (190.2 ± 205.7 ng mL(-1) ) than in intrinsic AKI (6250.1 ± 7167.2 ng mL(-1) , P < 0.001). Receiver-operating characteristic (ROC) analysis provided an AUC of 0.99. Mean NGAL concentrations were significantly higher in intrinsic than in pre-renal AKI as well (458.1 ± 695.3 vs. 64.8 ± 62.1 ng mL(-1) , P = 0.001) providing an AUC of 0.82. A combination of the present study population with the cohort of the proof of concept study led to a population of 188 subjects (58 pre-renal AKI, 90 intrinsic AKI, 40 healthy controls). ROC analyses provided an AUC of 0.97 for calprotectin and 0.76 for NGAL yielding sensitivity and specificity values of 93.3 and 94.8% (calprotectin) vs. 75.3 and 72.4% (NGAL). Optimal cut-off values were 440 ng mL(-1) (calprotectin) and 52 ng mL(-1) (NGAL). Pyuria increased calprotectin concentrations independent of renal failure. This study shows that both calprotectin and NGAL are able to differentiate between pre-renal and intrinsic AKI after exclusion of pyuria. In the present population, calprotectin presents a higher sensitivity and specificity than NGAL.


Mindfulness-based Intervention for Perinatal Grief Education and Reduction among Poor Women in Chhattisgarh, India: a Pilot Study.
Stillbirth is a significant public health problem in low-to-middle-income countries and results in perinatal grief, often with negative psychosocial impact. In low-resource settings, such as Chhattisgarh, India, where needs are high, it is imperative to utilize low-cost, effective interventions. Mindfulness-based stress reduction (MBSR) is an empirically sound intervention that has been utilized for a broad range of physical and mental health problems, and is adaptable to specific populations. The main objective of this pilot study was to explore the feasibility and effectiveness of a shortened, culturally adapted mindfulness-based intervention to address complex grief after stillbirth. We used an observational, pre-post-6-week post study design. The study instrument was made up of descriptive demographic questions and validated scales and was administered as a structured interview due to low literacy rates. We used a community participatory approach to culturally adapt the five-week mindfulness-based intervention and delivered it through two trained local nurses. Quantitative and qualitative data analyses explored study outcomes as well as acceptability and feasibility of the intervention. 29 women with a history of stillbirth enrolled, completed the pretest and began the intervention; 26 completed the five-week intervention and post-test (89.7%), and 23 completed the six-week follow-up assessment (88.5%). Pretest results included elevated psychological symptoms and high levels of perinatal grief, including the active grief, difficulty coping, and despair subscales. General linear modeling repeated measures was used to explore posttest and six-week follow up changes from baseline, controlling for significantly correlated demographic variables. These longitudinal results included significant reduction in psychological symptoms; four of the five facets of mindfulness changed in the desired direction, two significantly; as well as significant reduction in overall perinatal grief and on each of the three subscales. The shortened, culturally adapted, mindfulness-based intervention pilot study was well received and had very low attrition. We also found significant reductions of perinatal grief and mental health symptoms over time, as well as a high degree of practice of mindfulness skills by participants. This study not only sheds light on the tremendous mental health needs among rural women of various castes who have experienced stillbirth in Chhattisgarh, it also points to a promising effective intervention with potential to be taken to scale for wider delivery.


tRNA engineering for manipulating genetic code.
In ribosomal translation, only 20 kinds of proteinogenic amino acids (pAAs), namely 19 l-amino acids and glycine, are exclusively incorporated into polypeptide chain. To overcome this limitation, various methods to introduce non-proteinogenic amino acids (npAAs) other than the 20 pAAs have been developed to date. However, the repertoire of amino acids that can be simultaneously introduced is still limited. Moreover, the efficiency of npAA incorporation is not always sufficient depending on their structures. Fidelity of translation is sometimes low due to misincorporation of competing pAAs and/or undesired translation termination. Here, we provide an overview of efforts to solve these issues, focusing on the engineering of tRNAs.


Influenza D Virus in Animal Species in Guangdong Province, Southern China.
Molecular tests revealed influenza D viruses of D/OK lineage widely circulating in farmed animal species in Guangdong Province, southern China. In particular, we found high levels of influenza D virus infection in goats and pigs. We also detected viral RNA in serum specimens and feces of animals with certain severe diseases.


Endothelin-1 and Nitric Oxide Levels in Exudative Age-Related Macular Degeneration.
To evaluate plasma levels of endothelin-1 (ET-1) and nitric oxide (NO) in patients with exudative age-related macular degeneration (AMD). In this study, ET-1 levels, as well as nitrite plus nitrate concentrations as an indicator of plasma NO level, were measured in the plasma of 20 subjects with exudative AMD and compared with 20 healthy age and sex matched controls. Mean plasma ET-1 level was significantly higher in exudative AMD patients as compared to control subjects (0.35 ± 0.06 fmol/ml versus 0.17 ± 0.03 fmol/ml, P = 0.015). Patients with exudative AMD also showed significantly lower mean plasma levels of nitrite plus nitrate as compared to the controls (58.9 ± 2.7 µmol/l versus 82.6 ± 5.9 µmol/l, P = 0.001). Increased concentrations of ET-1 and reduced levels of NO in the plasma may suggest an imbalance between vasoconstrictor and vasodilator agents, respectively, as a reflection of endothelial dysfunction in the pathogenesis of AMD. These findings may also imply the role of vasoconstriction in exudative AMD.


Influence of the retinoid acitretin on erythrocyte microrheology in vitro.
To determine in vitro changes in the microrheology of red blood cells (RBCs) treated with acitretin (Ro 10-1670). Venous blood samples were obtained from 27 healthy donors. Washed erythrocytes (5 x 10(6) cells/ml) were incubated for 30 min at 37 degrees C in solutions of low (25 ng/ml) and high (400 ng/ml) acitretin concentration. The whole red cell deformability was measured using osmotic gradient ektacytometry. To assess the contribution of factors influencing changes in red cell deformability, the biophysical state of the phospholipid bilayer was determined using the cation osmotic hemolysis technique (COH) and the internal viscosity using electron paramagnetic resonance (EPR) spectroscopy. Osmotic deformability studies revealed that cells treated with acitretin at low concentration deformed almost normally in isotonic medium, but RBCs incubated with high acitretin concentration showed distinct loss of deformation. However, in hypotonic medium, cell deformability was reduced to abnormally low values and this change was most marked with high acitretin concentration. CHO measurements showed that incubation of red cells at low acitretin concentration caused a significant increase in hemolysis at ionic strengths from 123.2 - 154.0 mmol/1 NaCl in relation to the control (p < 0.001). A high concentration of acitretin caused a significant increase in COH with high ionic strengths in the range 107.8 - 154.0 mmol/l NaCl (p < 0.001) and at low ionic strengths in the range 15.4 mmol/l NaCl (p < 0.05). The measurement of RBC intracellular microviscosity showed no statistically significant differences between control (6.22+/-0.22 cP) and acitretin-treated (6.29+/-0.25 cP) cells. The data show that acitretin, even at low concentration, is capable of inducing the reduction of red cell deformability. A reduced tendency of acitretin-treated RBCs to deform might result from the ability of acitretin to perturb the cell shape and membrane viscoelastic properties.


Antidepressant-Like Effects of Chronic Guanosine in the Olfactory Bulbectomy Mouse Model.
Major depressive disorder (MDD) leads to pervasive changes in the health of afflicted patients. Despite advances in the understanding of MDD and its treatment, profound innovation is needed to develop fast-onset antidepressants with higher effectiveness. When acutely administered, the endogenous nucleoside guanosine (GUO) shows fast-onset antidepressant-like effects in several mouse models, including the olfactory bulbectomy (OBX) rodent model. OBX is advocated to possess translational value and be suitable to assess the time course of depressive-like behavior in rodents. This study aimed at investigating the long-term behavioral and neurochemical effects of GUO in a mouse model of depression induced by bilateral bulbectomy (OBX). Mice were submitted to OBX and, after 14 days of recovery, received daily (ip) administration of 7.5 mg/kg GUO or 40 mg/kg imipramine (IMI) for 45 days. GUO and IMI reversed the OBX-induced hyperlocomotion and recognition memory impairment, hippocampal BDNF increase, and redox imbalance (ROS, NO, and GSH levels). GUO also mitigated the OBX-induced hippocampal neuroinflammation (IL-1, IL-6, TNF-α, INF-γ, and IL-10). Brain microPET imaging ([18F]FDG) shows that GUO also prevented the OBX-induced increase in hippocampal FDG metabolism. These results provide additional evidence for GUO antidepressant-like effects, associated with beneficial neurochemical outcomes relevant to counteract depression.


Health interview surveys in developing countries: a review of the methods and results.
Health interview surveys are carried out to gain knowledge of people's perceived morbidity, their use of different kinds of health services, and their perceived need for health care. Many of such studies in less developed countries (LDCs) have failed to consider the methodological improvements which have been developed in health care research in recent years. In the first part of this paper the research on methodological issues is summarized and the inherent problems in health interview surveys are stressed. Some specific requirements for cross-cultural research are described. The second part deals with health interview surveys carried out on a national, provincial and local level in LDCs. Recommendations for a standardization of the methodology are given.


Compression Stockings for Prevention of Postthrombotic Syndrome: A Systematic Review and Meta-Analysis.
The present meta-analysis aimed to evaluate the efficacy and safety of compression stockings for postthrombotic syndrome (PTS) prevention in patients with deep venous thrombosis (DVT). Randomized controlled trials (RCTs) regarding the use of compression stockings for prevention of PTS were identified from the Medline, PubMed, and Embase databases as well as the Cochrane library. The resulting manuscripts were analyzed according to the criteria in the Cochrane Handbook for Systematic Reviews of Interventions. Six RCTs involving 1465 patients with DVT were included. The meta-analysis indicated no statistical differences between the compression stocking and the control groups in PTS incidence, using either the Villalta scale (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.23-1.74) or the Ginsberg scale (OR, 1.13; 95% CI, 0.72-1.77). Based on the Villalta scale categorization, there were no differences in the incidence of mild-moderate PTS (OR, 0.71; 95% CI, 0.36-1.41) or incidence of severe PTS (OR, 0.68; 95% CI, 0.15-3.11). The difference in the recurrence of venous thromboembolism (OR, 0.89; 95% CI, 0.61-1.30) was also not significant. In the 3 RCTs that reported side effects of compression stockings, they were primarily related to discomfort, including itching, erythema, and rash. The present meta-analysis has indicated that compression stockings may not prevent PTS, as determined by either the Villalta or the Ginsberg scale, in patients with DVT. However, owing to the limited number of trials, the evidence is not strong enough to draw a reliable conclusion. Further larger, randomized, double-blind, placebo-controlled, multicenter trials are needed.


Persistence of the 2009 pandemic influenza A (H1N1) virus on N95 respirators.
In the United States, the 2009 pandemic influenza A (H1N1) virus (pH1N1) infected almost 20% of the population and caused >200,000 hospitalizations and >10,000 deaths from April 2009 to April 2010. On 24 April 2009, the CDC posted interim guidance on infection control measures in health care settings explicitly for pH1N1 and recommended using filtering face respirators (FFRs) when in close contact with a suspected- or confirmed-to-be-infected individual, particularly when performing aerosol-generating procedures. The persistence and infectivity of pH1N1 were evaluated on FFRs, specifically N95 respirators, under various conditions of absolute humidity (AH) (4.1 × 10(5) mPa, 6.5 × 10(5) mPa, and 14.6 × 10(5) mPa), sample matrices (2% fetal bovine serum [FBS], 5 mg/ml mucin, and viral medium), and times (4, 12, 24, 48, 72, and 144 h). pH1N1 was distributed onto N95 coupons (3.8 to 4.2 cm(2)) and extracted by a vortex-centrifugation-filtration process, and the ability of the remaining virus to replicate was quantified using an enzyme-linked immunosorbent assay (ELISA) to determine the log10 concentration of the infectious virus per coupon. Overall, pH1N1 remained infectious for 6 days, with an approximately 1-log10 loss of virus concentrations over this time period. Time and AH both affected virus survival. We found significantly higher (P ≤ 0.01) reductions in virus concentrations at time points beyond 24 to 72 h (-0.52-log10 reduction) and 144 h (-0.74) at AHs of 6.5 × 10(5) mPa (-0.53) and 14.6 × 10(5) mPa (-0.47). This research supports discarding respirators after close contact with a person with suspected or confirmed influenza infection due to the virus's demonstrated ability to persist and remain infectious.


Monitoring of bacterial drug response by mass spectrometry of single cells.
The application of the laser microprobe mass analyser LAMMA 500 to the solution of problems in the field of microbiology is reported. The special features of this instrument allow the analysis of single bacterial cells, and questions can be answered which are not accessible to the normally applied integral methods. Thus it is possible to establish distributions of, for instance, elemental concentrations within a bacterial population and of correlations between measured characteristics of a bacterium with its morphology. The mass spectrum of a single bacterial cell comprises information on its intracellular cation contents as well as on the organic matrix. The relation between the sodium and potassium contents can serve as a criterion of the physiological state of a cell and of its viability. The information from the organic matrix can be extracted from the complex spectra of fragment ions produced by the interaction of the laser with the cell by applying multivariate data analysis, thus rendering additional information. Examples will be given for in vitro drug screening and in vivo therapy control in leprosy, an infection which is caused by a mycobacterial species, Mycobacterium leprae; this organism does not multiply in artificial growth media so that only limited numbers of organisms are available for microbiological investigations.


Antihypertensive effect of nicardipine hydrochloride in essential hypertension.
The antihypertensive effect of a new calcium antagonist, nicardipine hydrochloride (YC-93), was studied in 47 mild to moderate essential hypertensives. YC-93 (30-60 mg/day) was administered orally alone for 8 weeks (Group I, 31 patients) or in combination with diuretics, beta blockers, or both (Group II, 16 patients). Blood pressure was reduced from 173.6 +/- 2.2/103.5 +/- 1.7 to 139.7 +/- 2.0/87.2 +/- 1.1 mmHg in Group I and from 172.9 +/- 3.9/108.9 +/- 2.9 to 140.5 +/- 2.3/89.5 +/- 2.5 mm Hg in Group II. Pulse rate was not altered in Group I but increased transiently in Group II. The side effects seen in seven patients were mostly related to the vasodilatation and were generally transient and mild. These results indicate that YC-93 is an effective antihypertensive drug for the treatment of essential hypertension.


Diacetato-kappa2O-bis[(S)-1-(4-fluorophenyl)ethylamine-kappaN]palladium(II) and di-mu-acetato-kappa4O:O'-bis[[(S)-2-(1-aminoethyl)-5-fluorophenyl-kappa2C1,N]palladium(II)] benzene hemisolvate.
Complexes of the composition trans-[Pd(L)2(OAc)2] have been postulated as intermediates during cyclopalladation. The first structural characterization of such a precursor has now been achieved and its role in the reaction sequence has been established. Diacetato-kappa2O-bis[(S)-1-(4-fluorophenyl)ethylamine-kappaN]palladium(II), [Pd(O2CMe)2(4-FC6H3CHMeNH2)2] or [Pd(C2H3O2)2(C8H10FN)2], (I), was obtained from palladium(II) acetate and (S)-NH2CHMeC6H3F-4 in a 1:2 molar ratio. The intermediate was then reacted with additional palladium(II) acetate to give the acetate-bridged dinuclear complex di-mu-acetato-kappa4O:O'-bis[[(S)-2-(1-aminoethyl)-5-fluorophenyl-kappa2C1,N]palladium(II)] benzene hemisolvate, [Pd(4-FC6H3CHMeNH2)2(mu-O2CMe)]2.0.5C6H6 or [Pd2(C8H9FN)2(C2H3O2)2].0.5C6H6, (II).


Separation of neutral glycosphingolipids and sulfatides by thin-layer chromatography.
Two one-dimensional systems for separation of glycolipids from total lipid extracts of tissues by thin-layer chromatography are described. System I used, as adsorbent, an alkaline mixture of silica gel without CaSO(4) binder (75%) and magnesium silicate (25%), and the lipids were "developed" with three successive solvent mixtures. The separated compounds (from the fastest to the slowest moving) were: ceramide, ceramide monohexosides, sulfatides, ceramide dihexosides, psychosine, ceramide trihexosides, and ceramide N-acetylhexosamine trihexosides. In system II a two-step development was used on an adsorbent consisting of silica gel without CaSO(4) binder (80%) and magnesium silicate (20%). The separated compounds were: ceramides, ceramide monohexosides, and ceramide dihexosides. Psychosine and sulfatides as well as ceramide trihexosides and ceramide N-acetylhexosamine trihexosides were not separated. In both systems all neutral lipids moved to the very top of the chromatogram and phospholipids stayed at the origin. Application of systems I and II for separation of glycolipids was demonstrated on total lipid extracts from animal tissues.


The mid-thigh loop arteriovenous graft: patient selection, technique, and results.
As patient longevity on hemodialysis has increased, surgeons are increasingly challenged to provide vascular access to patients who have exhausted options for access in the upper extremity. A common operation performed on these patients has been the loop thigh arteriovenous (AV) graft based off the common femoral vessels. However, there are several disadvantages of placing prosthetic grafts in proximity to the groin. Our group has modified the thigh loop AV graft procedure by moving the anastomoses to the mid-superficial femoral artery and vein. The advantage of this location is that it preserves the proximal femoral vessels for graft revision and avoids the node-bearing tissue and overhanging panniculus of the groin. The purpose of this study was to review our technique, patient selection, and experience with the mid-thigh loop AV graft procedure. Between 2001 and 2003, 46 mid-thigh loop AV grafts were placed in 38 patients. Patient hospital, office, and dialysis clinic records were reviewed. The primary and secondary patency for AV grafts in this study by life-table was 40 per cent and 68 per cent at 1 year and 18 per cent and 43 per cent at 2 years. There were 10 infections (21%) requiring graft removal. Four patients underwent subsequent placement of a proximal loop thigh AV graft after mid-thigh graft failure. Patient survival was 86 per cent at 1 year and 82 per cent at 2 years. There were no patient deaths related to thigh graft placement. Our results with the mid-thigh loop AV graft compare favorably with published results for thigh loop AV grafts. The procedure preserves the proximal vasculature, permitting graft revision or subsequent proximal graft placement, and may be associated with fewer infectious complications. The mid-thigh loop AV graft procedure should be considered before placement of a thigh loop AV graft based off the common femoral artery and vein.


Prevalence of fetal exposure to cocaine in Toronto, 1990-1991.
There has been an increasing use of cocaine in North America among women of reproductive age. The potential effects of cocaine on the fetus have raised serious concerns about the health of large numbers of children exposed in utero to the drug. Using neonatal hair and urine tests for benzoylegconine (BE), we quantified the incidence of fetal exposure to cocaine among 600 babies born in 3 nurseries in Toronto from 1990-91. A total of 37 babies (6.25%) tested positive for cocaine exposure by either hair test, urine test, or both. The hair test detected 33 cases and failed to identify 4 babies who had low urine concentrations of BE. The urine test failed to identify 76% of the cases. In downtown Toronto, the overall rate of fetal exposure to cocaine was 12.5% (25/200), significantly higher than in the 2 suburban nurseries (3%; 12/400). Babies are born with hair which has grown during the last trimester of pregnancy; hence, our analysis identifies women who have used cocaine long after they became aware of pregnancy. Our figures translate to more than 5,000 babies annually in the greater Toronto area who are cared for postnatally by mothers regularly using cocaine. Because history and urine testing during delivery fail to identify the majority of these cases, most of these children are not likely to receive the appropriate medical and social services and follow-up.


Multidrug-resistant tuberculosis in the Northern Territory: A 10-year retrospective case series.
To describe the clinical characteristics, risk factors, diagnostic modalities, treatments, subsequent outcomes and complications of Multidrug-resistant tuberculosis (MDR-TB) cases residing in the Northern Territory. A retrospective case series was conducted of all patients treated for MDR-TB in the Northern Territory between 1 January 2004 and 31 December 2013. This is the first study to analyse data relating to the subset of MDR-TB cases treated in the Northern Territory. Cases were identified by the Northern Territory Centre for Disease Control (NT CDC): the public health unit responsible for the management of tuberculosis in the Northern Territory. Outcome measures included patient demographics, diagnostics, HIV status, treatment methods, outcomes, and complications. Six MDR-TB cases were treated in the Northern Territory; 5 of these were notified by the NT CDC during the study period (1.5% of all Northern Territory TB notifications). The median age of all 6 patients was 31 years (range 21 to 50 years), sex distribution was equal and all were born overseas. Country of birth in a World Health Organization (WHO) high burden MDR-TB country and previous treatment were most highly correlated with a current diagnosis of MDR-TB. Access to rapid drug susceptibility testing reduced the time to effective therapy from 45 to 27 days. Five patients met criteria for the WHO outcome term 'treatment success'. The median length of treatment for the 5 patients treated in Australia was 623 days (537 to 730 days). Side effects to therapy were common and serious. The incidence of MDR-TB in the Northern Territory is similar to other Australian states. Rapid drug susceptibility testing reduces the time to effective therapy. Treatment regimens are complex, toxic and have serious resource implications for health care providers. Successful treatment outcomes are possible with coordinated TB control programs. Commun Dis Intell 2016;40(3):E334-E339.


Giant lipoma in the index finger of the dominant hand of a swimmer: A case report.
Lipoma is a very common benign tumor that occurs in areas of adipose tissue and is commonly found on the whole body, although its occurrence in the hand and finger is rare. Giant lipoma, defined as over 5 cm long in diameter, is a rare benign tumor of abundant soft tissue in the finger. A 24-year-old male patient presented with a giant lipoma on the volar aspect of the index finger of his right hand. Magnetic resonance imaging (MRI) showed an encased multilobulated mass that measured 7.1x1.2x2.3 cm, and histopathological examination revealed lipoma without malignant transformation. Surgical resection of the tumor with a longitudinal and zig-zag incision of the palm was performed exposing the mass surrounding the palmar digital branch of the median nerve. The mass was completely removed, and neurorrhaphy was performed via the microscope to repair the damaged neurovascular bundle. At four months of postoperative follow-up, the patient was completely recovered with no finger paresthesia or limitation of range of motion. As a professional swimmer, the patient has experienced no subsequent difficulty in swimming due to his finger.


Exploring the intensity, distribution and evolution of teleconnections using climate network analysis.
Teleconnections refer to long-range climate system linkages occurring over typically thousands of kilometers. Generally speaking, most teleconnections are attributed to the transmission of energy and propagation of waves although the physical complexity and characteristics behind these waves are not fully understood. To address this knowledge gap, we develop a climate network-based approach to reveal their directions and distribution patterns, evaluate the intensity of teleconnections, and identify sensitive regions using global daily surface air temperature data. Our results reveal a stable average intensity distribution pattern for teleconnections across a substantial spatiotemporal scale from 1948 to 2021, with the extent and intensity of teleconnection impacts increasing more prominently in the Southern Hemisphere over the past 37 years. Furthermore, we pinpoint climate-sensitive regions, such as southeastern Australia, which are likely to face increasing impacts due to global warming. Our proposed method offers new insights into the dynamics of global climate patterns and can inform strategies to address climate change and extreme events.


Recent Advances in Co3O4-Based Composites: Synthesis and Application in Combustion of Methane.
In recent years, it has been found that adjusting the organizational structure of Co3O4 through solid solution and other methods can effectively improve its catalytic performance for the oxidation of low concentration methane. Its catalytic activity is close to that of metal Pd, which is expected to replace costly noble metal catalysts. Therefore, the in-depth research on the mechanism and methods of Co3O4 microstructure regulation has very important academic value and economic benefits. In this paper, we reviewed the catalytic oxidation mechanism, microstructure regulation mechanism, and methods of nano-Co3O4 on methane gas, which provides reference for the development of high-activity Co3O4-based methane combustion catalysts. Through literature investigation, it is found that the surface energy state of nano-Co3O4 can be adjusted by loading of noble metals, resulting in the reduction of Co-O bond strength, thus accelerating the formation of reactive oxygen species chemical bonds, and improving its catalytic effect. Secondly, the use of metal oxides and non-metallic oxide carriers helps to disperse and stabilize cobalt ions, improve the structural elasticity of Co3O4, and ultimately improve its catalytic performance. In addition, the performance of the catalyst can be improved by adjusting the microstructure of the composite catalyst and optimizing the preparation process. In this review, we summarize the catalytic mechanism and microstructure regulation of nano-Co3O4 and its composite catalysts (embedded with noble metals or combined with metallic and nonmetallic oxides) for methane combustion. Notably, this review delves into the substance of measures that can be used to improve the catalytic performance of Co3O4, highlighting the constructive role of components in composite catalysts that can improve the catalytic capacity of Co3O4. Firstly, the research status of Co3O4 composite catalyst is reviewed in this paper. It is hoped that relevant researchers can get inspiration from this paper and develop high-activity Co3O4-based methane combustion catalyst.


A Joint Bayesian Model for Integrating Microarray and RNA Sequencing Transcriptomic Data.
As the sequencing cost continued to drop in the past decade, RNA sequencing (RNA-seq) has replaced microarray to become the standard high-throughput experimental tool to analyze transcriptomic profile. As more and more datasets are generated and accumulated in the public domain, meta-analysis to combine multiple transcriptomic studies to increase statistical power has received increasing popularity. In this article, we propose a Bayesian hierarchical model to jointly integrate microarray and RNA-seq studies. Since systematic fold change differences across RNA-seq and microarray for detecting differentially expressed genes have been previously reported, we replicated this finding in several real datasets and showed that incorporation of a normalization procedure to account for the bias improves the detection accuracy and power. We compared our method with the popular two-stage Fisher's method using simulations and two real applications in a histological subtype (invasive lobular carcinoma) of breast cancer comparing PR+ versus PR- and early-stage versus late-stage patients. The result showed improved detection power and more significant and interpretable pathways enriched in the detected biomarkers from the proposed Bayesian model.


A single N1-methyladenosine on the large ribosomal subunit rRNA impacts locally its structure and the translation of key metabolic enzymes.
The entire chemical modification repertoire of yeast ribosomal RNAs and the enzymes responsible for it have recently been identified. Nonetheless, in most cases the precise roles played by these chemical modifications in ribosome structure, function and regulation remain totally unclear. Previously, we demonstrated that yeast Rrp8 methylates m1A645 of 25S rRNA in yeast. Here, using mung bean nuclease protection assays in combination with quantitative RP-HPLC and primer extension, we report that 25S/28S rRNA of S. pombe, C. albicans and humans also contain a single m1A methylation in the helix 25.1. We characterized nucleomethylin (NML) as a human homolog of yeast Rrp8 and demonstrate that NML catalyzes the m1A1322 methylation of 28S rRNA in humans. Our in vivo structural probing of 25S rRNA, using both DMS and SHAPE, revealed that the loss of the Rrp8-catalyzed m1A modification alters the conformation of domain I of yeast 25S rRNA causing translation initiation defects detectable as halfmers formation, likely because of incompetent loading of 60S on the 43S-preinitiation complex. Quantitative proteomic analysis of the yeast Δrrp8 mutant strain using 2D-DIGE, revealed that loss of m1A645 impacts production of specific set of proteins involved in carbohydrate metabolism, translation and ribosome synthesis. In mouse, NML has been characterized as a metabolic disease-associated gene linked to obesity. Our findings in yeast also point to a role of Rrp8 in primary metabolism. In conclusion, the m1A modification is crucial for maintaining an optimal 60S conformation, which in turn is important for regulating the production of key metabolic enzymes.


Effect of 2-deoxy-D-glucose on maintenance in culture of neonatal B cell of rat.
The effect of 2-deoxy-D-glucose on maintenance in culture of B cells of the neonatal rat was examined by supplementation of Medium 199 containing 5.5 mM glucose with 1 mM 2-deoxy-D-glucose. Islets maintained in medium with 5.5 mM glucose (basal medium) for 7 d underwent remarkable decreases in glucose sensitivity, and the levels of insulin in the medium dropped. By contrast, addition of 2-deoxy-D-glucose promoted a higher insulin content in medium and an increase in the glucose-induced insulin release and biosynthesis. Moreover, the addition of the deoxysugar caused a selective deletion of fibroblasts and prevented the deterioration of islet cells in basal medium, yielding clusters mostly consisting of islet cells at the end of culture.


Evaluation of Mansonia spp. Infestation on Aquatic Plants in Lentic and Lotic Environments of the Madeira River Basin in Porto Velho, Rondônia, Brazil.
The females of Mansonia are voraciously hematophagous. The spiracular apparatus of the immature, larval, and pupal forms is adapted to perforate submerged aquatic vegetation, from whose aeriferous aerenchyma they obtain the oxygen necessary for breathing. The proliferation of aquatic plants, in some cases linked to anthropic modifications that reduce water flow and/or increase organic matter content, may therefore contribute to the spread of these mosquitoes. This study aims to assess the presence of immature individuals of Mansonia in different aquatic plants of the Madeira River basin in 10 lentic and lotic environments and correlate their population density with abiotic factors such as water pH, dissolved O2, conductivity, and temperature. The sampling lasted from February 2016 to June 2018, a 29-month period during which 31,287 specimens belonging to the genus Mansonia were captured. Of the 12 species of macrophytes inspected, Eichhornia crassipes made up 70.1% of the samples. Lentic environments accounted for 58.9% of the samples and lotic environments for 41.1%. Immature individuals were most commonly found on Eichhornia crassipes, with this plant accounting for an average of 96.2% of all individuals, with a percentage ranging between 58.2% and 77.1% in different breeding areas. Only at the Foz do Igarapé Jirau site was a different distribution observed, with the number of aquatic plants more nearly equal: 83.3% of the larvae were found in Eichhornia crassipes, 9.2% in Ceratopteris pteridoides, 3.6% in E. azurea, 2.0% in Salvinia sp., and 1.9% in Pistia sp. The greatest richness was found in Iguapé do Raul. Concerning the larval/plant relationship, although less frequent, E. azurea had a higher larval density of Mansonia spp. It is important to emphasize that this finding may indicate a possible selection for this plant. Egg deposition by Mansonia spp. was more abundant in sample areas with Eichhornia crassipes and Pistia sp. The number of specimens collected was positively correlated with temperature, pH, and conductivity. These correlations showed a marked increase in the rainy season. Therefore, we were able to establish preliminary parameters of how environmental changes influence the ecology of this important genus of mosquitoes, the species of which are critical disease vectors.


One-Step Synthesis of Polypyrrole-Coated Gold Nanoparticles for Use as a Photothermally Active Nano-System.
This paper introduces a simple one-step and ultra-fast method for synthesis of highly photothermally active polypyrrole-coated gold nanoparticles. The synthesis process is so simple that the reaction is very fast without the need for any additives or complicated steps. Polypyrrole-coated gold nanoparticles (AuPpy NPs) were synthesized by reacting chloroauric acid (HAuCl4) with pyrrole (monomer) in aqueous medium at room temperature. These nanoparticles were characterized by UV-visible-NIR spectrometry, transmission electron microscopy (TEM), AC conductivity, zeta sizer and were evaluated for dark cytotoxicity and photocytotoxicity using human hepatocellular carcinoma (HepG2) cell line as a model for cancer cells. The synthesized AuPpy NPs showed a peak characteristic for gold nanoparticles (530-600 nm, molar ratio dependent) and a wide absorption band along the visible-NIR region with intensity about triple or even quadruple that of polypyrrole synthesized by the conventional FeCl3 method at the same concentration and under the same conditions. TEM imaging showed that the synthesized AuPpy NPs were composed of spherical or semi-spherical gold core(s) of about 4-10 nm coated with distinct layer(s) of polypyrrole seen either loosely or in clusters. Mean sizes of the synthesized nanoparticles range between ~25 and 220 nm (molar ratio dependent). Zeta potentials of the AuPpy NPs preparations indicate their good colloidal stability. AC conductivity values of AuPpy NPs highly surpass that of Ppy prepared by the conventional FeCl3 method. AuPpy NPs were non-toxic even at high concentrations (up to 1000 µM pyrrole monomer equivalent) under dark conditions. Unlikely, light activated the photothermal activity of AuPpy NPs in a dose-dependent manner. This method simply and successfully synthesized AuPpy NPs nanoparticles that represent a safe alternative photothermally active multifunctional tool instead of highly toxic and non-biodegradable gold nanorods.


MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number.
MeCP2 is a transcriptional repressor critical for normal neurological function. Prior studies demonstrated that either loss or doubling of MeCP2 results in postnatal neurodevelopmental disorders. To understand the impact of MeCP2 expression on neuronal function, we studied the synaptic properties of individual neurons from mice that either lack or express twice the normal levels of MeCP2. Hippocampal glutamatergic neurons that lack MeCP2 display a 46% reduction in synaptic response, whereas neurons with doubling of MeCP2 exhibit a 2-fold enhancement in synaptic response. Further analysis shows that these changes were primarily due to the number of synapses formed. These results reveal that MeCP2 is a key rate-limiting factor in regulating glutamatergic synapse formation in early postnatal development and that changes in excitatory synaptic strength may underlie global network alterations in neurological disorders due to altered MeCP2 levels.