Transforming growth factor-beta1 gene and protein expression associated with atherogenesis of cholesterol-fed rabbits.
Transforming growth factor-beta1 (TGF-1beta) has been shown to modulate both cell proliferation and the synthesis of extracellular matrix by vascular cells. This study was aimed to establish the temporal correlation between TGF-beta1 expression, the expression of the extracellular matrix protein fibronectin, and plaque development during atherogenesis of hypercholesterolemic rabbits. New Zealand White rabbits were fed with 2% cholesterol-supplemented chow for 1 week, 2 weeks, 3 weeks or 6 weeks. TGF-beta1 mRNA and protein expression was examined in serial sections of aorta by in situ hybridization and immunohistochemistry. Fibronectin expression was examined by immunohistochemistry. In the control and 1-week feeding group, the expression of TGF-beta1 mRNA and protein was not apparent. In 2-week feeding group, intimal thickening was detected in which TGF-beta1 mRNA and protein were not clearly observed, either. The 3-week and 6-week feeding groups exhibited fatty streaks in which TGF-beta1 mRNA and protein expression markedly increased as feeding proceeded. Cell type-specific staining indicated that TGF-beta1 was expressed by macrophages as well as smooth muscle cells of the fatty streaks. Immunostaining of fibronectin detected low expression levels in control, 1-week and 2-week feeding groups with pronounced upregulation in the thickened intima and the proximal media in 3-week and 6-week feeding groups. These results implicate a role for TGF-beta1 in modulating fatty streak formation and the synthesis of extracellular protein fibronectin during plaque development.


Ultraviolet-induced in situ gold nanoparticles for point-of-care testing of infectious diseases in loop-mediated isothermal amplification.
The present study investigated ultraviolet-induced in situ gold nanoparticles (AuNPs) coupled with loop-mediated isothermal amplification (LAMP) for the point-of-care testing (POCT) of two major infectious pathogens, namely, Coronavirus (COVID-19) and Enterococcus faecium (E. faecium spp.). In the process, gold ions in a gold chloride (HAuCl4) solution were reduced using trisodium citrate (Na3Ct), a reducing agent, and upon UV illumination, red-colored AuNPs were produced in the presence of LAMP amplicons. The nitrogenous bases of the target deoxyribonucleic acid (DNA) acted as a physical support for capturing gold ions dissolved in the sample. The high affinity of gold with the nitrogenous bases enabled facile detection within 10 min, and the detection limit of COVID-19 plasmid DNA was as low as 42 fg μL-1. To ensure POCT, we designed a portable device that contained arrays of reagent chambers and detection chambers. In the portable device, colorimetric reagents such as HAuCl4 and Na3Ct were contained in the reagent chambers; these reagents were subsequently transferred to the detection chambers where LAMP amplicons were present and thus allowed convenient sample delivery and multiplex detection. Owing to the high sensitivity of the in situ AuNPs, simplicity of portable device fabrication, and rapid colorimetric detection, we strongly believe that the fabricated portable device could serve as a kit for rapid POCT for instantaneous detection of infectious diseases, and could be readily usable at the bedside.


[Posterior exenteration with plastic reconstruction in advanced vulvar cancer].
Between 1984 and 1990, twenty-four patients suffering from advanced primary (7) or recurrent (17) valvular carcinoma were treated by posterior exenteration and myocutaneous reconstruction of the defect. During a follow-up of 34 months, the overall survival was 49%. Eight patients died. Tumour diameter and tumour-free margins of the resected specimens were the most important prognostic factors. In all cases, an improved quality of life could be achieved by the operation. It is concluded that, even in extremely difficult situations, posterior exenteration, followed by plastic reconstruction entails an essential benefit for the patient.


[The possibility of registering in the Spanish Civil Registry children born abroad from surrogate mothers].
In the Spanish Civil Registry it is now possible to register "natural" children of a homosexual marriage born overseas through surrogate pregnancy. And this is despite article 10.1 of the current Spanish law regarding assisted human reproduction techniques, which declares fully null and void contracts renouncing maternal relationship, and orders imperatively that in these cases, the relationship of children is determined by birth. This article analyses and formulates a criticism regarding the Resolution of the Office of Registries and Notaries, of February 18, 2009, insisting on some relevant issues such as legal security and greater interest of the minor, in the context of the analysis of the facts of the case and the arguments put forward in the resolution.


Species specific immunoassays to measure blood platelet and coagulation activation in the rat.
The purpose of this study was to develop specific and sensitive immunoassays to detect early indices of hypercoagulability in the rat. Rat platelet factor 4 (rPF4) and rat fibrinopeptide A (rFPA) assays, tools for the detection of activation of platelets and coagulation respectively, were designed using antibodies raised against purified rPF4 and against synthetic rFPA. The relevance of these new assays and of the commercially available ELISA kit for thrombin-antithrombin III (TAT) complexes was demonstrated in a rat model of a prethrombotic state induced by intravenous infusion of varying doses of thrombo-plastin (90 to 2400 microliters/kg/h). In this model, the immunoassays allowed simultaneous detection of low levels of rFPA and rPF4 which were correlated with fibrinogen and platelet consumption and TAT generation and further proved to be of higher sensitivity than the classical methods of platelet count or measurement of fibrinogen levels. Plasma concentrations of rFPA, rPF4 and TAT were dependent on infusion time and thromboplastin dose, while hirudin (1 mg/kg) prevented their appearance. Thus the new specific immunoassays for rPF4 and rFPA and the commercial human TAT assay represent useful tools for pathophysiological studies or the screening of antithrombotic drugs in rats.


Honeybee drones are attracted by groups of consexuals in a walking simulator.
During the mating season, honeybee males, the drones, gather in congregation areas 10-40 m above ground. When a receptive female, a queen, enters the congregation, drones are attracted to her by queen-produced pheromones and visual cues and attempt to mate with the queen in mid-air. It is still unclear how drones and queens find the congregations. Visual cues on the horizon are most probably used for long-range orientation. For shorter-range orientation, however, attraction by a drone-produced aggregation pheromone has been proposed, yet so far its existence has not been confirmed conclusively. The low accessibility of congregation areas high up in the air is a major hurdle and precise control of experimental conditions often remains unsatisfactory in field studies. Here, we used a locomotion compensator-based walking simulator to investigate drones' innate odor preferences under controlled laboratory conditions. We tested behavioral responses of drones to 9-oxo-2-decenoic acid (9-ODA), the major queen-produced sexual attractant, and to queen mandibular pheromone (QMP), an artificial blend of 9-ODA and several other queen-derived components. While 9-ODA strongly dominates the odor bouquet of virgin queens, QMP rather resembles the bouquet of mated queens. In our assay, drones were attracted by 9-ODA, but not by QMP. We also investigated the potential attractiveness of male-derived odors by testing drones' orientation responses to the odor bouquet of groups of 10 living drones or workers. Our results demonstrate that honeybee drones are attracted by groups of other drones (but not by workers), which may indicate a role of drone-emitted cues for the formation of congregations.


Electro-oxidation of ethanol and acetaldehyde on platinum single-crystal electrodes.
The electrochemical oxidation of ethanol and acetaldehyde in sulfuric acid and perchloric acid were studied at Pt (111), Pt (110), and a number of Pt [n(l11)x(111)] single-crystal electrodes. The oxidation of ethanol shows a marked dependence on the surface structure, roughly increasing as the surface step density increases. The oxidation of acetaldehyde shows a reversed correlation, the activity decreasing with increasing step density. Based on the results obtained here and reported earlier in electrochemical and ultrahigh vacuum literature, a detailed reaction scheme for the ethanol oxidation mechanism is suggested.


Development of a Composite Primary Outcome Score for Children with Attention-Deficit/Hyperactivity Disorder and Emotional Dysregulation.
Objective: Study goals were to (1) provide a rationale for developing a composite primary outcome score that includes symptom severity for attention-deficit/hyperactivity disorder (ADHD) and emotional dysregulation, plus symptom-induced impairment; (2) demonstrate weighting methods to calculate the composite score using a sample of children diagnosed with ADHD and aggression; and (3) identify the optimal weighting method most sensitive to change, as measured by effect sizes. Methods: We conducted secondary data analyses from the previously conducted Treatment of Severe Childhood Aggression (TOSCA) study. Children aged 6-12 years were recruited through academic medical centers or community referrals. The composite primary outcome comprised the ADHD, oppositional defiant disorder, disruptive mood dysregulation disorder, and peer conflict subscales from the Child and Adolescent Symptom Inventory (CASI), a DSM (Diagnostic and Statistical Manual)-referenced rating scale of symptom severity and symptom-induced impairment. Five weighting methods were tested based on input from senior statisticians. Results: The composite score demonstrated a larger (Cohen's d) effect size than the individual CASI subscales, irrespective of the weighting method (10%-55% larger). Across all weighting methods, effect sizes were similar and substantial: approximately a two-standard deviation symptom reduction (range: -1.97 to -2.04), highest for equal item and equal subscale weighting, was demonstrated, from baseline to week 9, among all TOSCA participants. The composite score showed a medium positive correlation with the Clinical Global Impressions-Severity scores, 0.46-0.47 for all weighting methods. Conclusions: A composite score that included severity and impairment ratings of ADHD and emotional dysregulation demonstrated a more robust pre-post change than individual subscales. This composite may be a more useful indicator of clinically relevant improvement in heterogeneous samples with ADHD than single subscales, avoiding some of the statistical limitations associated with multiple comparisons. Among the five similar weighting methods, the two best appear to be the equal item and equal subscale weighting methods.


Nanoliposome improves inhibitory effects of naringenin on nonalcoholic fatty liver disease in mice.
Aim: To prepare naringenin nanoliposome (NRG-Nanolipo) and investigate its inhibitory effects on nonalcoholic fatty liver disease (NAFLD). Materials & methods: NRG-Nanolipo was prepared by thin-film rehydration method. Its characterizations and effects on NAFLD in mice induced by methionine choline deficient diet were investigated. Results: NRG-Nanolipo had high-drug loading percentage and showed a sustained release profile. The nanoliposome formulation significantly increased oral absorption of naringenin (NRG). NRG-Nanolipo showed comparable inhibitory effects as NRG crude drug at a dose fourfold lower than the crude drug on NAFLD. Conclusion: It is the first study to report the inhibitory effects of NRG on NAFLD, and the NRG-Nanolipo significantly improved oral absorption of NRG, thus improved liver protective effects of NRG on NAFLD.


Nonparametric tests of associations with disease based on U-statistics.
In case-control studies, association analysis was designed to test whether genetic variants were associated with human diseases. To evaluate the association, analysing one genetic marker at a time suffered from weak power, because of the correction for multiple testing and possibly small genetic effects. An alternative strategy was to test simultaneous effects of multiple markers, which was believed to be more powerful. However, when the number of markers under investigation was large, they would be subjected to weak power as well, because of the greater degrees of freedom. To conquer these limitations in case-control studies, we proposed a novel method that could test joint association of several loci (i.e. haplotype), with only a single degree of freedom. In this research, we developed a nonparametric approach, which was based on U-statistics. We also introduced a new kernel for U-statistic, which could combine the haplotype structure information, and was expected to enhance the power. Simulations indicated that our proposed approach offered merits in identifying the associations between diseases and haplotypes. Application of our method to a study of candidate genes for internalising disorder illustrated its virtue in utility and interpretation, and provided an excellent result in detecting the associations.


The Design of the Electronic Health Record in Type 1 Diabetes Centers: Implications for Metrics and Data Availability for a Quality Collaborative.
Systematic and comprehensive data acquisition from the electronic health record (EHR) is critical to the quality of data used to improve patient care. We described EHR tools, workflows, and data elements that contribute to core quality metrics in the Type 1 Diabetes Exchange Quality Improvement Collaborative (T1DX-QI). We conducted interviews with quality improvement (QI) representatives at 13 T1DX-QI centers about their EHR tools, clinic workflows, and data elements. All centers had access to structured data tools, nine had access to patient questionnaires and two had integration with a device platform. There was significant variability in EHR tools, workflows, and data elements, thus the number of available metrics per center ranged from four to 17 at each site. Thirteen centers had information about glycemic outcomes and diabetes technology use. Seven centers had measurements of additional self-management behaviors. Centers captured patient-reported outcomes including social determinants of health (n = 9), depression (n = 11), transition to adult care (n = 7), and diabetes distress (n = 3). Various stakeholders captured data including health care professionals, educators, medical assistants, and QI coordinators. Centers that had a paired staffing model in clinic encounters distributed the burden of data capture across the health care team and was associated with a higher number of available data elements. The lack of standardization in EHR tools, workflows, and data elements captured resulted in variability in available metrics across centers. Further work is needed to support measurement and subsequent improvement in quality of care for individuals with type 1 diabetes.


Belowground competition among invading detritivores.
The factors regulating soil animal communities are poorly understood. Current theory favors niche complementarity and facilitation over competition as the primary forms of non-trophic interspecific interaction in soil fauna; however, competition has frequently been suggested as an important community-structuring factor in earthworms, ecosystem engineers that influence belowground processes. To date, direct evidence of competition in earthworms is lacking due to the difficulty inherent in identifying a limiting resource for saprophagous animals. In the present study, we offer the first direct evidence of interspecific competition for food in this dominant soil detritivore group by combining field observations with laboratory mesocosm experiments using 13C and 15N double-enriched leaf litter to track consumption patterns. In our experiments, the Asian invasive species Amynthas hilgendorfi was a dominant competitor for leaf litter against two European species currently invading the temperate deciduous forests in North America. This competitive advantage may account for recent invasion success of A. hilgendorfi in forests with established populations of European species, and we hypothesize that specific phenological differences play an important role in determining the outcome of the belowground competition. In contrast, Eisenoides lonnbergi, a common native species in the Eastern United States, occupied a unique trophic position with limited interactions with other species, which may contribute to its persistence in habitats dominated by invasive species. Furthermore, our results supported neither the hypothesis that facilitation occurs between species of different functional groups nor the hypothesis that species in the same group exhibit functional equivalency in C and N translocation in the soil. We propose that species identity is a more powerful approach to understand earthworm invasion and its impacts on belowground processes.


A systematic review of how studies describe educational interventions for evidence-based practice: stage 1 of the development of a reporting guideline.
The aim of this systematic review was to identify which information is included when reporting educational interventions used to facilitate foundational skills and knowledge of evidence-based practice (EBP) training for health professionals. This systematic review comprised the first stage in the three stage development process for a reporting guideline for educational interventions for EBP. The review question was 'What information has been reported when describing educational interventions targeting foundational evidence-based practice knowledge and skills?'MEDLINE, Academic Search Premier, ERIC, CINAHL, Scopus, Embase, Informit health, Cochrane Library and Web of Science databases were searched from inception until October - December 2011. Randomised and non-randomised controlled trials reporting original data on educational interventions specific to developing foundational knowledge and skills of evidence-based practice were included.Studies were not appraised for methodological bias, however, reporting frequency and item commonality were compared between a random selection of studies included in the systematic review and a random selection of studies excluded as they were not controlled trials. Twenty-five data items were extracted by two independent reviewers (consistency > 90%). Sixty-one studies met the inclusion criteria (n = 29 randomised, n = 32 non-randomised). The most consistently reported items were the learner's stage of training, professional discipline and the evaluation methods used (100%). The least consistently reported items were the instructor(s) previous teaching experience (n = 8, 13%), and student effort outside face to face contact (n = 1, 2%). This systematic review demonstrates inconsistencies in describing educational interventions for EBP in randomised and non-randomised trials. To enable educational interventions to be replicable and comparable, improvements in the reporting for educational interventions for EBP are required. In the absence of a specific reporting guideline, there are a range of items which are reported with variable frequency. Identifying the important items for describing educational interventions for facilitating foundational knowledge and skills in EBP remains to be determined. The findings of this systematic review will be used to inform the next stage in the development of a reporting guideline for educational interventions for EBP.


Study of lymphoid cells from inflamed synovial membranes.
Synovectomy specimens from patients with rheumatoid arthritis were cultured and after 24 hours the nonadherent cells were removed. These were found to include cells with the morphological characteristics of lymphocytes. Using the sheep-cell rosetting test, up to 94% of these cells were found to be T cells, and while T cells could be found in all the supernatant cell populations studied, not all made a mitogen response. None or only a very small number of B cells were found by staining for surface immunoglobulin. The possible roles which T lymphocytes might play in chronic inflammation in the rheumatoid synovium are discussed in relation to experimental work, and factors which attract T cells into areas of nonspecific inflammation are similarly considered in the light of animal experiments.


Targeting intra-viral conserved nucleocapsid (N) proteins as novel vaccines against SARS-CoVs.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global pandemic of the Coronavirus disease in late 2019 (COVID-19). Vaccine development efforts have predominantly been aimed at 'Extra-viral' Spike (S) protein as vaccine vehicles, but there are concerns regarding 'viral immune escape' since multiple mutations may enable the mutated virus strains to escape from immunity against S protein. The 'Intra-viral' Nucleocapsid (N-protein) is relatively conserved among mutant strains of coronaviruses during spread and evolution. Herein, we demonstrate novel vaccine candidates against SARS-CoV-2 by using the whole conserved N-protein or its fragment/peptides. Using ELISA assay, we showed that high titers of specific anti-N antibodies (IgG, IgG1, IgG2a, IgM) were maintained for a reasonably long duration (> 5 months), suggesting that N-protein is an excellent immunogen to stimulate host immune system and robust B-cell activation. We synthesized three peptides located at the conserved regions of N-protein among CoVs. One peptide showed as a good immunogen for vaccination as well. Cytokine arrays on post-vaccination mouse sera showed progressive up-regulation of various cytokines such as IFN-γ and CCL5, suggesting that TH1 associated responses are also stimulated. Furthermore, vaccinated mice exhibited an elevated memory T cells population. Here, we propose an unconventional vaccine strategy targeting the conserved N-protein as an alternative vaccine target for coronaviruses. Moreover, we generated a mouse monoclonal antibody specifically against an epitope shared between SARS-CoV and SARS-CoV-2, and we are currently developing the First-in-Class humanized anti-N-protein antibody to potentially treat patients infected by various CoVs in the future.


Hypertension control: how well are we doing?
We compared blood pressure (BP) control in a recent cohort of hypertensive military veterans with BP control in a previous cohort and examined whether hypertension treatment practices, as defined by the frequency of antihypertensive medication dosage increases, have changed over time. We abstracted 1999 outpatient chart data including visit type, BP measurements, comorbidities, and medication use for 981 randomly selected hypertensive veterans. We examined overall BP control and control in subgroups with diabetes mellitus and renal disease, and compared results with those of a sample of 800 veterans studied from 1990 to 1995. We also compared the frequency of antihypertensive medication dosage increases in the 2 samples. Mean BPs were significantly lower in 1999. The mean systolic drop was 3.1 mm Hg and reached 13.7 mm Hg for the subgroups with diabetes and renal disease. Even larger decreases were seen in mean diastolic BPs. In 1999, 57% of patients had BP measurements of 140/90 mm Hg or higher, vs 69% of patients in the 1990-1995 study (P<.001). In 1999, the BP control of patients with diabetes was similar to that of patients without diabetes, as 60% of the former had BP measurements of 140/90 mm Hg or higher. Patients with renal disease had better control than those without, however, as only 43% had BP measurements of 140/90 mm Hg or higher. When comparing samples, patients with diabetes, renal disease, or both had better BP control in 1999 than their counterparts in the 1990-1995 study (P<.003 in all cases). In 1999, more medical visits were associated with medication dosage increases than in the 1990-1995 study. Although overall BP control has improved, BP measurements still exceeded recommended levels in most patients. For patients with diabetes and renal disease BP was much better controlled in the more recent sample. However, BP control of patients with diabetes was similar to that of patients without diabetes, and not in agreement with the guideline-recommended tighter control. Thus, room for improvement remains, especially in this subgroup.


Influence of Zwitterionic Buffer Effects with Thermal Modification Treatments of Wood on Symbiotic Protists in Reticulitermes grassei Clément.
The majority of thermal modification processes are at temperatures greater than 180 °C, resulting in a product with some properties enhanced and some diminished (e.g., mechanical properties). However, the durability of thermally modified wood to termite attack is recognised as low. Recent attempts at combining thermal modification with chemical modification, either prior to or directly after the thermal process, are promising. Buffers, although not influencing the reaction systems, may interact on exposure to certain conditions, potentially acting as promoters of biological changes. In this study, two zwitterionic buffers, bicine and tricine, chosen for their potential to form Maillard-type products with fragmented hemicelluloses/volatiles, were assessed with and without thermal modification for two wood species (spruce and beech), with subsequent evaluation of their effect against subterranean termites (Reticulitermes grassei Clément) and their symbiotic protists. The effect of the wood treatments on termites and their symbionts was visible after four weeks, especially for spruce treated with tricine and bicine and heat treatment (bicine HT), and for beech treated with bicine and bicine and heat treatment (bicine HT). The chemical behaviour of these substances should be further investigated when in contact with wood and also after heat treatment. This is the first study evaluating the effect of potential Maillard reactions with zwitterionic buffers on subterranean termite symbiotic fauna.


Effect of surfactants on PAH biodegradation by a bacterial consortium and on the dynamics of the bacterial community during the process.
The aim of this work was to evaluate the effect of a non-biodegradable (Tergitol NP-10) and a biodegradable (Tween-80) surfactant on growth, degradation rate and microbial dynamics of a polycyclic aromatic hydrocarbon (PAHs) degrading consortium (C2PL05) from a petroleum polluted soil, applying cultivable and non cultivable techniques. Growth and degradation rate were significantly lower with Tergitol NP-10 than that with Tween-80. Toxicity did not show any significant reduction with Tergitol NP-10 whereas with Tween-80 toxicity was almost depleted (30%) after 40 days. Regarding to the cultured bacteria, Pseudomonas and Stenotrophomonas groups were dominant during PAH degradation with Tergitol NP-10, whereas Enterobacter and Stenotrophomonas were dominant with Tween-80. DGGE analyses (PRIMER and MDS) showed that bacteria composition was more similar between treatments when PAHs were consumed than when PAHs concentration was still high. Community changes between treatments were a consequence of Pseudomonas sp., Sphingomonas sp., Sphingobium sp. and Agromonas sp.


[The effect of calcium-regulating hormones on pain sensitivity in rats].
Analgesic effect of calcitonin administered in doses of 1, 3, and 5 U/100 g was studied in rats. Intrathecal administration of calcitonin (0.015 U) results in higher increase in analgesic effect compared to intraventricular injection. Intramuscular (1, 3, and 5 U/100 g) and intraventricular (0.1 U) injection of parathormone exert no analgesic effect, whereas intrathecal injection in a dose of 0.1 U resulted in statistically significant analgesia. High correlation was found for nociception and calcium level in blood. Nifedipine and isoptin (1, 5, and 10 mg/kg) were shown to reduce significantly the analgesic effect of calcitonin. On the membrane of the isolated neuron of mollusk calcitonin (10(-9) - 10(-7) M) increased and in a concentration of 10(-6) M decreased JCa. Inhibiting effect of isoptin on JCa was found for combined action of calcitonin and isoptin on the neuron membrane.


Using theories of practice to understand HIV-positive persons varied engagement with HIV services: a qualitative study in six Sub-Saharan African countries.
This article considers the potential of 'theories of practice' for studying and understanding varied (dis)engagement with HIV care and treatment services and begins to unpack the assemblage of elements and practices that shape the nature and duration of individuals' interactions with HIV services. We obtained data from a multicountry qualitative study that explores the use of HIV care and treatment services, with a focus on examining the social organisation of engagement with care as a practice and as manifested in the lives of people living with HIV in sub-Saharan Africa. The dataset comprised of 356 interviews with participants from six countries. We noted fluctuating interactions with HIV services in all countries. In line with theories of practice, we found that such varied engagement can be explained by (1) the availability, absence and connections between requisite 'materialities' (eg, health infrastructure, medicines), 'competencies' (eg, knowing how to live with HIV) and 'meanings' (eg, trust in HIV services, stigma, normalisation of HIV) and (2) a host of other life practices, such as working or parenting. These dynamics either facilitated or inhibited engagement with HIV services and were intrinsically linked to the discursive, cultural, political and economic fabric of the participating countries. Practice theory provides HIV researchers and practitioners with a useful vocabulary and analytical tools to understand and steer people's differentiated HIV service (dis)engagement. Our application of practice theory to engagement in HIV care, as experienced by HIV service users and providers in six sub-Saharan African countries, highlights the need for a practice-based approach in the delivery of differentiated and patient-centred HIV services.


Structure, Function of Serine and Metallo-β-lactamases and their Inhibitors.
Antibiotic resistance in gram-negative bacteria has emerged as a major health threat that occurs because these bacteria actively produce β-lactamases responsible for the inactivation of β-lactam antibiotics. The first β lactamase was reported in E. coli back in 1940, before the release of the first antibiotic penicillin in clinical settings. Later on, large numbers of β-lactamases have been discovered in Gram-positive, Gram-negative bacteria as well as mycobacteria. Currently, numerous three-dimensional structures of serine and metallo-β-lactamases have been solved. The serine β-lactamases essentially consist of two structural domains (an all α and an α/β domain) and the active site is located at the groove between the two domains. The catalysis of serine β-lactamase proceeds via acylation and deacylation reactions. The three dimensional structure of metallo-β-lactamases displayed a common four layer "αβ/βα" motif, with a central "ββ"- sandwich by Zn2+ ion(s), and two α-helices are located on the either side. The active site of metallo-β-lactamases contain either 1 or 2 Zn2+ ions, which is coordinated to metal ligating amino acids and polarized water molecule(s) necessary for the hydrolysis of β-lactam antibiotics. Keeping the above views in mind, in this review we have shed light on the current knowledge of the structures and mechanisms of catalysis of serine and metallo-β-lactamases. Moreover, mutational studies on β-lactamases highlight the importance of the active site residues and residues in the vicinity to the active site pocket in the catalysis. To combat bacterial infections more effeciently novel inhibitors of β-lactamase in combination with antibiotics have been used which also form the theme of the review.


Antimicrobial peptides in nasal secretion and mucosa with respect to S. aureus colonisation in Wegener´s granulomatosis.
Nasal S. aureus carrier rates are significantly higher in patients with Wegener's granulomatosis (WG) compared to healthy controls (HC), and nasal colonisation is a risk-factor for relapse. Antimicrobial peptides (AMP) are important defence molecules maintaining an intact barrier function. It is the aim of this study to see if there is a possible link between the nasal AMP pattern and S. aureus colonisation, a link which has not been investigated so far. ELISA was applied to quantify LL-37 and hBD-3 concentrations in nasal secretions (14 WG patients, 13 HC) with and without nasal S. aureus colonisation. Immunohistochemistry was used to detect the cellular sources of AMP in the nasal mucosa. Functional analyses of primary nasal epithelial cell cultures (NEC) of these groups stimulated with S. aureus were performed. LL-37 was found in significantly higher concentrations in colonised individuals (WG: p=0.001; HC: p=0.014).Using immunohistochemistry, local cellular sources for AMP could be demonstrated. After stimulation with S. aureus, significantly higher concentrations of LL-37 and hBD-3 could be detected in the supernatant of NEC of WG patients (LL-37: p=0.001; hBD-3: p=0.001) and HC (LL-37: p=0.019; hBD-3: p=0.001). HBD-3 concentrations were significantly lower in the supernatant of stimulated NEC of WG patients compared to the NEC of HC (p=0.032), and the dynamic range of the hBD-3 answer was significantly smaller in WG compared to HC (p=0.016). The dynamic response towards challenges with microbes is dysregulated in WG, and this might be one reason for higher S. aureus colonisation rates in WG.


The impact of non-steroidal anti-inflammatory drugs on the small intestinal epithelium.
The small intestine has been called as a dark continent of digestive tract and it had been very difficult to diagnose or treat the disease of small intestine. However recent technological development including video capsule endoscopy or balloon-assisted endoscopy has made us to aware the various diseases of small intestine. By using capsule endoscopy, many researchers reported that more than 70% of patients treated continuously with non-steroidal anti-inflammatory drugs (NSAID) exhibit the mucosal damage of small intestine. In some cases, NSAID not only causes mucosal damage but also results in life threatening bleeding from small intestine, which had not been prevented or cured by gastro-protective drug or anti-gastric acid secretion drug administration. Therefore to investigate and identify the effective drug that protects small intestine from mucosal damage is urgently expected. In spite of extensive investigation in clinical field, only a few drugs such as misoprostol, a synthetic prostaglandin E1 analogue, has been reported as an effective one but is not satisfactory enough to fulfill the requirement of patients who suffer from NSAID-induced mucosal damage of small intestine. And now, extensive study is being performed using several gastro-mucoprotective drugs by many researchers. In this review, we introduce the current clinical situation in small intestinal injury of patients under NSAID treatment, and to summarize the molecular mechanism by which NSAID, including acetyl salicylic acid, cause small intestinal damage. In addition, we present results of clinical trials performed so far, and refer the possible preventive method or treatment in the near future.


Utility of palliative prognostic index and neutrophil-to-lymphocyte ratio in predicting prognosis of end-stage squamous cell carcinoma of head and neck.
The purpose of this study was to examine the factors influencing the prognosis of end-stage head and neck squamous cell carcinoma (HNSCC) and to develop a more useful prognostic index. This retrospective observational study included 79 patients with end-stage HNSCC. Patients were grouped by patient factors and prognostic indicators, and overall survival from the start of Best Supportive Care was compared for each group. In addition, overall survival was compared between patients with palliative prognostic index (PPI) ≥6 and neutrophil-to-lymphocyte ratio (NLR) ≥10 and patients with PPI <6 or NLR <10. PPI ≥6 and NLR ≥10 were associated with significantly more frequent poor prognoses (p = 0.01 and p = 0.002, respectively). The median survival was 32 days in cases with PPI ≥6 and NLR ≥10, and 64 days for PPI <6 or NLR <10 (p < 0.001). The combination of PPI and NLR is a useful indicator for predicting the prognosis of patients with end-stage HNSCC.


Ion Exchange Thermodynamics at the Rutile-Water Interface: Flow Microcalorimetric Measurements and Surface Complexation Modeling of Na-K-Rb-Cl-NO3 Adsorption.
Flow microcalorimetry was used to investigate the energetics associated with Rb+, K+, Na+, Cl-, and NO3- exchange at the rutile-water interface. Heats of exchange reflected differences in bulk hydration/dehydration enthalpies (Na+ > K+ > Rb+, and Cl- > NO3-) such that exchanging Na+ or Cl- from the surface was exothermic, reflecting their greater bulk hydration enthalpies. Exchange heats were measured at pH 2, 3.25, 5.8, and 11 and exhibited considerable differences as well as pH dependence. These trends were rationalized with the aid of a molecularly constrained surface complexation model (SCM) that incorporated the inner-sphere binding observed for the cations on the rutile (110) surface. Explicitly accounting for the inner-sphere binding configuration differences between Rb+, K+, and Na+, as well as accompanying differences in negative surface charge development, resulted in much better agreement with measured exchange ratios than by considering bulk hydration enthalpies alone. The observation that calculated exchange ratios agreed with those measured experimentally lends additional credence to the SCM. Consequently, flow microcalorimetry and surface complexation modeling are a useful complement of techniques for probing the energetics associated with ion exchange and adsorption processes and should also serve to help validate molecular simulations of interfacial energetics.


Increased Human Wildtype Tau Attenuates Axonal Transport Deficits Caused by Loss of APP in Mouse Models.
Amyloid precursor protein (APP) is implicated in axonal elongation, synaptic plasticity, and axonal transport. However, the role of APP on axonal transport in conjunction with the microtubule associated protein tau continues to be debated. Here we measured in vivo axonal transport in APP knockout mice with Manganese Enhanced MRI (MEMRI) to determine whether APP is necessary for maintaining normal axonal transport. We also tested how overexpression and mutations of tau affect axonal transport in the presence or absence of APP. In vivo axonal transport reduced significantly in the absence of functional APP. Overexpression of human wildtype tau maintained normal axonal transport and resulted in a transient compensation of axonal transport deficits in the absence of APP. Mutant R406Wtau in combination with the absence of APP compounded axonal transport deficits and these deficits persisted with age. These results indicate that APP is necessary for axonal transport, and overexpression of human wildtype tau can compensate for the absence of APP at an early age.


Integration and saturation within the circadian photic entrainment pathway of hamsters.
The sensitivity of the visual pathway that subserves circadian entrainment was measured in hamsters after prior stimulation and using trains of multiple pulses. Immediately after subsaturating stimulation in the late subjective night, there was a significant decrease in responsiveness that persisted for at least 1 h. The reduced responsiveness was not due to light adaptation (shifting of the stimulus-response curve) but rather to response saturation, which appeared to reduce the sensitivity to subsequent stimulation and limit the maximum response of the pacemaker. The system, therefore, integrates the total number of photons delivered in two light stimuli separated in time by up to 1 h. The responsiveness was also measured using stimulus trains containing 10-1,000 individual pulses of equal irradiance and equal total photons. Results suggest that this pathway is responsive to the total photons delivered in all of the stimuli and is not responsive to light onsets or offsets associated with individual stimuli. These data outline several fundamental characteristics of phase shifting for the circadian photic entrainment pathway in hamsters. Knowledge of these characteristics is important for designing and interpreting results of future studies to dissect the cellular and molecular nature of the mammalian circadian clock and for understanding how visual information affects the cellular clock during entrainment.


Study of flow behaviors on single-cell manipulation and shear stress reduction in microfluidic chips using computational fluid dynamics simulations.
Various single-cell retention structures (SCRSs) were reported for analysis of single cells within microfluidic devices. Undesirable flow behaviors within micro-environments not only influence single-cell manipulation and retention significantly but also lead to cell damage, biochemical heterogeneity among different individual cells (e.g., different cell signaling pathways induced by shear stress). However, the fundamentals in flow behaviors for single-cell manipulation and shear stress reduction, especially comparison of these behaviors in different microstructures, were not fully investigated in previous reports. Herein, flow distribution and induced shear stress in two different single-cell retention structures (SCRS I and SCRS II) were investigated in detail to study their effects on single-cell trapping using computational fluid dynamics (CFD) methods. The results were successfully verified by experimental results. Comparison between these two SCRS shows that the wasp-waisted configuration of SCRS II has a better performance in trapping and manipulating long cylinder-shaped cardiac myocytes and provides a safer "harbor" for fragile cells to prevent cell damage due to the shear stress induced from strong flows. The simulation results have not only explained flow phenomena observed in experiments but also predict new flow phenomena, providing guidelines for new chip design and optimization, and a better understanding of the cell micro-environment and fundamentals of microfluidic flows in single-cell manipulation and analysis.


[The human corpse in arts and bioethics: Michelangelo´s Pietà Rondanini].
According to bioethics, life is a fundamental but not an absolute good. Therefore the value of a person resides in being alive, no matter in which state such person is. The concept of brain death is legally and ethically accepted as the definition of death. In artworks, human beings are revealed as they are. Michelangelo's Pietà Rondanini captures and captures what a human corpse is, in its most intimate appearance. The artist boldly reveals its essence.


Albinism and Hermansky-Pudlak syndrome in Puerto Rico.
Five types of oculocutaneous albinism and two types of ocular albinism were found among 349 Puerto Rican albinos. The most prevalent type of albinism was the Hermansky-Pudlak syndrome (HPS). HPS was observed in five of every six albinos in Puerto Rico. The prevalence of HPS was highest in the northwestern quarter of the island, affecting approximately one in 1,800 persons, and approximately one in 22 are carriers of the gene. HPS is an autosomal recessively inherited triad of a tyrosinase-positive type of albinism, a hemorrhagic diathesis due to storage pool deficient platelets and accumulation of ceroid in tissues. The pigmentary phenotype of HPS albinos resembled that of any other type of oculocutaneous or ocular albinism. The most reliable method of diagnosing HPS is by a deficiency of platelet dense bodies observed by electron microscopy. The accumulation of ceroid in the tissues is associated with fibrotic restrictive lung disease and granulomatous enteropathic disease. The enteropathic disorder resembles Crohn's disease and with few exceptions, had its onset after 13 years of age. The major causes of death were fibrotic restrictive pulmonary disease, hemorrhagic episodes and sequelae of granulomatous enteropathic disease. Menometrorrhagia was common in women with HPS. No immune deficiency was found in HPS patients. The majority of patients with HPS had visual acuities of 20/200 or worse and consequently were legally blind. Albinos of all types, including HPS, lacked binocular vision due to nearly complete crossing of the optic tracts.


Keeping it light: (re)analyzing community-wide datasets without major infrastructure.
DNA sequencing technology has revolutionized the field of biology, shifting biology from a data-limited to data-rich state. Central to the interpretation of sequencing data are the computational tools and approaches that convert raw data into biologically meaningful information. Both the tools and the generation of data are actively evolving, yet the practice of re-analysis of previously generated data with new tools is not commonplace. Re-analysis of existing data provides an affordable means of generating new information and will likely become more routine within biology, yet necessitates a new set of considerations for best practices and resource development. Here, we discuss several practices that we believe to be broadly applicable when re-analyzing data, especially when done by small research groups.


[Results of surgical treatment of malignant brain tumors].
Although surgical treatment seldom cures any malignant brain tumours, it remains the basis of the management of these tumours. Studies by others and our own statistical studies demonstrate the absence of any real or significant improvement in survival time for most of the patients. Hence we must await progress in other oncological disciplines to provide a solution.


A method for the sensitive targeted screening of synthetic cannabinoids and opioids in whole blood by LC-QTOF-MS with simultaneous suspect screening using HighResNPS.com.
A sensitive method for the qualitative screening of synthetic cannabinoids and opioids in whole blood was developed and validated using alkaline liquid-liquid extraction (LLE) and liquid chromatography-time-of-flight mass spectrometry (LC-QTOF-MS). Estimated limits of detection for validated compounds ranged from 0.03 to 0.29 µg/L (median, 0.04 µg/L) for the 27 opioids and from 0.04 to 0.5 µg/L (median, 0.07 µg/L) for the 23 synthetic cannabinoids. Data processing occurred in two stages; first, a targeted screen was performed using an in-house database containing retention times, accurate masses and MS-MS spectra for 79 cannabinoids and 53 opioids. Suspect screening was then performed using a database downloaded from the crowd sourced NPS data website HighResNPS.com which contains mass, consensus MS-MS data and laboratory-specific predicted retention times for a far greater number of compounds. The method was applied to 61 forensic cases where synthetic cannabinoid or opioid screening was requested by the client or their use was suspected due to case information. CUMYL-PEGACLONE was detected in two cases and etodesnitazine, 5 F-MDMB-PICA, 4-cyano-CUMYL-BUTINACA and carfentanil were detected in one case each. These compounds were within the targeted scope of the method but were also detected through the suspect screening workflow. The method forms a solid base for expansion as more compounds emerge onto the illicit drug market.


KEAP1 polymorphisms and neurodevelopmental outcomes in children with exposure to prenatal MeHg from the Seychelles Child Development Study Nutrition Cohort 2.
Humans differ in the metabolism of the neurotoxicant methyl mercury (MeHg). This variation may be partially due to variation in genes encoding the transcription factor Nuclear factor E2-related factor 2 (NRF2) and its negative regulator Kelch-like ECH-Associated Protein 1 (KEAP1), which regulate glutathione and related transporter and antioxidant proteins that play a role in the metabolism and neurotoxicity of MeHg. To elucidate a potential risk from genetic variation in NFE2L2 (encoding NRF2) and KEAP1 toward prenatal mercury exposure and child neurodevelopmental outcomes at 20 months and 7 years of age in a population with variable prenatal exposure to MeHg from maternal fish consumption. Nutrition Cohort 2 is a mother-child cohort in the Republic of Seychelles. Children were genotyped for NFE2L2 (rs2364723, rs13001694) and KEAP1 (rs8113472, rs9676881) polymorphisms (N = 1285 after removing siblings). Total mercury (Hg) was measured in cord blood as a biomarker for prenatal MeHg exposure. Child neurodevelopmental outcomes included the Bayley Scales of Infant Development II administered at 20 months of age, and outcomes across multiple neurodevelopmental domains from 14 tests administered in children and 3 instruments completed by parents when children were 7 years of age. The mean cord blood MeHg concentration was 34 (95% CI 11, 75) µg/L. None of the four polymorphisms had a significant association (p < 0.05) with either cord MeHg or neurodevelopmental test results at 20 months. There were no significant associations between either NFE2L2 polymorphism and any developmental test scores. At 7 years, children carrying KEAP1 rs8113472 CA showed significantly worse performance on psychomotor function than children with the CC variant (finger tapping, dominant hand: β - 1.19, SE 0.34; finger tapping, non-dominant hand: β - 0.92, SE 0.31) and worse social communication (SCQ Total: β 0.65, SE 0.27). Children carrying rs8113472 AA, versus children with CC, showed significantly better performance on social communication (SRS Total: β - 8.88, SE 3.60). Children carrying KEAP1 rs9676881 AG, versus children with GG, showed significantly worse performance on psychomotor function (trailmaking A time: β 8.66, SE 3.37) and cognition (KBIT Matrices: β - 0.96, SE 0.36). No associations between NFE2L2 and KEAP1 polymorphisms and MeHg concentration were identified. However, at 7 years, KEAP1 polymorphisms were associated with differences in neurodevelopmental outcomes in children from a population with high fish intake.


Determination of the stability constants in alkanol/alpha-cyclodextrin mixed system.
The simultaneous determination of the stability constants for inclusion of alkanols with alpha-cyclodextrin (alpha-CD) was investigated in a mixed alkanol system using static head-space gas chromatography (SHSGC). The 1:1 stability constants obtained were in fair agreement with those obtained previously using other methods. The time required for determination of the stability constant was markedly reduced using this simultaneous SHSGC method.


Effect of acupressure on milk volume of breastfeeding mothers referring to selected health care centers in Tehran.
Breast milk is the main food source for infants' growth and development. Insufficient milk is one of the obstacles to the adequate use of this substance. One of the treatments to help this issue is acupressure. Therefore, the present study was designed to determine the effect of acupressure on maternal milk volume. This study is a randomized clinical trial in which 60 breastfeeding mothers complaining of hypogalactia and meeting the inclusion criteria were studied. In addition to providing routine education, bilateral acupressure was performed for 12 consequentia l days on the acupoints of SI1, LI4, and GB21 in the intervention group, as three sessions per week with each session conducted 2-5 times. The control group received only routine education. In both groups, breast milk volume before intervention and 2 and 4 weeks after intervention was evaluated by an electric pump. Data were analyzed by descriptive and inferential statistical analysis through SPSS. The t-test showed no significant difference in the mean volume of milk in the two groups (P = 0.543). Mean volumes of milk before and 2 and 4 weeks after the intervention were 10.5 (8.3), 33 (13.44), and 36.2 (12.8), respectively, in the acupressure group and 9.5 (7.7), 17.7 (9.4), 18 (9.5), respectively, in the control group. Analysis of variance (ANOVA) test showed a significant difference in the mean volume of milk at 2 and 4 weeks after the intervention (P < 0.001). Both acupressure and general education methods were effective on the milk volume of breastfeeding mothers. Acupressure method was more effective than the other method. Therefore, application of acupressure as a method of alternative medicine to increase breastfeeding is suggested.


Combretastatin A4 prodrug study of effect on the growth and the microvasculature of colorectal liver metastases in a murine model.
Combretastatin A4P (CA4P) is a prodrug that, in active form, binds to tubulin microtubules of capillary endothelial cells. Studies to date indicate it has significant activity as a specific tumor vascular targeting agent. The goals were to assess the effects of CA4P on tumor growth and microvasculature of colorectal liver metastases in the mouse model, using stereological and histological methods to measure tumor growth, and vascular corrosion casting and laser doppler flowmetry to assess effect on the microvasculature. Continuous s.c. infusion of CA4P produced a major reduction in tumor growth. The percentage of the liver occupied by metastases decreased from 20.55 +/- 13.3% in controls to 7.46 +/- 5.99% in treated animals (P = 0.03). Ultrastructural study of tumor microvasculature after a single dose of CA4P revealed marked effects 1 h after treatment. There was loss of patent microvessels at the normal liver-tumor interface. Central microvascular density was reduced, with constriction and tapering of vessels. CA4P appeared to cause no damage to normal liver tissue or vasculature. Tumor blood flow decreased from 37.6 +/- 13.9% in controls to 24.4 +/- 6.1% in tumors >5 mm in diameter, 1 h after treatment with CA4P (P < 0.03). Quantitative histology of tissue at 6 and 24 h after CA4P treatment showed a significant increase in tumor necrosis (48.7 +/- 21% and 55.5 +/- 19% compared with controls, 20.6 +/- 8%; P = 0.01). Continuous infusion with CA4P causes marked reduction in tumor volume. A single dose of CA4P causes major changes of the tumor microvasculature, reduction of tumor blood flow, and increase in tumor necrosis. CA4P has a potential role in the management of patients with liver metastases.


Common questions about late-term and postterm pregnancy.
Pregnancy is considered late term from 41 weeks, 0 days' to 41 weeks, 6 days' gestation, and postterm at 42 weeks' gestation. Early dating of the pregnancy is important for accurately determining when a pregnancy is late- or postterm, and first-trimester ultrasonography should be performed if clinical dating is uncertain. Optimal management of a low-risk, late-term pregnancy should consider maternal preference and balance the benefits and risks of induction vs. waiting for spontaneous labor. Compared with expectant management, induction at 41 weeks' gestation is associated with a small absolute decrease in perinatal mortality and decreases in other fetal and maternal risks without an increased risk of cesarean delivery. Although there is no clear evidence that antenatal testing beginning at 41 weeks' gestation prevents intrauterine fetal demise, it is often performed because the risks are low. When expectant management is chosen, most experts recommend beginning twice-weekly antenatal surveillance at 41 weeks with biophysical profile or nonstress testing plus amniotic fluid index (modified biophysical profile); induction may be deferred until 42 weeks if this surveillance is reassuring.


Cryopreserved allogenic vascular graft in free-flap reconstructive microsurgery: case report.
The use of cryopreserved allogenic vascular graft in reconstructive microsurgery has rarely been reported. Here, we report a case of lower extremity reconstruction using cryopreserved hepatic artery as the vein conduit. Postoperative flap perfusion was uneventful with satisfactory wound healing, and graft patency was observed on follow-up color Doppler. Thus, cryopreserved allogenic vascular graft could be a source of vascular conduit in microsurgery.


Association between esophagogastric varices in hepatocellular carcinoma and poor prognosis after transarterial chemoembolization: A propensity score matching analysis.
Whether esophagogastric varices (EGV) can determine the outcome of patients with hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) remains unknown. This study aimed to assess the impact of EGV on the prognosis of HCC patients after TACE. From 2007 to 2012, we retrospectively enrolled 251 treatment-naïve HCC patients who underwent TACE and received esophagogastroduodenoscopy when HCC was diagnosed. The prognostic factors were analyzed using a Cox proportional hazards model and propensity score-matching analysis. There were 120 (47.8%) patients with EGV. Compared to those without EGV, patients with EGV had worse liver functional reserve. After a median follow-up of 14.7 months (25th-75th percentiles, 6.4-35.6 months), 152 patients died. The cumulative 5-year overall survival (OS) rates were 11.2% and 38.8% in patients with and without EGV, respectively (p < 0.001). Multivariate analysis showed that presence of EGV, presence of ascites, tumor size >5 cm, serum alpha-fetoprotein >20 ng/mL, progressive disease by modified Response Evaluation Criteria in Solid Tumors, Assessment for Retreatment with TACE score ≥2.5, and higher albumin-bilirubin grades were the independent predictors of poor OS. Subgroup analysis also demonstrated that EGV was associated with poor OS in most of the subgroups. After propensity score matching, the EGV group still had a lower OS rate than their counterparts (p = 0.004). HCC patients with EGV had worse liver functional reserve compared to those without EGV. Moreover, EGV was an independent risk factor to predict poor prognosis in patients with HCC after TACE.


Dynamics of Fibril Collagen Remodeling by Tumor Cells: A Model of Tumor-Associated Collagen Signatures.
Many solid tumors are characterized by a dense extracellular matrix (ECM) composed of various ECM fibril proteins. These proteins provide structural support and a biological context for the residing cells. The reciprocal interactions between growing and migrating tumor cells and the surrounding stroma result in dynamic changes in the ECM architecture and its properties. With the use of advanced imaging techniques, several specific patterns in the collagen surrounding the breast tumor have been identified in both tumor murine models and clinical histology images. These tumor-associated collagen signatures (TACS) include loosely organized fibrils far from the tumor and fibrils aligned either parallel or perpendicular to tumor colonies. They are correlated with tumor behavior, such as benign growth or invasive migration. However, it is not fully understood how one specific fibril pattern can be dynamically remodeled to form another alignment. Here, we present a novel multi-cellular lattice-free (MultiCell-LF) agent-based model of ECM that, in contrast to static histology images, can simulate dynamic changes between TACSs. This model allowed us to identify the rules of cell-ECM physical interplay and feedback that guided the emergence and transition among various TACSs.


Time-Resolved and Comprehensive Analysis of Surface Glycoproteins Reveals Distinct Responses of Monocytes and Macrophages to Bacterial Infection.
Glycoproteins on the surface of immune cells play extremely important roles in response to pathogens. Yet, a systematic and time-resolved investigation of surface glycoproteins during the immune response remains to be explored. Integrating selective enrichment of surface glycoproteins with multiplexed proteomics, we globally and site-specifically quantified the dynamics of surface glycoproteins on THP-1 monocytes and macrophages in response to bacterial infection and during the monocyte-to-macrophage differentiation. The time-resolved analysis reveals transient changes and differential remodeling of surface glycoproteins on both cell types, and potential upstream regulators and downstream effects of the regulated glycoproteins. Besides, we identified novel surface glycoproteins participating in the immune response such as APMAP, and site-specific changes of glycoproteins. This study provides unprecedented information to deepen our understanding of glycoproteins and cellular activities.


Characterization of a cytosolic heat-shock protein-caveolin chaperone complex. Involvement in cholesterol trafficking.
Caveolin is a 22-kDa protein that appears to play a critical role in regulating the cholesterol concentration of caveolae. Even though caveolin is thought to be a membrane protein, several reports suggest that this peculiar protein can traffic independently of membrane vesicles. We now present evidence that a cytosolic pool of caveolin is part of a heat-shock protein-immunophilin chaperone complex consisting of caveolin, heat-shock protein 56, cyclophilin 40, cyclophilin A, and cholesterol. Treatment of NIH 3T3 cells with 1 microM cyclosporin A or 100 nM rapamycin disrupted the putative transport complex and prevented rapid (10-20 min) transport of cholesterol to caveolae. The lymphoid cell line, L1210-JF, does not express caveolin, does not form an immunophilin-caveolin complex, and does not transport newly synthesized cholesterol to caveolae. Transfection of caveolin cDNA into L1210-JF cells allowed the assembly of a transport complex identical to that found in NIH 3T3 cells. In addition, newly synthesized cholesterol in transfected cells was rapidly (10-20 min) and specifically transported to caveolae. These data strongly suggest that a caveolin-chaperone complex is a mechanism by which newly synthesized cholesterol is transported from the endoplasmic reticulum through the cytoplasm to caveolae.


"What shall I do when I grow up?" Adolescents with cancer on the Youth Project in Milan play with their imagination and photography.
Adolescents diagnosed with cancer have to temporarily stop pursuing several vital needs and making plans for the future. The Youth Project in Milan, Italy, focuses on such issues in young cancer patients' personal lives. Uncertainty about the future had already emerged in several artistic projects designed to help these patients voice their emotions. We describe a project revolving around the question "What shall I do when I grow up?" Twenty-seven 15- to 26-year-old patients wrote a brief account of what they hoped to do as adults. Using theatrical costumes, they then dressed up in their chosen role for a photo shoot with a well-known professional photographer. The results were published in one of Italy's main national dailies. Participants reacted differently: some lightheartedly, others more seriously. They often expressed the wish to help others, desiring to return the support and protection they had received as patients. Another common theme concerned their need for normality. By writing about their dreams, these patients gave their doctors a glimpse of their inner world. The project proved an important complement to more conventional forms of psychosocial support and interaction with young patients.


Hypothalamic nitric oxide synthase is depressed in cholestatic rats.
We examined hypothalamic nitric oxide synthase (NOS) levels and release as well as steady-state mRNA levels in rats with cholestasis due to bile duct resection (BDR) and in sham-resected control rats. BDR rats had a significant reduction in hypothalamic NOS-containing neurons in the hypothalamic paraventricular nucleus as determined by NADPH-diaphorase staining, compared with sham-resected controls. In addition, NOS activity, measured indirectly by determining nitrite release from hypothalamic explants, was significantly lower in BDR rats compared with sham-resected animals. Hypothalamic steady-state NOS mRNA levels [brain constitutive NOS (bNOS)] were determined by semiquantitative reverse transcription-polymerase chain reaction and were found to be increased 1.5-fold in BDR rats compared with sham rats. In summary, BDR rats have diminished hypothalamic NOS levels and activity coupled with enhanced steady-state bNOS mRNA levels, suggesting that depressed hypothalamic NOS protein levels are due to posttranscriptional defects.


Season of birth variations in suicide methods in relation to any history of psychiatric contacts support an independent suicidality trait.
Due to reports on season of birth variations in suicidal behaviour as well as in cerebrospinal fluid levels of monoamine metabolites, we investigated season of birth variations in suicide methods for completed suicides in relation to any history of psychiatric contacts. Relationships with the psychiatric diagnoses for those with psychiatric contacts were also studied. Sociodemographic variables and suicide methods were examined for all the 693 suicide victims during 1961-1980 in Västerbotten, Sweden. Information on any history of psychiatric contacts was obtained from psychiatric in-patient and out-patient records. Gender differences in the choice of suicide method were found in the group without any history of psychiatric contacts, but not in those with such a history. Only those without a history of psychiatric contacts showed season of birth variations for suicide methods -- those born during February to April were significantly more likely, and those born during October to January significantly less likely, to have preferred hanging rather than poisoning or petrol gases. These associations were stronger for the determined suicides, for males, and for urban residence. Suicide victims with a history of psychiatric contacts were significantly younger than those without. No psychological autopsies for those without psychiatric contacts. No information on eventual contacts with general practitioners. No measures of monoamine neurotransmitters were available. Season of birth association for suicide methods is likely to be mediated by a suicidality trait independently of specific major psychiatric disorders. Monoamine neurotransmitters, particularly serotonin, are likely to underlie such a trait.


On the size of the toxic particle passing the intestinal barrier in botulism.
On the basis of toxicity assays using partition centrifugation cells it was established that the sedimentation coefficient of type A botulinum toxin appearing in the lymph of orally poisoned rats was 7.9 x 10(-18) cm. per dyne sec. with 95 per cent confidence limits of 4.4 to 11.4 x 10(-13) cm. per dyne sec. This is a significantly lower value than that obtained for crystalline toxin but is well within the range of size for proteins. Exposure of crystalline toxin for 2 hours to digestive processes in a section of the duodenum of living rats did not significantly reduce the sedimentation coefficient of the toxin. The S(20) of crystalline toxin employed in the present study ranged between 12 and 21 with a mean value of 17.9. While it was observed that both botulinum toxin and albumin sedimented from lymph in glycerol gradient tubes to essentially the same level no evidence was developed to indicate association between toxin in lymph and serum albumin. The electrophoretic mobility of toxin in lymph is like that of crystalline toxin and not albumin. Dialysis of toxic lymph against serum albumin does not result in the appearance of toxin in the dialysate.


Electron Microscopic and Immunohistochemical Examination of the Effect of 2-Aminoethoxydiphenyl Borate on Optic Nerve Injury in A Rat Model.
We conducted this study to explore the possible protective effect of 2-aminoethoxydiphenyl borate (2-APB) on experimentally induced optic nerve injury in an acute ischemia-reperfusion (AIR) model. A total of 30 Wistar albino rats were randomly divided into sham, AIR, and AIR+treatment (AIR10) groups. In the sham group, AIR model was not created. In the AIR group, AIR model was created without the administration of drug. In the AIR10 group, 2-APB was administered 10 min before reperfusion. Tissue samples were subjected to histological, immunohistochemical, and electron microscopic procedures. Histopathological examination revealed intense hypertrophic cells, more glial cells, capillary dilatation, and intense demyelination areas in the AIR group compared to those in the sham and AIR10 groups. Immunohistochemical staining demonstrated an increase in Orai1 and STIM1 immunoreactivity in the AIR group but less intense staining in the AIR10 group. Electron microscopy revealed injury in optic nerve axons in the AIR group, whereas this type of injury occurred to a lesser extent in the AIR10 group. In rats, store-operated Ca2+ entry in the cell had an essential role in optic nerve ischemia-reperfusion injury, and 2-ABP may have a protective effect on optic nerve injury caused due to AIR.


Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children.
The aim of this study was to analyze a possible association between cesarean delivery and enteric inflammatory diseases in children. A retrospective, multicenter, case-control study that included 1950 children was performed in cooperation with 26 university and 16 nonacademic children's hospitals. Information on intestinal disease manifestation, together with mode of delivery and gestational age at birth, postnatal complications, and breastfeeding, was collected by the attending physician from children and their parents who were visiting a gastrointestinal outpatient clinic for Crohn disease (CD; 516 cases), ulcerative colitis (250 cases), celiac disease (157 cases), and other gastrointestinal diseases (165 cases) and control subjects who were visiting ophthalmologic, orthodontic, and dental outpatient clinics (862 cases). Whereas the rate of cesarean delivery of children with Crohn disease or ulcerative colitis was similar to that of control subjects, a significantly enhanced likelihood of being born by cesarean delivery was found in children with celiac disease compared with control subjects (odds ratio: 1.8 [95% confidence interval: 1.13-2.88]; P = .014). The mode of delivery and associated alterations in the development of the enteric homeostasis during the neonatal period might influence the incidence of celiac disease.


Role of heteromer formation in GABAB receptor function.
Recently, GBR1, a seven-transmembrane domain protein with high affinity for gamma-aminobutyric acid (GABA)B receptor antagonists, was identified. Here, a GBR1-related protein, GBR2, was shown to be coexpressed with GBR1 in many brain regions and to interact with it through a short domain in the carboxyl-terminal cytoplasmic tail. Heterologously expressed GBR2 mediated inhibition of adenylyl cyclase; however, inwardly rectifying potassium channels were activated by GABAB receptor agonists only upon coexpression with GBR1 and GBR2. Thus, the interaction of these receptors appears to be crucial for important physiological effects of GABA and provides a mechanism in receptor signaling pathways that involve a heterotrimeric GTP-binding protein.


The association between the CT severity index and the pulmonary artery area in COVID-19 pneumonia.
The pulmonary artery area (PAA) is a valuable non-invasive method for the diagnosis of pulmonary hypertension. To compare the change in PAA in patients with COVID-19 with the computed tomography (CT) severity index using follow-up imaging. A total of 81 patients who were followed up and underwent CT assessment more than once at our hospital's pandemic department were evaluated retrospectively. Patients with progression were separated into three groups: progression ranging from mild-to-mild infiltration (Group A, CT severity index of 0-2); progression from mild to severe infiltration (Group B, CT severity index of 0-2 to 3-5); and progression from severe-to-severe infiltration (Group C, CT severity index of 3-5). The PAAs were calculated separately. The mean age was 56 ± 12 years. In terms of those patients showing progression in the CT images, the number of patients in Groups A, B, and C was 29, 40, and 12 in the right lung; 32, 45, and 4 in the left lung; 23, 45, and 13 on both lungs, respectively. There was no significant difference between the main, right, and left PAAs in Group A (P > 0.05). In Group B, there were significant increases in the areas of the main, right, and left PAAs (P < 0.05). There were also significant increases in the areas of the right and main pulmonary arteries in Group C (P < 0.05). PAAs increase as disease involvement advances in cases with COVID-19 pneumonia, which is thought to be correlated with progression.


Evaluation of several methodological challenges in circulating miRNA qPCR studies in patients with head and neck cancer.
Circulating microRNAs (ci-miRNAs) in blood have emerged as promising diagnostic, prognostic and predictive biomarkers in cancer. Many clinical studies currently incorporate studies that assess ci-miRNAs. Validation of the clinical significance of candidate biomarker miRNAs has proven to be difficult, potentially resulting from vast discrepancies in the detection methodology as well as biological variability. In the current study, the influence of several methodological factors on ci-miRNA detection was evaluated as well as short-term biological variability in patients with head and neck cancer. RNA was isolated from 124 serum and plasma samples originating from patients with head and neck cancer and healthy volunteers. The miRNA levels were measured using RT-qPCR and the influence of pre-analytical factors, different normalization strategies and temporal reproducibility was assessed. RNA carriers improved ci-miRNA detection in serum and plasma specimens. A prolonged pre-processing time correlated with an increased hemolytic index in serum samples only. Hemolysis differentially affected the detection of individual miRNAs. Optimal normalization was achieved using the averaged detection values of spike-in cel-miR-39-3p and endogenous miR-16-5p. Comparing biological replicates from patients with head and neck cancer, the intra-individual miRNA levels were relatively stable (average interval 7 days). Differences in the ci-miRNA detection methodology and limitations of currently used technologies can greatly affect the results and may explain inconsistent outcomes between studies. Prior to the implementation of ci-miRNAs as useful clinical biomarkers, further advances in the standardization of the detection methodology and reduction of technical variability are needed.


[Abdominal pain caused by mobile caecum with strangulation].
An 84-year-old woman was admitted to the emergency department of the St. Elisabeth Hospital in Curaçao for acute diffuse abdominal pain. Her medical history revealed an 'irritable bowel syndrome' with symptoms of chronic progressive abdominal pain. Plain abdominal radiography and computed tomography showed a substantially dilated bowel with torsion of the organ structures and suspected strangulation of the colon. Perioperative examination revealed a distended mobile caecum and right hemicolon. There was also strangulation and herniation of both structures through the foramen of Winslow around the hepatoduodenal ligament, protruding through the minor omentum. After destrangulation and closure of the herniation a caecopexy with an additional appendectomy was performed. Mobile caecum is defined as a failure of the right colon to fuse to the posterior parietal peritoneum. The symptoms of chronic abdominal pain may have been the result of the pre-existing mobile caecum.


Incidence and outcomes after infolding or collapse of thoracic stent grafts.
Device-related complications in the thoracic aorta are partly due to the unavoidable proximal angulation and increased flow-related forces. The present study evaluated the incidence, predictors, and outcome of the complication of infolding with the GORE TAG thoracic endoprosthesis (TAG device) to better understand the factors that might help predict these events. We reviewed all complaints reported to W. L. Gore and Associates (Flagstaff, Ariz) related to device infolding after the use of the GORE TAG device on or before December 2008. Events related to device infolding were evaluated. Reporting physicians and local company representatives were contacted, when necessary, to assemble all available imaging, data, and outcomes related to these case reports. When available, computed tomography images were reviewed to confirm aortic landing zone diameters, which were subsequently compared with the implanted device size. From 1998 through December 2008, device infolding was reported in 139 patients (mean age, 40 ± 17 years; 73.4% men) from 33,289 device implants (reported incidence, 0.4%). Events were noted in implants for trauma (60%), dissection (19%), aneurysm (10%), and other (9%) and unknown (2%) etiologies. In 77 patients with available imaging, the average minimum aortic diameter was 21.4 ± 4.4 mm. The mean device diameter was 28.5 ± 3.5 mm, with an average oversizing of nearly 33%. Of reported patients, 51% were asymptomatic, with the diagnosis being made on routine chest imaging. Time to diagnosis was 76 ± 222 days (median, 9.5 days). Only 16 patients received no intervention after the diagnosis of device infolding, all of whom were asymptomatic. The other 123 patients underwent 135 interventions. Of these, 30 patients (24%) underwent open surgical conversion and complete or partial endograft removal. The other interventions included a variety of endovascular techniques, such as large balloon-expandable stent(s) in 40%, relining with additional endograft(s) in 31%, and repeat ballooning in seven patients. Ten patients died after device infolding, all after one or more attempts to repair the infolded device: five died of symptoms related to the infolding and five secondary to the intervention undertaken to correct the device infolding. TAG device infolding appears to be an infrequent event, primarily occurring in young trauma patients secondary to excessive oversizing and severe proximal aortic angulation. However, there clearly exists a need for devices that treat such patients. As a result, future device designs should consider the compression failure mode when being designed in order to help prevent such events.


[Physiology of the GH-IGF axis].
Growth, the main characteristic of childhood and adolescence, has a similar pattern in the majority of the individuals. Genetic background and GH-IGF axis are the factors that directly influence this process. Pituitary GH acts on growth mainly through the regulation of IGF system. The IGFs (IGF-1 and IGF-2) are growth factors produced in the majority of the organs and body tissues. They have autocrine, paracrine and endocrine actions on metabolism and cell proliferation, growth and differentiation. The IGFs bind with high specificity and affinity to a family of 6 binding proteins, called IGFBPs (1 to 6) that modulate their bioactivity. Most of the known IGF actions are mediated via IGF type 1 receptor (IGF1R). In this article we are going to review the composition and regulation of the GH-IGF axis and the role of each component in the regulation of the growth process.


Genome sequences and phylogenetic analysis of K88- and F18-positive porcine enterotoxigenic Escherichia coli.
Porcine enterotoxigenic Escherichia coli (ETEC) continues to result in major morbidity and mortality in the swine industry via postweaning diarrhea. The key virulence factors of ETEC strains, their serotypes, and their fimbrial components have been well studied. However, most studies to date have focused on plasmid-encoded traits related to colonization and toxin production, and the chromosomal backgrounds of these strains have been largely understudied. Here, we generated the genomic sequences of K88-positive and F18-positive porcine ETEC strains and examined the phylogenetic distribution of clinical porcine ETEC strains and their plasmid-associated genetic content. The genomes of porcine ETEC strains UMNK88 and UMNF18 were both found to contain remarkable plasmid complements containing known virulence factors, potential novel virulence factors, and antimicrobial resistance-associated elements. The chromosomes of these strains also possessed several unique genomic islands containing hypothetical genes with similarity to classical virulence factors, although phage-associated genomic islands dominated the accessory genomes of these strains. Phylogenetic analysis of 78 clinical isolates associated with neonatal and porcine diarrhea revealed that a limited subset of porcine ETEC lineages exist that generally contain common toxin and fimbrial profiles, with many of the isolates belonging to the ST10, ST23, and ST169 multilocus sequencing types. These lineages were generally distinct from existing human ETEC database isolates. Overall, most porcine ETEC strains appear to have emerged from a limited subset of E. coli lineages that either have an increased propensity to carry plasmid-encoded virulence factors or have the appropriate ETEC core genome required for virulence.


Arthroscopic management of the stiff elbow.
Elbow stiffness is a challenge to manage effectively. Elbow contractures commonly result from both intrinsic and extrinsic factors, causing limited motion. Recent technical advances in elbow arthroscopy have led to the development of minimally invasive procedures for the management of select cases of recalcitrant elbow stiffness. As with most arthroscopic procedures, a notable learning curve is associated with the safe, effective execution of these surgical techniques. Certain clinical scenarios require that special attention be paid to the ulnar nerve and the posterior bundle of the medial ulnar collateral ligament to improve motion safely. Arthroscopic capsular release of the elbow is effective for restoring a functional arc of motion in the short term in most patients with extrinsic contractures.


Hydrological controls on cascade reservoirs regulating phosphorus retention and downriver fluxes.
Many coastal rivers have a system of cascade reservoirs, but the role of these reservoirs in regulating nutrient transport from watershed to coast is still unknown. In this study, phosphorus (P) in surface water and top sediment was investigated along the North Jiulong River (southeast China) under three hydrological conditions (high flow, medium flow and low flow) in 2012-2013, and P dynamics in a cascade reservoir (Xipi Reservoir) were studied on a monthly scale. Results showed that the concentrations of dissolved reactive phosphorus (DRP) consistently decreased longitudinally in the upper river with the lowest values observed in the section of cascade reservoirs, likely due to tributary inputs and in situ uptakes. The decrease was most rapid during base flow when DRP was highest in the free-flowing river section and lowest in cascade reservoirs. Results from monthly monitoring on the Xipi Reservoir showed general downriver decreases in DRP, total particulate phosphorus (TPP) and total phosphorus (TP) in the riverine zone and transition zone. Mass balance results on an annual basis suggest that the Xipi Reservoir (lacustrine zone) was an overall sink for TPP (6 % retention) but somewhat a source of DRP (-0.3 %) with TP retention (1 %). Even scaled up to the whole cascade reservoir system, P retention was low compared with worldwide reservoirs, which we ascribe to the high P loading and short hydraulic residence time. Nevertheless, major processes controlling P retention in coastal rivers with cascade reservoirs varied from sedimentation in the dry-cold season to biotic transformation in the wet-warm season, thereby affecting loading and composition of P from watershed to the coast. This study highlights the hydrological controls on the role of cascade reservoirs in regulating P retention and downriver fluxes in different seasons.


Treatment seeking for problematic pornography use among women.
Background and aims Previous studies examined psychological factors related to treatment seeking for problematic pornography use (PU) among males. In this study, we focused on females who seek treatment for problematic PU and compared them with non-problematic pornography users with regard to variables related to problematic PU. Second, we investigated the relationships between critical constructs related to problematic PU with the path analysis method, emphasizing the predictors for treatment seeking among women. We also compared our results with previous studies on males. Methods A survey study was conducted on 719 Polish-speaking Caucasian females, 14-63 years old, including 39 treatment seekers for problematic PU. Results The positive relationship between the mere amount of PU and treatment seeking loses its significance after introducing two other predictors of treatment-seeking: religiosity and negative symptoms associated with PU. This pattern is different from the results obtained in previous studies on males. Discussion Different from previous studies on male samples, our analysis showed that in the case of women, mere amount of PU may be related to treatment-seeking behavior even after accounting for negative symptoms associated with PU. Moreover, religiousness is a significant predictor of treatment seeking among women, which may indicate that in the case of women, treatment seeking for problematic PU is motivated not only by experienced negative symptoms of PU but also by personal beliefs about PU and social norms. Conclusion For females, negative symptoms associated with PU, the amount of PU and religiosity is associated with treatment seeking. Those factors should be considered in treatment.


Carfilzomib suppressed LDHA-mediated metabolic reprogramming by targeting ATF3 in esophageal squamous cell carcinoma.
Carfilzomib, a second-generation proteasome inhibitor, has been approved as a treatment for relapsed and/or refractory multiple myeloma. Nevertheless, the molecular mechanism by which Carfilzomib inhibits esophageal squamous cell carcinoma (ESCC) progression largely remains to be determined. In the present study, we found that Carfilzomib demonstrated potent anti-tumor activity against esophageal squamous cell carcinoma both in vitro and in vivo. Mechanistically, carfilzomib triggers mitochondrial apoptosis and reprograms cellular metabolism in ESCC cells. Moreover, it has been identified that activating transcription factor 3 (ATF3) plays a crucial cellular target role in ESCC cells treated with Carfilzomib. Overexpression of ATF3 effectively antagonized the effects of carfilzomib on ESCC cell proliferation, apoptosis, and metabolic reprogramming. Furthermore, the ATF3 protein is specifically bound to lactate dehydrogenase A (LDHA) to effectively suppress LDHA-mediated metabolic reprogramming in response to carfilzomib treatment. Research conducted in xenograft models demonstrates that ATF3 mediates the anti-tumor activity of Carfilzomib. The examination of human esophageal squamous cell carcinoma indicated that ATF3 and LDHA have the potential to function as innovative targets for therapeutic intervention in the treatment of ESCC. Our findings demonstrate the novel function of Carfilzomib in modulating ESCC metabolism and progression, highlighting the potential of Carfilzomib as a promising therapeutic agent for the treatment of ESCC.


Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma.
Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first-degree relatives (and second-degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy-catecholamines and bi-annual rapid whole-body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre-symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow-up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.


Inhibition of copper/zinc superoxide dismutase impairs NO.-mediated endothelium-dependent relaxations.
The superoxide anion (O-2.) appears to be an important modulator of nitric oxide (NO.) bioavailability. The present study was designed to characterize the role of copper/zinc superoxide dismutase (Cu/Zn SOD) in endothelium-dependent relaxations. Cu/Zn SOD was inhibited with the Cu2+ chelator diethyldithiocarbamic acid (DETCA). In isolated canine basilar arteries, DETCA (7.6 x 10(-3) M) inhibited total vascular SOD activity by 46% (P < 0.0001, n = 6-8 dogs). DETCA (7.6 x 10(-3) M) significantly reduced relaxations to bradykinin and A-23187 (P < 0.05, n = 7-11). The inhibitory effect of DETCA was abolished by the O-2. scavenger 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron; 9.4 x 10(-3) M; P < 0.05, n = 6-13). Tiron significantly potentiated the relaxations to bradykinin in control rings (P < 0.05, n = 13), and the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 3 x 10(-4) M) abolished these relaxations (P < 0.0001, n = 6). DETCA and Tiron had no effect on the relaxations to diethylamine-NONOate or forskolin (P > 0.05, n = 6). Our results demonstrate that endothelium-dependent relaxations mediated by NO. are impaired after the inhibition of Cu/Zn SOD. Relaxations to bradykinin (but not A-23187) were significantly augmented by Tiron. Pharmacological scavenging of O-2. reverses the effect of Cu/Zn SOD inhibition.


Phosphoinositide metabolism in intestinal smooth muscle: preferential production of Ins(1,4,5)P3 in circular muscle cells.
The pattern of inositol phospholipid metabolism in response to stimulation by contractile agonists was examined in muscle cells isolated separately from circular and longitudinal muscle layers of guinea pig intestine. Addition of cholecystokinin octapeptide (CCK-8) to circular muscle cells caused a prompt decrease in phosphatidylinositol 4,5-bisphosphate (PtdInsP2) (50 +/- 6%) and PtdInsP (38 +/- 9%), which reached a nadir in 15 s. Addition of CCK-8 to longitudinal muscle cells caused a decrease in PtdInsP only (42 +/- 6%); PtdInsP2 levels, which were three times lower in this cell type, did not change throughout the period of stimulation. Hydrolysis of PtdInsP2 in circular muscle cells was accompanied by a concentration-dependent increase in inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]; the maximal increase was 10 to 16 times greater in circular muscle cells as measured by radioreceptor assay and by ion-exchange chromatography. The small amounts of InsP3 produced in longitudinal muscle cells did not result from more rapid degradation, since the rates of disappearance of exogenous Ins(1,4,5)P3 in both cell types were similar. Within 5 s after addition of CCK-8, InsP3 comprised 73 +/- 5% of total inositol phosphates produced in circular muscle cells and 2.0 +/- 0.2% in longitudinal muscle cells. These divergent patterns indicate that inositol phospholipid metabolism is channeled toward generation of InsP3 in circular muscle cells only; the metabolic pattern in these cells parallels the selective presence of high-affinity InsP3 receptors and the pattern of intracellular Ca2+ mobilization.


[Effect of hydrocortisone on sodium and potassium distribution in the sections of the cerebral cortex of rats after their electric stimulation].
Sections of the rat brain cortex were incubated in various physiological media using container-electrodes, similar to the McIlwain's type. The shifts of sodium and potassium distribution between the extra- and intracellular spaces of the slices after different stimulation parameters and the subsequent restoration were measured. The administration of hydrocortisone (for 7 days, 5 mg/100 g daily) usually increased the response of the slices to the stimulation in incubation in the glutamate devoid medium. When 0.2--0.5 mM of glutamate was added to the media the effect of hydrocortisone disappeared. Possible physiological significance of the mentioned results is discussed.


Assessing the risk of malaria local transmission and re-introduction in China from pre-elimination to elimination: A systematic review.
Assessing the risk of malaria local transmission and re-introduction is crucial for the preparation and implementation of an effective elimination campaign and the prevention of malaria re-introduction in China. Therefore, this review aims to evaluate the risk factors for malaria local transmission and re-introduction in China over the period of pre-elimination to elimination. Data were obtained from six databases searched for studies that assessed malaria local transmission risk before malaria elimination and re-introduction risk after the achievement of malaria elimination in China since the launch of the NMEP in 2010, employing the keywords "malaria" AND ("transmission" OR "re-introduction") and their synonyms. A total of 8,124 articles were screened and 53 articles describing 55 malaria risk assessment models in China from 2010 to 2023, including 40 models assessing malaria local transmission risk (72.7%) and 15 models assessing malaria re-introduction risk (27.3%). Factors incorporated in the 55 models were extracted and classified into six categories, including environmental and meteorological factors (39/55, 70.9%), historical epidemiology (35/55, 63.6%), vectorial factors (32/55, 58.2%), socio-demographic information (15/26, 53.8%), factors related to surveillance and response capacity (18/55, 32.7%), and population migration aspects (13/55, 23.6%). Environmental and meteorological factors as well as vectorial factors were most commonly incorporated in models assessing malaria local transmission risk (29/40, 72.5% and 21/40, 52.5%) and re-introduction risk (10/15, 66.7% and 11/15, 73.3%). Factors related to surveillance and response capacity and population migration were also important in malaria re-introduction risk models (9/15, 60%, and 6/15, 40.0%). A total of 18 models (18/55, 32.7%) reported the modeling performance. Only six models were validated internally and five models were validated externally. Of 53 incorporated studies, 45 studies had a quality assessment score of seven and above. Environmental and meteorological factors as well as vectorial factors play a significant role in malaria local transmission and re-introduction risk assessment. The factors related to surveillance and response capacity and population migration are more important in assessing malaria re-introduction risk. The internal and external validation of the existing models needs to be strengthened in future studies.


Recommendations for Working with Culturally and Linguistically Diverse Families: A Report from the Field.
Given the persistent shift in racial and ethnic demographics in the United States, board certified behavior analysts (BCBAs) will increasingly serve culturally and linguistically diverse families. There has been a recent increase in published resources to help behavior analysis practitioners navigate working with diverse populations. The purpose of this article is to add to these resources and demonstrate how these recommendations can be put into action. We outline five recommendations for working with culturally and linguistically diverse families in the context of a small company that has incorporated these practices in their own work focused on serving a large percentage of immigrant families.


Normal values and ranges of the lateral capitello-humeral angle in healthy children.
The lateral capitello-humeral angle (LCHA), which is an index of sagittal alignment of the elbow, has gradually been adopted for the postoperative assessment of radiographic results. However, the normal values and ranges of the LCHA remain unclear. A retrospective cohort study was performed to evaluate the normal values and ranges of the LCHA in a sample of healthy children with even distributions of age, sex and laterality. A total of 168 radiographs of the elbows of healthy children (age range, 0-11 years) with even distributions of age, sex and laterality were reviewed. The primary aim was to analyze the normal values and ranges of the LCHA categorized by age, sex and laterality. The secondary aim was to assess the association of the LCHA with increasing age. The LCHA between sex or laterality in each age category was also compared. The mean LCHA of the 168 patients was 47.1° (range, 27°-63°). There was a weak association between the LCHA and increasing age (r = 0.41). The mean LCHA in females (49.1°) was significantly larger than that in males (45.1°). Significant sex-related differences were observed in age categories between 2 and 7 years. Results of this study will be useful in the postoperative radiographic assessment of sagittal alignment of the elbow in children.