Comparison between the 1% and 2% ibopamine provocative test in primary open-angle glaucoma patients: sensitivity, specificity and tolerability.
To compare intraocular pressure (IOP) rise in normal individuals and primary open-angle glaucoma patients and the safety and efficacy of ibopamine eye drops in different concentrations as a provocative test for glaucoma. Glaucoma patients underwent (same eye) the ibopamine provocative test with two concentrations, 1% and 2%, in a random sequence at least 3 weeks apart, but not more than 3 months. The normal individuals were randomly submitted to one of the concentrations of ibopamine (1% and 2%). The test was considered positive if there was an IOP rise greater than 3 or 4 mmHg at 30 or 45 minutes to test which subset of the test has the best sensitivity (Se)/specificity (Sp). There was no statistically significant difference in any of the IOP measurements, comparing 1% with 2% ibopamine. The IOP was significantly higher at 30 and 45 minutes with both concentrations (p < 0.001). The best sensitivity/specificity ratio was achieved with the cutoff point set as greater than 3 mmHg at 45 minutes with 2% ibopamine (area under the ROC curve: 0.864, Se: 84.6%; Sp:73.3%). All patients described a slight burning after ibopamine's instillation. 2% ibopamine is recommended as a provocative test for glaucoma. Because both concentrations have similar ability to rise IOP, 1% ibopamine may be used to treat ocular hypotony.


Vitamin K, vertebral fractures, vascular calcifications, and mortality: VItamin K Italian (VIKI) dialysis study.
Vitamin K (vitamin K1 or phylloquinone and vitamin K2, a series of menaquinones [MKs]) is involved in the production of bone and matrix amino acid γ-carboxy-glutamic acid (Gla) proteins, regulating bone and vascular calcification. Low vitamin K concentrations are associated with increased risks of fractures and vascular calcification, and frequent complications in hemodialysis patients. We carried out an observational study to establish the prevalence of vitamin K deficiency and to assess the relationship between vitamin K status, vertebral fractures, vascular calcification, and survival in 387 patients on hemodialysis for ≥1 year. We determined plasma levels of vitamin K compound, bone-Gla-protein, matrix-Gla-protein, and routine biochemistry. Vertebral fractures (reduction in vertebral body height by ≥20%) and aortic and iliac calcifications were also investigated in a spine (D(5) -L(4)) radiograph. Three-year patient survival was analyzed. Important proportions of patients had deficiency of MK7 (35.4%), vitamin K1 (23.5%), and MK4 (14.5%). A total of 55.3% of patients had vertebral fractures, 80.6% had abdominal aorta calcification, and 56.1% had iliac calcification. Vitamin K1 deficiency was the strongest predictor of vertebral fractures (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.38-6.26). MK4 deficiency was a predictor of aortic calcification (OR, 2.82; 95% CI, 1.14-7.01), whereas MK5 deficiency actually protected against it (OR, 0.38; 95% CI, 0.15-0.95). MK7 deficiency was a predictor of iliac calcification (OR, 1.64; 95% CI, 1.03-2.60). The presence of vertebral fractures was also a predictor of vascular calcifications (OR, 1.76; 95% CI, 1.00-3.08). Increased alkaline phosphatase and C reactive protein (CRP), age, and cerebrovascular events were predictors of mortality. Our study suggests that the vitamin K system may be important for preserving bone mass and avoiding vascular calcification in hemodialysis patients, pointing out a possible role of vitamin K in bone and vascular health. Based on our results, we suggest that the general population should also be studied for vitamin K deficiency as a possible cause of both vertebral fractures and vascular calcification.


Assessment of the B-lymphocyte population in agammaglobulinemia.
The population of B lymphocytes was assessed in the blood of 16 patients with agammaglobulinemia using immunofluorescence and EAC1423 reactivity as B-cell markers. Lymphocytes were fractionated on gradients of bovine serum albumin which are capable of separating lymphocytes into B-cell-rich and T-cell-rich populations. There was complete absence of B lymphocytes in the majority of patients with X-linked agammaglobulinemia. Normal or increased numbers of B lymphocytes were found in all patients with common variable agammaglobulinemia.


Limited Effects of Type I Interferons on Kyasanur Forest Disease Virus in Cell Culture.
The tick-borne flavivirus, Kyasanur Forest disease virus (KFDV) causes seasonal infections and periodic outbreaks in south-west India. The current vaccine offers poor protection with reported issues of coverage and immunogenicity. Since there are no approved prophylactic therapeutics for KFDV, type I IFN-α/β subtypes were assessed for antiviral potency against KFDV in cell culture. The continued passage of KFDV-infected cells with re-administered IFN-α2a treatment did not eliminate KFDV and had little effect on infectious particle production whereas the IFN-sensitive, green fluorescent protein-expressing vesicular stomatitis virus (VSV-GFP) infection was controlled. Further evaluation of the other IFN-α/β subtypes versus KFDV infection indicated that single treatments of either IFN-αWA and IFN-αΚ appeared to be more effective than IFN-α2a at reducing KFDV titres. Concentration-dependent analysis of these IFN-α/β subtypes revealed that regardless of subtype, low concentrations of IFN were able to limit cytopathic effects (CPE), while significantly higher concentrations were needed for inhibition of virion release. Furthermore, expression of the KFDV NS5 in cell culture before IFN addition enabled VSV-GFP to overcome the effects of IFN-α/β signalling, producing a robust infection. Treatment of cell culture with IFN does not appear to be suitable for KFDV eradication and the assay used for such studies should be carefully considered. Further, it appears that the NS5 protein is sufficient to permit KFDV to bypass the antiviral properties of IFN. We suggest that other prophylactic therapeutics should be evaluated in place of IFN for treatment of individuals with KFDV disease.


Interface engineering of CeO2 nanoparticle/Bi2WO6 nanosheet nanohybrids with oxygen vacancies for oxygen evolution reactions under alkaline conditions.
Because of the interactive combination synergy effect, hetero interface engineering is used way for advancing electrocatalytic activity and durability. In this study, we demonstrate that a CeO2/Bi2WO6 heterostructure is synthesized by a hydrothermal method. Electrochemical measurement results indicate that CeO2/Bi2WO6 displays not only more OER catalytic active sites with an overpotential of 390 mV and a Tafel slope of 117 mV dec-1 but also durability for 10 h (97.57%). Such outstanding characteristics are primarily attributed to (1) the considerable activities by CeO2 nanoparticles uniformly distributed on Bi2WO6 nanosheets and (2) the plentiful Bi-O-Ce and W-O-Ce species playing the role of strong couples between CeO2 nanoparticles and Bi2WO6 nanosheets and oxygen vacancy existence in CeO2 nanoparticles, which can improve the electrochemical active surface area (ECSA) and activity, and enhance the conductivity for OERs. This CeO2/Bi2WO6 consists of the heterojunction engineering that can open a modern method of thinking for high effective OER electrocatalysts.


Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani.
Despite extensive use of antimonial compounds in the treatment of leishmaniasis, their mode of action remains uncertain. Here we show that trivalent antimony (Sb(III)) interferes with trypanothione metabolism in drug-sensitive Leishmania parasites by two inherently distinct mechanisms. First, Sb(III) decreases thiol buffering capacity by inducing rapid efflux of intracellular trypanothione and glutathione in approximately equimolar amounts. Second, Sb(III) inhibits trypanothione reductase in intact cells resulting in accumulation of the disulfide forms of trypanothione and glutathione. These two mechanisms combine to profoundly compromise the thiol redox potential in both amastigote and promastigote stages of the life cycle. Furthermore, we demonstrate that sodium stibogluconate, a pentavalent antimonial used clinically for the treatment for leishmaniasis, induces similar effects on thiol redox metabolism in axenically cultured amastigotes. These observations suggest ways in which current antimony therapies could be improved, overcoming the growing problem of antimony resistance.


Differences in Cardiac Output and Aerobic Capacity Between Sexes Are Explained by Blood Volume and Oxygen Carrying Capacity.
Whether average sex differences in cardiorespiratory fitness can be mainly explained by blood inequalities in the healthy circulatory system remains unresolved. This study evaluated the contribution of blood volume (BV) and oxygen (O2) carrying capacity to the sex gap in cardiac and aerobic capacities in healthy young individuals. Healthy young women and men (n = 28, age range = 20-43 years) were matched by age and physical activity. Echocardiography, blood pressures, and O2 uptake were measured during incremental exercise. Left ventricular end-diastolic volume (LVEDV), stroke volume (SV), cardiac output (Q), peak O2 uptake (VO2peak ), and BV were assessed with precise methods. The test was repeated in men after blood withdrawal and reduction of O2 carrying capacity, reaching women's levels. Before blood normalization, exercise cardiac volumes and output (LVEDV, SV, Q) adjusted by body size and VO2peak (42 ± 9 vs. 50 ± 11 ml⋅min-1⋅kg-1, P < 0.05) were lower in women relative to men. Blood normalization abolished sex differences in cardiac volumes and output during exercise (P ≥ 0.100). Likewise, VO2peak was similar between women and men after blood normalization (42 ± 9 vs. 40 ± 8 ml⋅min-1⋅kg-1, P = 0.416). In conclusion, sex differences in cardiac output and aerobic capacity are not present in experimental conditions matching BV and O2 carrying capacity between healthy young women and men.


Understanding individuals' desire for change, perceptions of impairment, benefits, and barriers of change for pathological personality traits.
Despite clinical theory suggesting that individuals are largely unaware of personality-related problems (Gallrein et al., 2013; Oltmanns & Powers, 2012); work in this area shows that individuals possess insight into their pathological traits and the impairment they may cause. Individuals generally dislike pathological traits and desire change in the direction of greater adaptivity (Lamkin et al., 2018; Miller et al., 2018). Individuals may also be able to make small, intentional changes in some personality domains (e.g., neuroticism; Hudson & Fraley, 2015; Hudson & Roberts, 2014) but not others (no positive change in conscientiousness or agreeableness). It remains unclear why many individuals exhibit relatively little change in their pathological traits (e.g., antagonism), given their awareness of the problems these traits cause and their desire for change. The goal of the present study was to explore the relation between personality disorder (PD) traits and desire for change, perceived impairment and benefits, and barriers to change among an online sample (N = 497). Findings suggest that most individuals were uninterested in changing their trait levels; however, individuals with elevated PD traits were more interested in change than those with lower levels. Pathological traits were generally perceived as impairing rather than beneficial; however, mean level analyses revealed similar levels of perceived impairment and benefits for those relatively high on antagonism. Individuals reported that personality change was stymied in part because it was too hard, they were unmotivated to make the changes, or they did not know how to go about making such changes. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Long-term biodiversity intervention shapes health-associated commensal microbiota among urban day-care children.
In modern urban environments children have a high incidence of inflammatory disorders, including allergies, asthma, and type1 diabetes. The underlying cause of these disorders, according to the biodiversity hypothesis, is an imbalance in immune regulation caused by a weak interaction with environmental microbes. In this 2-year study, we analyzed bacterial community shifts in the soil surface in day-care centers and commensal bacteria inhabiting the mouth, skin, and gut of children. We compared two different day-care environments: standard urban day-care centers and intervention day-care centers. Yards in the latter were amended with biodiverse forest floor vegetation and sod at the beginning of the study. Intervention caused a long-standing increase in the relative abundance of nonpathogenic environmental mycobacteria in the surface soils. Treatment-specific shifts became evident in the community composition of Gammaproteobacteria, Negativicutes, and Bacilli, which jointly accounted for almost 40 and 50% of the taxa on the intervention day-care children's skin and in saliva, respectively. In the year-one skin swabs, richness of Alpha-, Beta-, and Gammaproteobacteria was higher, and the relative abundance of potentially pathogenic bacteria, including Haemophilus parainfluenzae, Streptococcus sp., and Veillonella sp., was lower among children in intervention day-care centers compared with children in standard day-care centers. In the gut, the relative abundance of Clostridium sensu stricto decreased, particularly among the intervention children. This study shows that a 2-year biodiversity intervention shapes human commensal microbiota, including taxa that have been associated with immune regulation. Results indicate that intervention enriched commensal microbiota and suppressed the potentially pathogenic bacteria on the skin. We recommend future studies that expand intervention strategies to immune response and eventually the incidence of immune-mediated diseases.


The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs.
As the blockade of inhibitory surface-molecules such as CTLA-4 on T cells has led to recent advances in antitumor immune therapy, there is great interest in identifying novel mechanisms of action of CD8+ T cells to evoke effective cytotoxic antitumor responses. Using in vitro and in vivo models, we investigated the molecular pathways underlying the CTLA-4-mediated differentiation of IL-17-producing CD8+ T cells (Tc17 cells) that strongly impairs cytotoxicity. Our studies demonstrate that Tc17 cells lacking CTLA-4 signaling have limited production of STAT3-target gene products such as IL-17, IL-21, IL-23R and RORγt. Upon re-stimulation with IL-12, these cells display fast downregulation of Tc17 hallmarks and acquire Tc1 characteristics such as IFNγ and TNF-α co-expression, which is known to correlate with tumor control. Indeed, upon adoptive transfer, these cells were highly efficient in the antigen-specific rejection of established OVA-expressing B16 melanoma in vivo. Mechanistically, in primary and re-stimulated Tc17 cells, STAT3 binding to the IL-17 promoter was strongly augmented by CTLA-4, associated with less binding of STAT5 and reduced relative activation of STAT1 which is known to block STAT3 activity. Inhibiting CTLA-4-induced STAT3 activity reverses enhancement of signature Tc17 gene products, rendering Tc17 cells susceptible to conversion to Tc1-like cells with enhanced cytotoxic potential. Thus, CTLA-4 critically shapes the characteristics of Tc17 cells by regulating relative STAT3 activation, which provides new perspectives to enhance cytotoxicity of antitumor responses.


Characterization and Potential Antitumor Activity of Polysaccharide from Gracilariopsis lemaneiformis.
Substances with valuable antitumor properties have been identified in many marine algae, including an edible polysaccharide from the marine alga Gracilariopsis lemaneiformis (PGL). We previously reported transcriptome profiling data showing that PGL induced transcriptional alterations generate anti-lung cancer activity. To identify how PGL is detrimental to tumors, we purified PGL to characterize its chemical composition, molecular weight, and sugar and protein content and investigated its antitumor activity. We demonstrated that PGL exerted its antitumor activities by modulating cell viability, morphology, apoptosis, and the apoptosis-related Fas/FasL signaling pathway in the human lung cancer cell line A549, the gastric cancer cell line MKN28, and the mouse melanoma cell line B16. Our data provide the first evidence that PGL inhibits cell proliferation by inducing apoptosis, which is largely mediated by Fas/FasL in cancer cells, suggesting that PGL might be a novel therapeutic agent against cancer.


Transfer Learning Based on Optimal Transport for Motor Imagery Brain-Computer Interfaces.
This paper tackles the cross-sessions variability of electroencephalography-based brain-computer interfaces (BCIs) in order to avoid the lengthy recalibration step of the decoding method before every use. We develop a new approach of domain adaptation based on optimal transport to tackle brain signal variability between sessions of motor imagery BCIs. We propose a backward method where, unlike the original formulation, the data from a new session are transported to a calibration session, and thereby avoiding model retraining. Several domain adaptation approaches are evaluated and compared. We simulated two possible online scenarios: i) block-wise adaptation and ii) sample-wise adaptation. In this study, we collect a dataset of 10 subjects performing a hand motor imagery task in 2 sessions. A publicly available dataset is also used. For the first scenario, results indicate that classifier retraining can be avoided by means of our backward formulation yielding to equivalent classification performance as compared to retraining solutions. In the second scenario, classification performance rises up to 90.23% overall accuracy when the label of the indicated mental task is used to learn the transport. Adaptive time is between 10 and 80 times faster than the other methods. The proposed method is able to mitigate the cross-session variability in motor imagery BCIs. The backward formulation is an efficient retraining-free approach built to avoid lengthy calibration times. Thus, the BCI can be actively used after just a few minutes of setup. This is important for practical applications such as BCI-based motor rehabilitation.


Cerebral white matter integrity during primary HIV infection.
Inflammation and infection within the central nervous system is initiated during primary HIV infection (PHI), but the association of these processes with the integrity of brain white matter during PHI is unknown. We used diffusion tensor imaging (DTI) in this prospective cross-sectional neuroimaging study to determine the extent of white matter involvement in early HIV infection. Antiretroviral-naive PHI (defined as <1 year after infection, n = 62), chronic HIV infection (CHI, n = 16), and HIV-uninfected (n = 19) participants had DTI, laboratory, and neuropsychometric performance assessments. DTI metrics were examined using region of interest and whole brain voxelwise analyses. Linear mixed-effects models assessed correlations between DTI measures and laboratory and neuropsychometric performance values. PHI participants were assessed at a median 4.1 months after estimated infection, and had median CD4 cell count of 573 cells/μl, and HIV-1 RNA viral load of 4.5 log10 copies/ml in plasma and 2.6 log10 copies/ml in cerebrospinal fluid (CSF). DTI metrics in PHI individuals were similar to HIV- participants and correlated with disruptions in the blood-brain barrier (indicated by CSF/plasma albumin ratio and CSF protein). CHI participants had significant loss of white matter integrity that correlated with biomarkers of infection and inflammation (blood viral load, CD4 T-cell count, and neopterin, and CSF white blood cell). Within the PHI group, DTI metrics inversely correlated with increasing days since infection. In individuals assessed during PHI, group DTI measures suggested relative preservation of white matter microstructural integrity, but were associated with disruption of the blood-brain barrier and estimated duration of infection.


Polysialic acid bioengineering of neuronal cells by N-acyl sialic acid precursor treatment.
The inherent promiscuity of the polysialic acid (PSA) biosynthetic pathway has been exploited by the use of exogenous unnatural sialic acid precursor molecules to introduce unnatural modifications into cellular PSA, and has found applications in nervous system development and tumor vaccine studies. The sialic acid precursor molecules N-propionyl- and N-butanoyl-mannosamine (ManPr, ManBu) have been variably reported to affect PSA biosynthesis ranging from complete inhibition to de novo production of modified PSA, thus illustrating the need for further investigation into their effects. In this study, we have used a monoclonal antibody (mAb) 13D9, specific to both N-propionyl-PSA and N-butanoyl-PSA (NPrPSA and NBuPSA), together with flow cytometry, to study precursor-treated tumor cells and NT2 neurons at different stages of their maturation. We report that both ManPr and ManBu sialic acid precursors are metabolized and the resultant unnatural sialic acids are incorporated into de novo surface sialylglycoconjugates in murine and human tumor cells and, for the first time, in human NT2 neurons. Furthermore, neither precursor treatment deleteriously affected endogenous PSA expression; however, with NT2 cells, PSA levels were naturally downregulated as a function of their maturation into polarized neurons independent of sialic acid precursor treatment.


Biology and pathology of the uterine microenvironment and its natural killer cells.
Tissues are the new frontier of discoveries in immunology. Cells of the immune system are an integral part of tissue physiology and immunity. Determining how immune cells inhabit, housekeep, and defend gut, lung, brain, liver, uterus, and other organs helps revealing the intimate details of tissue physiology and may offer new therapeutic targets to treat pathologies. The uterine microenvironment modulates the development and function of innate lymphoid cells [ILC, largely represented by natural killer (NK) cells], macrophages, T cells, and dendritic cells. These immune cells, in turn, contribute to tissue homeostasis. Regulated by ovarian hormones, the human uterine mucosa (endometrium) undergoes ~400 monthly cycles of breakdown and regeneration from menarche to menopause, with its fibroblasts, glands, blood vessels, and immune cells remodeling the tissue into the transient decidua. Even more transformative changes occur upon blastocyst implantation. Before the placenta is formed, the endometrial glands feed the embryo by histiotrophic nutrition while the uterine spiral arteries are stripped of their endothelial layer and smooth muscle actin. This arterial remodeling is carried out by invading fetal trophoblast and maternal immune cells, chiefly uterine NK (uNK) cells, which also assist fetal growth. The transformed arteries no longer respond to maternal stimuli and meet the increasing demands of the growing fetus. This review focuses on how the everchanging uterine microenvironment affects uNK cells and how uNK cells regulate homeostasis of the decidua, placenta development, and fetal growth. Determining these pathways will help understand the causes of major pregnancy complications.


Mapping, in the rat central nervous system, of morphine-induced changes in turnover of 5-hydroxytryptamine.
1. It is known that the full clinical effect of morphine is not seen if those neurones of the central nervous system which contain 5-hydroxytryptamine (5-HT) have been inactivated. Morphine increases 5-HT turnover in brain and cord, and the present work is an attempt at mapping the sites at which turnover is accelerated. 2. The degree of interaction at various sites of the C.N.S. was measured by the increment in the content of 5-hydroxyindol-3-yl acetic acid (5-HIAA) elicited by morphine in rats pre-treated with probenecid. The effect was produced by as little as 3.5 mg morphine hydrochloride/kg; for the sake of convenience this dose was doubled in most experiments. Pre-treatment with probenecid was not necessary for the effect, but a minimum interval of 90 min between injection of morphine and analysis of the brain was essential. 3. Morphine did not act indiscriminately on all 5-HT neurons, as seen by the fact that the increment in 5-HIAA formation was independent of the density of 5-HT neurones in the tissue. Nor was there any relation between basal 5-HT turnover of a region and the size of its response to morphine. 4. Highly reactive sites were found in dorsal cord, medulla, superior colliculi, substantia nigra, thalamus, hypothalamus, amygdala and striatum. Cortical areas were less responsive, but with large differences among themselves. Hippocampus, central grey, olfactory bulb, cerebellum and white matter had lower or negligible increases in 5-HT turnover. There was no increase in the turnover of the (non-neural) 5-HT of the pineal gland. 5. The relation of the reactive sites to their content in endogenous opioids and to the probable localization of the pharmacological actions of morphine is discussed.


[Methods for the detection of viral contamination in food of animal origin].
Contamination of foods of animal origin with pathogenic human viruses may occur during handling or through polluted water. Most of these viruses are pathogens originating from the human gastrointestinal tract. They can be transmitted by the consumption of contaminated food and often cause disease. A survey is given of DNA- and RNA-viruses that may occur as contaminants of foods. In addition, the classical methods for detecting viral contaminations in foods are summarized. They are based on the effects after virus inoculation of cell cultures. Besides the fact that these methods are not economic and time consuming, they do not permit detection of some of the most important foodborne gastroenteritis viruses. The possibility of replacing these methods by detecting the viral genomes using hybridization and polymerase chain reaction (PCR) is discussed.


Coccidioidomycosis osteomyelitis masquerading as a bone tumor. A report of 2 cases.
Coccidioidomycosis involving the lung is common in endemic areas. However, it is unusual for it to present as a solitary bone lesion. Two cases of Coccidioides immitis osteomyelitis clinically and radiographically mimicked a primary bone tumor. Fine needle aspiration (FNA) biopsy of these lytic bone lesions yielded diagnostic material. Aspirated material in 1 case showed a suppurative, granulomatous inflammation and scattered spherules with refractile walls, some containing endospores consistent with coccidioidomycosis. Smears in the other case showed acute inflammation and necrosis, and rare spherules were identified with the Gomori-mathenamine-silver stain. C immitis infection was confirmed by culture in both cases. Although rare, coccidioidomycosis can involve the bone and mimic a primary bone tumor. FNA biopsy is helpful in differentiating between inflammatory and neoplastic processes involving bone by acquiring material for cytologic studies and cultures.


Long-Term Treatment with Thrombomodulin Improves Functional Outcomes after Cerebral Ischemia Even if Administration is Delayed.
Our previous study indicated that recombinant human soluble thrombomodulin (rhsTM) could attenuate brain damage when administered as a bolus in the cerebral ischaemic early phase. Then, we considered that treatment with rhsTM may show therapeutic effects even when administered in the ischaemic delayed phase, because rhsTM has an action of inhibiting high-mobility group box 1 (HMGB1) as a late mediator of lethal systemic inflammation. This study was performed to investigate the effects of delayed treatment with rhsTM on ischaemic brain damage induced by high HMGB1 level in mice subjected to 4-hour middle cerebral artery occlusion (MCAO). One day after MCAO, rhsTM was administered intraperitoneally at a dose of 1 or 5 mg/kg once a day for 7 days. Neurological score, motor coordination and HMGB1 levels were measured 1, 3 and 7 days after MCAO. The presence of activated microglia was evaluated 7 days after MCAO. Systemic HMGB1 levels increased 1 to 7 days after MCAO and were higher at 7 days compared with day 1. At the same time, survival rate decreased, and activated microglia increased in the infarct area. Treatment with rhsTM improved neurological score, motor coordination, survival and prevented brain damage. Moreover, rhsTM decreased both HMGB1 level and number of activated M1 microglia. The results of this study indicated that rhsTM improved functional outcomes via inhibition of HMGB1 up-regulation and M1 microglial activation in the cerebral ischaemic delayed phase. rhsTM may become a new therapeutic agent with a wide therapeutic time window in patients with cerebral ischaemia.


Post-Polio Syndrome in a Primary Care Setting: A Case Report.
Post-Polio Syndrome (PPS) is a sequela of poliovirus infection that causes weakness in previously infected polio patients years after the initial infection. The diagnosis is one of exclusion and entails the following: 1) a prior episode of poliomyelitis with residual motor neuron function loss, 2) a period of at least 15 years or more after the acute onset of polio with neurologic and functional stability, and 3) a gradual onset of new weakness and abnormal muscle fatigability that has persisted for at least one year. While the exact etiology is unknown, the prevalence of PPS has increased as patients who have previously survived polio are getting older. In this report, we discuss a patient presenting to his primary care provider for evaluation of worsening lower extremity weakness over the course of the past three years. In addition to general characteristics of PPS, we will review the use of electromyography (EMG)/nerve conduction studies and imaging for evaluation. This report will also review prevention methods with vaccinations and identify potential treatment regimens including aerobic exercise and medications ranging from tricyclic antidepressants (TCAs) to dopamine agonists. The goal of this paper is to not only shine a light on PPS in general, but to show how social determinants i.e., economic stability, healthcare access and quality of health may affect the diagnosis of uncommon conditions.


Immobilization of glucose oxidase on polymer membranes treated by low-temperature plasma.
Low-temperature plasma was employed for activation of polymer membranes as a carrier for enzyme immobilization. Glucose oxidase was immobilized on polypropylene (PP), polyvinylidene fluoride (PVDF), or polytetrafluoroethylene (PTFE) membrane surfaces treated by nitrogen or ammonia gas plasma using glutaraldehyde as a linking agent. Enzyme activity was evaluated by the response of glucose sensor composed of the immobilized enzyme membrane and a dissolved oxygen electrode. The sensor response was found to depend on the kind of carrier membrane and to become maximum at suitable conditions of plasma treatment.


Indications for Magnetic Resonance Imaging in Patients With Behcet Uveitis.
Behcet disease is a systemic vasculitis, which may involve the eyes and central nervous system. The true prevalence of neurological involvement is not precisely known but may be associated with ocular involvement. This study investigates the association between Behcet uveitis and neuro-Behcet disease. A retrospective single-center analysis was conducted for consecutive patients with Behcet uveitis at the Massachusetts Eye Research and Surgery Institution. Uveitis characteristics, neurological symptoms, fluorescein fundus angiography, and MRI results were recorded. Our population included 108 patients with Behcet uveitis, and 26 (24.1%) were found to have neurological involvement associated with Behcet disease. Optic nerve leakage on fundus angiography and neurological symptoms were associated with an increased risk of neurological involvement. Three cases (11.5%) were nonparenchymal, while 23 (88.5%) were parenchymal with lesions in the cortex, subcortical white matter, thalamus, basal ganglia, and brainstem. There is a high comorbidity between ocular and neurological involvement in Behcet disease. Careful assessment of neurological symptoms and baseline fluorescein fundus angiography are recommended for patients with Behcet disease. MRI has a high diagnostic yield and should be pursued if there is concern for progressive or pre-existing neurological involvement.


Knockdown of placental growth factor (PLGF) mitigates hyperoxia-induced acute lung injury in neonatal rats: Suppressive effects on NFκB signaling pathway.
Although supplemental high-level oxygen treatment can promote the survival of premature infants, hyperoxia may adversely induce acute lung injury (ALI) in newborns. Our prior work illustrated that hyperoxic exposure could enhance the release of placental growth factor (PLGF) in the lungs of neonatal rats. We therefore postulated that PLGF contributed to hyperoxic ALI in newborns and evaluated the anti-PLGF treatment mediated by systematic delivery of lentivirus in hyperoxic ALI in this study. Lentivirus particles containing PLGF specific shRNA were injected into neonatal rats prior to hyperoxic exposure (90% oxygen for 72h) to inhibit PLGF expression. Hyperoxia induced oxidative damages in lung tissues as evidenced by the increased malondialdehyde and myeloperoxidase, and the decreased antioxidant superoxide dismutase. Also, hyperoxia caused excessive infiltration of inflammatory cells and overproduction of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β and interleukin-6) in rat lung tissue. These pathological alterations were partly reversed by PLGF shRNA delivery. The expression levels and activities of metalloproteinase (MMP)-2 and MMP9 were up-regulated in response to hyperoxia, whereas down-regulated when PLGF was inhibited. Moreover, PLGF shRNA inhibited nuclear factor kappa B (NFκB) signaling delivery in hyperoxic rat lungs. Additionally, exogenous PLGF-induced activation of MMPs in rat RLE-6TN alveolar epithelial cells was suppressed by NFκB inhibitor pyrrolidine dithiocarbamate. These results suggest that therapy targeting PLGF may be beneficial for infants with hyperoxic ALI.


Hepatic microvascular development in relation to the morphogenesis of hepatocellular plates in neonatal rats.
The development of hepatic microvascular heterogeneity after birth, and its temporal relationship to the development of parenchymal cell plates have received little attention. As a result, the morphogenesis of some of the parameters contributing to this heterogeneity in suckling and weaned rats was studied as a function of time between postpartum days 4 and 30 using in vivo light microscopic, electron microscopic, and immunocytochemical methods. During the early suckling period, the sinusoid network is highly anastomotic, with little evidence of zonation, and the parenchymal cell plates contain multiple cells and are irregularly arranged throughout the lobule. Sinusoidal endothelial fenestration is sparse at 4 days, but phagocytic Kupffer cell (KC) function already exists and exhibits zonal heterogeneity, with more cells located in the periportal zone. With increasing age, endothelial fenestrae increase and organize as sieve plates. Widened centrilobular radial sinusoids form through a loss ("drop-out") of intersinusoidal sinusoids (ISS). Concomitantly, the associated cell plates straighten and become one cell thick. Hepatocyte DNA synthesis and mitosis are higher in the periportal zone, which retains thickened cell plates and anastomotic sinusoids. The centrilobular sinusoids may widen to accommodate the increased volume of blood that results from the loss of ISS as well as the increased numbers of periportal sinusoids containing flow that feed these vessels. KC phagocytic activity increases during the suckling period concomitant with an increase of gut-derived endotoxin in the portal blood, which suggests that the KCs may be releasing mediators that affect sinusoid diameter, blood flow, endothelial fenestration, and perhaps parenchymal growth either directly or through the stimulation of growth factors.


Three new species of squat lobsters of the genus Munidopsis Whiteaves, 1874, from Guadeloupe Island, Caribbean Sea (Crustacea, Decapoda, Munidopsidae).
The genus Munidopsis is one of the most diverse genera within squat lobsters. Here, three new species of Munidopsis, M. cornuata n. sp., M. senticosa n. sp., and M. turgida n. sp., from <500 m off Guadeloupe Island (Caribbean Sea), are fully described and illustrated. Among the Atlantic species of the genus, M. cornuata n. sp. belongs to the group of species having the dorsal surface of the carapace with spines and is most similar to M. robusta (A. Milne-Edwards, 1880), from the Gulf of Mexico and Caribbean Sea. Munidopsis senticosa n. sp. resembles M. barbarae (Boone, 1927) from the Bahamas and the Gulf of Mexico and M. penescabra Pequegnat Williams 1995, from off Georgia and Gulf of Mexico; the three species belong to the group having the carapace covered with sharp spines. Finally, M. turgida n. sp. is characterized by having the dorsal surface of the carapace, abdomen and pereiopods covered by granules; and resembles M. granulens Mayo, 1972, from NW Caribbean Sea. Apart from the morphological evidence, the analysis of mitochondrial genes (COI and 16S) supports establishing these new species, showing very high genetic divergences compared to their congeners (from 14.5 to 17% for COI, and 7.7 to 12.8% for 16S data).


Glucocorticoid Treatment Strategies in Liver Failure.
Liver failure is characterized by serious liver decompensation and high mortality. The activation of systemic immune responses and systemic inflammation are widely accepted as the core pathogenesis of liver failure. Glucocorticoids (GCs) are most regularly utilized to suppress excessive inflammatory reactions and immunological responses. GCs have been used in the clinical treatment of liver failure for nearly 60 years. While there has been no unanimity on the feasibility and application of GC treatment in liver failure until recently. The most recent trials have produced conflicting results when it comes to the dose and time for GC therapy of different etiology of liver failure. Our review outlines the issues and options in managing GC treatment in liver failure based on an investigation of the molecular mechanism that GC may give in the treatment.


Metal storage in reeds from an acid mine drainage contaminated field.
Phragmites australis has been used to treat acid mine drainage (AMD)-contaminated soil. However, the mechanism about metal translocation in reeds was not widely reported. This study investigated metal (Fe, Al, and Mn) storage location in reeds grown in five different sampling sites of an AMD field. As expected, the more metals in soil, the more metals entered the belowground organs of plants. Reeds grown in soils with the highest levels of metals accumulated 0.16 ± 0.04 mg/g Mn, 16.29 ± 4.15 mg/g Fe, and 1.31 ± 0.22 mg/g Al in roots. Most of the iron was sequestered in the roots, while Al was transferred to the shoots. Histological staining found that most of the iron was sequestered in the exodermis, while Al extended the endodermis of roots. Al even entered the stele of roots grown in soil with higher Al levels. The epidermis, cortex, and central cylinder of rhizomes were the main tissues for Fe and Al storage. The more metals in rhizomes, the stronger intensity of the staining was observed around the vascular systems of rhizomes. No structural difference was observed among reeds collected from different sites. Further studies may be needed to enhance the transfer of metals in reeds and increase the phytoremediation efficiency.


[Parkinson's disease as seen by a patient with this disease].
The idea of writing this paper stemmed from the interest shown by Dr Francisco Javier Jiménez-Jiménez in giving a firsthand description of the experiences of a patient suffering from Parkinson's disease, as a complement to the scientific view. The author is not a member of the medical profession. This study is based on the analysis of the disease as seen by the person actually suffering from it. From this biography we analyze the possible causes that could have exerted an influence on the development of the disease, and the physical causes are also outlined. We analyze the drugs that are administered as therapy and we establish the relations that exist between the symptoms presented by the author and the possible deterioration of the governing centres of the brain which should control them but, due to the degeneration brought about by the disease, do not. The effects produced by the medication are studied and we also describe how help can be obtained from the outside by employing other types of medicine that are not strictly allopathic. In the final part of the paper the relations between the patient and the people around them are discussed. It becomes clear that there is a void in our knowledge about this disease due to our not knowing what exactly causes it. This means that therapies are directed towards palliating the symptoms rather than fighting the causes. Something that must be highlighted is the important role played by the patient's will to fight against the disease.


Development of allele-specific PCR and RT-PCR assays for clustered resistance genes using a potato late blight resistance transgene as a model.
Members of the NBS-LRR gene family impart resistance to a wide variety of pathogens and are often found clustered within a plant genome. This clustering of homologous sequences can complicate PCR-based characterizations, especially the study of transgenes. We have developed allele-specific PCR and RT-PCR assays for the potato late blight resistance gene RB. Our assay utilizes two approaches toward primer design, allowing discrimination between the RB transgene and both the endogenous RB gene and numerous RB homeologs. First, a reverse primer was designed to take advantage of an indel present in the RB transgene but absent in rb susceptibility alleles, enhancing specificity for the transgene, though not fully discriminating against RB homeologs. Second, a forward primer was designed according to the principles of mismatch amplification mutation assay (MAMA) PCR, targeting SNPs introduced during the cloning of RB. Together, the indel reverse primer and the MAMA forward primer provide an assay that is highly specific for the RB transgene, being capable of distinguishing the transgene from all RB endogenous gene copies and from all RB paralogs in a diverse collection of wild and cultivated potato genotypes. These primers have been successfully multiplexed with primers of an internal control. The multiplexed assay is useful for both PCR and RT-PCR applications. Double MAMA-PCR, in which both PCR primers target separate transgene-specific SNPs, was also tested and shown to be equally specific for the RB transgene. We propose extending the use of MAMA for the characterization of resistance transgenes.


Covering by a flap induces apoptosis of granulation tissue myofibroblasts and vascular cells.
It has recently been shown that during the healing of an open wound, apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Because reduced contraction and a decrease in the number of fibroblastic cells have been described in wounds covered with a successful skin graft, we hypothesized that apoptosis could be responsible for these phenomena. Using in situ labeling of fragmented DNA, immunohistochemistry for alpha-smooth muscle actin, and electron microscopy, we have studied in rats the evolution of 10-day-old wound tissue covered with a total skin flap (containing epidermis, dermis, and the cutaneous muscle). In 10-day-old wound tissue, few apoptotic vascular cells and rare apoptotic myofibroblasts were present; the number of apoptotic cells increased slightly 72 hours later. In wounds covered with total skin flaps, the number of apoptotic vascular and myofibroblastic cells increased drastically 6 hours after flap application with a maximum at 24 and 48 hours, respectively. A decrease of apoptotic cell number was noted at 72 hours; at this time, the size of the granulation tissue was greatly reduced and showed extracellular matrix remodeling. Total flaps were more efficient in the induction of granulation tissue cell apoptosis compared with dermo-epidermal flaps. Moreover, the control application of full-thickness skin autografts, which were not viable 7 days later, did not induce apoptosis 24 hours after implantation. Our results indicate that covering granulation tissue with a skin flap results in a massive apoptotic process, possibly by means of a (some) locally released substance(s).


Vervet monkeys and whole-food diets for studying the effects of dietary lipids on plasma lipoprotein metabolism and atherosclerosis.
It is well established that some species of nonhuman primates are models of choice for polygenic hyperlipoproteinaemia and atherosclerosis induced and promoted by diets as occur in man. The Vervet monkey (Cercopithecus aethiops) has proved to be one such model. Our group has used this model extensively to determine the effects of a variety of dietary lipid components on plasma lipoprotein metabolism and atherosclerosis against a background of a Western atherogenic or prudent diet. The diets fed in all these studies were formulated entirely from cooked foods that are normal components of Westernised diet with no extra synthetic cholesterol added. This model has been used successfully to evaluate the effect of fish oil, amount and degree of dietary fat unsaturation and w-6/w-3 fatty acid ratio and lipid-lowering agents on plasma lipoprotein metabolism and atherosclerosis. Dietary manipulation in this model is simple, relatively inexpensive and offers almost unlimited options for future dietary intervention studies.


Structure and control of pyridoxal phosphate dependent allosteric threonine deaminase.
Feedback inhibition of biosynthetic threonine deaminase (TD) from Escherichia coli provided one of the earliest examples of protein-based metabolic regulation. Isoleucine, the pathway end-product, and valine, the product of a parallel pathway, serve as allosteric inhibitor and activator, respectively. This enzyme is thus a useful model system for studying the structural basis of allosteric control mechanisms. We report the crystal structure of TD at 2.8 A resolution. The tetramer has 222 symmetry, with C-terminal regulatory domains projecting out from a core of catalytic PLP-containing N-terminal domains. The subunits, and especially the regulatory domains, associate extensively to form dimers, which associate less extensively to form the tetramer. Within the dimer, each monomer twists approximately 150 degrees around a thin neck between the domains to place its catalytic domain adjacent to the regulatory domain of the other subunit. The structure of TD and its comparison with related structures and other data lead to the tentative identification of the regulatory binding site and revealed several implications for the allosteric mechanism. This work prepares the way for detailed structure/function studies of the complex allosteric behaviour of this enzyme.


Near ultraviolet photodissociation spectroscopy of Mn(+)(H2O) and Mn(+)(D2O).
The electronic spectra of Mn(+)(H2O) and Mn(+)(D2O) have been measured from 30,000 to 35,000 cm(-1) using photodissociation spectroscopy. Transitions are observed from the (7)A1 ground state in which the Mn(+) is in a 3d(5)4s(1) electronic configuration, to the (7)B2 (3d(5)4py) and (7)B1 (3d(5)4px) excited states with T0 = 30,210 and 32,274 cm(-1), respectively. Each electronic transition has partially resolved rotational and extensive vibrational structure with an extended progression in the metal-ligand stretch at a frequency of ∼450 cm(-1). There are also progressions in the in-plane bend in the (7)B2 state, due to vibronic coupling, and the out-of-plane bend in the (7)B1 state, where the calculation illustrates that this state is slightly non-planar. Electronic structure computations at the CCSD(T)/aug-cc-pVTZ and TD-DFT B3LYP/6-311++G(3df,3pd) level are also used to characterize the ground and excited states, respectively. These calculations predict a ground state Mn-O bond length of 2.18 Å. Analysis of the experimentally observed vibrational intensities reveals that this bond length decreases by 0.15 ± 0.015 Å and 0.14 ± 0.01 Å in the excited states. The behavior is accounted for by the less repulsive px and py orbitals causing the Mn(+) to interact more strongly with water in the excited states than the ground state. The result is a decrease in the Mn-O bond length, along with an increase in the H-O-H angle. The spectra have well resolved K rotational structure. Fitting this structure gives spin-rotation constants ɛaa″ = -3 ± 1 cm(-1) for the ground state and ɛaa' = 0.5 ± 0.5 cm(-1) and εaa' = -4.2 ± 0.7 cm(-1) for the first and second excited states, respectively, and A' = 12.8 ± 0.7 cm(-1) for the first excited state. Vibrationally mediated photodissociation studies determine the O-H antisymmetric stretching frequency in the ground electronic state to be 3658 cm(-1).


Protective Effect of Gymnema sylvestre Ethanol Extract on High Fat Diet-induced Obese Diabetic Wistar Rats.
Obesity is associated with numerous co-morbidities such as cardiovascular diseases, type 2 diabetes, hypertension and others. Therefore, the present study was planned to investigate the effect of water- soluble fraction of Gymnema sylvestre ethanol extract on biochemical and molecular alterations in obese diabetic rats. Diabetes was induced by single i.v. injection of streptozotocin (45 mg/kg) via tail vein. Obesity was induced by oral feeding of high fat diet for a period of 28 days in diabetic rats. Body weight gain, food intake, water intake, hemodynamic parameters (systolic, diastolic, mean arterial blood pressures and heart rate), serum biochemical parameters (leptin, insulin, lipid levels, apolipoprotein B and glucose), cardiomyocyte apoptosis (cardiac caspase-3, Na(+)/K(+) ATPase activity and DNA fragmentation) organs and visceral fat pad weight and oxidative stress parameters were measured. Oral treatment with water soluble fraction of Gymnema sylvestre ethanol extracts (120 mg/kg/p.o.) for a period of 21 days, resulted in significant reduction in heart rate, mean arterial pressure, serum leptin, insulin, apolipoprotein B, lipids, glucose, cardiac caspase-3 levels, Na(+)/K(+) ATPase activity and DNA laddering, visceral fat pad and organ's weight and improved the antioxidant enzymes levels in the high fat diet induced obesity in diabetic rats. The results of present study reveal that water soluble fraction of Gymnema sylvestre ethanol extract could be useful intervention in the treatment of obesity and type-2 diabetes mellitus.


Direct Comparison of Real-world Effectiveness of Biologics for Psoriasis using Absolute and Relative Psoriasis Area and Severity Index Scores in a Prospective Multicentre Cohort.
Real-world evidence, directly comparing the effectiveness of interleukin (IL)17-inhibitors, IL23-inhibitors, tumour necrosis factor alpha (TNF-α)-inhibitors and an IL12/23-inhibitor in psoriasis, is scarce. The aim of this study was to directly compare the first-year effectiveness of biologic therapies for psoriasis, corrected for confounders. This prospective, multicentre cohort study assessed BioCAPTURE data on etanercept, adalimumab, ustekinumab, secukinumab, ixekizumab, and guselkumab in 1,080 treatment episodes of 700 patients with psoriasis. The course of the mean absolute Psoriasis Area and Severity Index (PASI) and the proportion of patients who achieved PASI90/PASI75 were compared using linear mixed models and mixed logistic regression models respectively, corrected for baseline PASI, biologic naivety, and weight. Patients treated with adalimumab, ustekinumab, secukinumab, ixekizumab, or guselkumab all had a significantly lower mean PASI after 12 months compared with etanercept, and significantly higher overall odds of reaching PASI90 than those treated with etanercept. Patients treated with ixekizumab or guselkumab also had higher probabilities of reaching PASI90 than adalimumab, ustekinumab, and secukinumab. Relative to randomized controlled trials, the proportions of patients who reached PASI90/75 were lower in this real-world study.


Size and shape of rabbit skeletal muscle calsequestrin.
Calsequestrin, a calcium-binding protein isolated from rabbit skeletal muscle sarcoplasmic reticulum, was subjected to physiochemical analysis using sodium dodecyl sulfate gel electrophoresis, gel filtration, sedimentation, viscosity, and circular dichroism techniques. The effects of sodium dodecyl sulfate, alkaline pH, guanidine hydrochloride, and calcium ions on the hydrodynamic properties of the protein were studied. Calsequestrin, in the absence of calcium, had a random coil conformation with an alpha-helical content of 11%. Calsequestrin bound 1.7 mg of sodium dodecyl sulfate per mg of protein resulting in an increase in the alpha-helical content to 20%. The protein was completely random coil in guanidine hydrochloride and had a molecular weight of 42,000 as determined by gel filtration in the presence of this denaturant. Sedimentation equilibrium studies showed that calsequestrin was not subjected to aggregation and had a molecular weight of 38,000. Calsequestrin had a low sedimentation coefficient (2.20 S), a high Stokes radius (45 A), and a high intrinsic viscosity (27.1 ml/g) that increased slightly to 32 ml/g in the presence of guanidine hydrochloride, all indicative of a highly extended structure. Similar studies, performed at pH 9.5, revealed that the protein was even more asymmetric at alkaline pH. Calsequestrin bound 50 mol of calcium ions per mol of protein with an affinity of 1 mM as determined by gel filtration. Calcium binding was accompanied by a change of the protein from a highly extended structure (Rs = 45 A) to a much more compact structure (Rs = 35 A).


Characterization of the [Ag(dmb)(2)(+)](n) oligomers (dmb = 1,8-diisocyano-p-menthane) in solution.
The crystallographically characterized polymers [[Ag(dmb)(2)]Y](n) (Y = BF(4)(-), NO(3)(-), ClO(4)(-)) extensively dissociate in solution, contrarily to the Cu analogue, and common molecular weight determination techniques such as light scattering, osmometric, and intrinsic viscosity measurements fail to provide data allowing full characterization. Using pulsed NMR experiments, notably (13)C NMR T(1) (spin lattice relaxation time) and NOE (nuclear Overhauser enhancement) measurements on various ionic [[Ag(dmb)(2)]Y](n) materials (Y = BF(4)(-), NO(3)(-), ClO(4)(-)) and their related mononuclear [Ag (CN-t-Bu)(4)]Y salts in acetonitrile-d(3) (as comparative standards), the dipole-dipole spin lattice relaxation times (T(1)(DD)) of a selected quaternary (13)C probe are measured. These data allow us to extract the correlation times (tau(c)), which in turn permit us to estimate the volume of the tumbling species in solution. The comparison of the data between the [Ag(dmb)(2)(+)](n) and Ag(CN-t-Bu)(4)(+) species indicates the oligomeric nature of the former species, where the average number of Ag(dmb)(2)(+) approximately 8 (M(n) approximately 4000-5000).


Community health workers to reduce unmet surgical needs in an urban slum in India: an implementation study.
The Surgical Accredited & Trained Healthcare Initiative (SATHI) project demonstrates how community healthcare workers (CHWs) with merely 8 y of formal schooling and training for a short period can reduce unmet surgical needs. A pilot study was carried out in the slums of a metropolitan city in India to know the effectiveness of a SATHI in reducing the burden of unmet surgical needs. In total, 12 730 people from 3000 households were included in the study for a duration of 6 months. We found 10% surgical needs (n=293) out of which 57% had unmet surgical needs. Out of total surgical needs, about half of the needs were cataract and abdominal, followed by extremities and chest conditions. SATHIs were able to convert 99 patients (60%) from unmet to met needs, who underwent surgery/treatment. The conversion from unmet to met among all surgery needs was highest for abdominal conditions (29%) followed by cataracts (17%). SATHIs with short training can reduce the burden of unmet surgical needs. SATHIs were able to convert a significant proportion of unmet to met needs by trust building, facilitating access to healthcare and ensuring post-operative adherence. Scaling up could help in the achievement of equitable healthcare across India.


Multiple stress response of lowland stream benthic macroinvertebrates depends on habitat type.
Worldwide, lowland stream ecosystems are exposed to multiple anthropogenic stress due to the combination of water scarcity, eutrophication, and fine sedimentation. The understanding of the effects of such multiple stress on stream benthic macroinvertebrates has been growing in recent years. However, the interdependence of multiple stress and stream habitat characteristics has received little attention, although single stressor studies indicate that habitat characteristics may be decisive in shaping the macroinvertebrate response. We conducted an experiment in large outdoor flumes to assess the effects of low flow, fine sedimentation, and nutrient enrichment on the structure of the benthic macroinvertebrate community in riffle and run habitats of lowland streams. For most taxa, we found a negative effect of low flow on macroinvertebrate abundance in the riffle habitat, an effect which was mitigated by fine sedimentation for overall community composition and the dominant shredder species (Gammarus pulex) and by nutrient enrichment for the dominant grazer species (Baetis rhodani). In contrast, fine sediment in combination with low flow rapidly affected macroinvertebrate composition in the run habitat, with decreasing abundances of many species. We conclude that the effects of typical multiple stressor scenarios on lowland stream benthic macroinvertebrates are highly dependent on habitat conditions and that high habitat diversity needs to be given priority by stream managers to maximize the resilience of stream macroinvertebrate communities to multiple stress.


[Effects of different dose berberine on hemodynamic parameters and [Ca2+]i of cardiac myocytes of diastolic heart failure rat model].
To study the effects of different doses of berberine on hemodynamic parameters and calcium ion concentration ([Ca2+]i) of diastole heart failure rat models. The mouse models of diastole heart failure were made by the imcomplete ligation of abdominal aorta. Forty Wistar heart failure rats were divided randomly into four groups, with 10 for each group (n = 10). Heart failure rats were treated according to different doses drugs as follows: Model (natrii chloride 2 mL), berberine (63 mg x kg(-1) x d(-1)), berberine (42 mg x kg(-1) x d(-1)), berberine (21 mg x kg(-1) x d(-1)) ig, for each of the four groups respectively, 4 weeks after coarctation of ascending aorta operation; and 10 age matched sham operation group was taken as control (natrii chloridi, 2 mL). After administration four weeks, cardiac function was determined by catheter. Isolate single cardiomyocytes of rat which were loaded with Ca(2+)-sensitive fluorescent indicator Fluo-3/AM. [Ca2+]i represented by fluorescent intensity [FI] was measured by laser scanning cofocal microscope [LSCM]. The rats of operation group have no significant changes with those of the control on left ventricular systolic pressure (LVSP) and maximal rising rate of ventricular pressure (+dp/dt(max)), left ventricular end diastolic pressure (LVEDP) was much higher in operation group (P < 0.01), but maximal falling rate of ventricular pressure (-dp/dt(max)) was depressed (P < 0.01), left ventricular relax time constant quantity (T) was markedly extended (P < 0.01). [Ca2+]i level in carkiac muscle cell was elevated markedly (P < 0.05). Compared with operation group, high dose of Ber can decrease LEVDP, improve (-dp/dt(max)) (P < 0.01), decurtate left ventricular relax time constant quantity (P < 0.01) and decrease [Ca2+]i level better than those of middle and low dose group (P < 0.01). Berberine is an effective new potent drug for conspicuous symptom relief of heart failure with positive dose dependency and step down [Ca2+]i of myocardial cell.


Some effects of prestimulus activity and length of prestimulus observation on judgments of newborns' responses to sounds.
Previous work on the effects of prestimulus state on newborn auditory response is briefly reviewed. Subjectively assessed responses of nine newborns by five observers were studied as a function of (1) prestimulus activity level and (2) duration of prestimulus observation period. Response assessment was significantly affected for the former but not by the latter. For sounds which elicited a high proportion of responses, the prestimulus activity level had relatively little effect on judgment of response, whereas for sounds (and no-sound "control" trials) to which few responses were ascribed, prestimulus activity tended to be associated with positive ratings of response.


Cooperation between Single-Handed and Group Practices Ensures the Replacement of Gastrostomy Tubes and Tracheal Cannulas in Home Medical Care Settings.
In Japan, patients who require home medical care are increasing especially in the elderly. In home medical care settings, devices such as gastrostomy tubes, tracheal cannulas, and urethral catheters are usually replaced by visiting physicians or nurses. However, device replacement services are not always available in Japan. Unless device replacement services are sufficiently provided to patients at home, patients have to suffer various disadvantages, including a forced visit to a hospital for device replacement despite inability to walk. We therefore investigated background factors of clinics and nursing stations providing home-care visits using a cross-sectional postal survey from August to September 2013. We targeted physicians from 5,828 clinics providing home medical care and nurses from 1,798 home-visit nursing stations across six prefectures (Tokyo, Kanagawa, Saitama, Chiba, Miyagi and Iwate). Responses were received from 933 clinics (16.5%) and 552 stations (31.3%). We analyzed the responses using multivariable logistic regression with two models. "Model 1" mainly included the number of full-time staff and the availability of a 24-hour care service system, and "Model 2" mainly included the number of clinics, the number of home-visit nursing stations, and the ratio of the population aged ≥ 65 years to study the influence of medical resources. We thus found that clinic staff numbers and 24-hour care availability were associated with physicians' replacement of gastrostomy tubes and tracheal cannulas (p < 0.001 for each). In conclusion, single-handed and group practices need to cooperate to ensure the replacement of these devices in home medical care settings.


Neurotransmitters and neurodegenerative disorders.
It is 25 years since biochemical analysis of neurotransmitters in autopsied human brains was first applied to elucidation of the underlying mechanisms in functional neuronal disorders. In this time this line of research has revealed a selective decrease in catecholamines and of their synthesizing enzyme activities which occur in Parkinson's disease, and has led to the development of L-DOPA replacement therapy. Much attention is now being given to the other neurodegenerative disorders. This paper summarizes recent advances in research on neurotransmitter abnormalities in Parkinson's disease, Huntington's disease and the spinocerebellar degeneration.


Success of a cervical cancer screening program: trends in incidence in songkhla, southern Thailand, 1989-2010, and prediction of future incidences to 2030.
Cervical cancer has been a leading female cancer in Thailand for decades, and has been second to breast cancer after 2007. The Ministry of Public Health (MoPH) has provided opportunistic screening with Pap smears for more than 30 years. In 2002, the MoPH and the National Health Security Office provided countrywide systematic screening of cervical cancer to all Thai women aged 35-60 years under universal health care coverage insurance scheme at 5-year intervals. This study characterized the cervical cancer incidence trends in Songkhla in southern Thailand using joinpoint and age period cohort (APC) analysis to observe the effect of cervical cancer screening activities in the past decades, and to project cervical cancer rates in the province, to 2030. Invasive and in situ cervical cancer cases were extracted from the Songkhla Cancer Registry from 1990 through 2010. Age standardized incidence rates were estimated. Trends in incidences were evaluated by joinpoint and APC regression models. The Norpred package was modified for R and was used to project the future trends to 2030 using the power of 5 function and cut trend method. Cervical cancer incidence in Songkhla peaked around 1998-2000 and then dropped by -4.7% per year. APC analysis demonstrated that in situ tumors caused an increase in incidence in early ages, younger cohorts, and in later years of diagnosis. Both joinpoint and APC analysis give the same conclusion in continuation of a declining trend of cervical cancer to 2030 but with different rates and the predicted goal of ASR below 10 or even 5 per 100,000 women by 2030 would be achieved. Thus, maintenance and improvement of the screening program should be continued. Other population based cancer registries in Thailand should analyze their data to confirm the success of cervical cancer screening policy of Thailand.


Adenolipoma of the liver. A unique case with ultrasound and CT patterns.
Lipomas rarely occur in the liver. However, because of the widespread use of ultrasound and CT in the diagnosis of liver disease, one should be familiar with their appearance, as confirmed diagnosis may spare the patient major investigations. The value of CT is emphasized in association with percutaneous biopsy when the appearance of the tumour is not classical. Ultrasound patterns are discussed.


Are HPV-negative lesions concerned for the introduction of primary HPV testing for cervical cancer screening in Japan?
In Japan, primary human papilloma virus (HPV) testing has not been introduced for cervical cancer screening due to concerns that HPV-negative lesions may be missed and a lack of Japanese data. The purpose of this study was to evaluate the validity of primary HPV testing in Japan by analyzing cervical intraepithelial neoplasia 2 (CIN2) or more/high-risk HPV- (CIN2+/hrHPV-) cases in cervical cancer screening. Data from 35 525 cervical cancer screenings with HPV testing and cervical cytology from 2011 to 2019 in Saga City, Japan, were reviewed. The cases with low-grade squamous intraepithelial lesion (LSIL+)/hrHPV- were analyzed in detail. The results of the 35 525 examinees were as follows: 31 123 were negative for intraepithelial lesion or malignancy (NILM)/hrHPV-, 2612 were NILM/hrHPV+, 262 were atypical squamous cells of undetermined significance (ASC-US)/hrHPV-, 213 were ASC-US/hrHPV+, 291 were LSIL+/hrHPV-, and 1024 were LSIL+/hrHPV+. Of the 256 LSIL+/hrHPV- examinees for whom histology was available, CIN2+ were CIN2 9.4% (24/256), CIN3 3.9% (10/256), cervical adenocarcinoma 0.4% (1/256), uterine corpus cancer 1.2% (3/256), and uterine sarcoma 0.4% (1/256). Overall, the rate of LSIL+/hrHPV- was 0.82% (291/35.525), 0.1% (36/35525) of which were cervical lesions with CIN2+. Only one cervical adenocarcinoma was detected, but gastric-type adenocarcinoma was not included. HPV-negative CIN2+ or cervical adenocarcinoma is not a concern for the introduction of primary HPV screening in Japan. Primary HPV testing in cervical cancer screening is considered a feasible method that can be used in Japan, although an algorithm suitable for Japan and a national-level management system need to be established.


The antioxidant and cytotoxic activities of Sonchus oleraceus L. extracts.
This study investigated in vitro antioxidant activity of Sonchus oleraceus L. by extraction solvent, which were examined by reducing power, hydroxyl radical-scavenging activity(HRSA) and 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assays. 70% MeOH extract had the greatest reducing power while EtOH extract had the greatest HRSA. The antioxidant activity of S. oleraceus extracts was concentration dependent and its IC(50) values ranged from 47.1 to 210.5 microg/ml and IC(50) of 70% MeOH, boiling water and 70% EtOH extracts were 47.1, 52.7 and 56.5 microg/ml, respectively. 70% MeOH extract of S. oleraceus contained the greatest amount of both phenolic and flavonoid contents. The extracts tested had greater nitrite scavenging effects at lower pH conditions. The cytotoxic activity showed that EtOH extract had the best activity against the growth of stomach cancer cell. These results suggest that S. oleraceus extract could be used as a potential source of natural antioxidants.


Stabilization of protein structure through π-π interaction in the second coordination sphere of pseudoazurin.
Noncovalent, weak interactions in the second coordination sphere of the copper active site of Pseudoazurin (PAz) from Achromobacter cycloclastes were examined using a series of Met16X variants. In this study, the differences in protein stability due to the changes in the nature of the 16th amino acid (Met, Phe, Val, Ile) were investigated by electrospray ionization mass spectrometry (ESI-MS) and far-UV circular dichroism (CD) as a result of acid denaturation. The percentage of native states (folded holo forms) of Met16Phe variants was estimated to be 75% at pH 2.9 although the wild-type (WT), Met16Val and Met16Ile PAz, became completely unfolded. The high stability under acidic conditions is correlated with the result of the active site being stabilized by the aromatic substitution of the Met16 residue. The π-π interaction in the second coordination sphere makes a significant contribution to the stability of active site and the protein matrix.


Disease-modifying effects of phosphocitrate and phosphocitrate-β-ethyl ester on partial meniscectomy-induced osteoarthritis.
It is believed that phosphocitrate (PC) exerts its disease-modifying effects on osteoarthritis (OA) by inhibiting the formation of crystals. However, recent findings suggest that PC exerts its disease-modifying effect, at least in part, through a crystal-independent action. This study sought to examine the disease-modifying effects of PC and its analogue PC-β-ethyl ester (PC-E) on partial meniscectomy-induced OA and the structure-activity relationship. Calcification- and proliferation-inhibitory activities were examined in OA fibroblast-like synoviocytes (FLSs) culture. Disease-modifying effects were examined using Hartley guinea pigs undergoing partial meniscectomy. Cartilage degeneration was examined with Indian ink, safranin-O, and picrosirius red. Levels of matrix metalloproteinase-13 (MMP-13), ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5), chemokine (C-C motif) ligand 5 (CCL5), and cyclooxygenase-2 (Cox-2) were examined with immunostaining. The effects of PC-E and PC on gene expressions in OA FLSs were examined with microarray. Results are expressed as mean ± standard deviation and analyzed using Student's t test or Wilcoxon rank sum test. PC-E was slightly less powerful than PC as a calcification inhibitor but as powerful as PC in the inhibition of OA FLSs proliferation. PC significantly inhibited cartilage degeneration in the partial meniscectomied right knee. PC-E was less powerful than PC as a disease-modifying drug, especially in the inhibition of cartilage degeneration in the non-operated left knee. PC significantly reduced the levels of ADAMTS5, MMP-13 and CCL5, whereas PC-E reduced the levels of ADAMTS5 and CCL5. Microarray analyses revealed that PC-E failed to downregulate the expression of many PC-downregulated genes classified in angiogenesis and inflammatory response. PC is a disease-modifying drug for posttraumatic OA therapy. PC exerts its disease-modifying effect through two independent actions: inhibiting pathological calcification and modulating the expression of many genes implicated in OA. The β-carboxyl group of PC plays an important role in the inhibition of cartilage degeneration, little role in the inhibition of FLSs proliferation, and a moderate role in the inhibition of FLSs-mediated calcification.


Outbreaks of Duck Hepatitis A Virus in Egyptian Duckling Flocks.
During 2015, duck farms (n = 27) in Sharkia Province, Egypt, experienced several disease outbreaks leading to mortality and nervous manifestations. Upon necropsy, the affected ducklings showed liver lesions, such as hemorrhage or necrosis, suggestive of duck virus hepatitis (DVH). Reverse transcription-PCR (RT-PCR), on the basis of the 3D gene, found duck livers from 21 farms to be positive for duck hepatitis A virus serotype 1 (DHAV-1). All duck breeds (Pekin, Mallard, and Muscovy) were infected. The virus was isolated in embryonated chicken eggs, which showed embryonic mortality (40%-80%) within 5-7 days, stunting or dwarfing (69.6%), and necrotic liver foci (60.9%). The VP1 gene of 11 DHAV-1 strains was characterized by RT-PCR and Sanger sequencing. All study strains were clustered in a monophyletic branch within subclade B2 of Group 4 and were separated from the Egyptian vaccine strain. Several amino acid (aa) residues, such as V129, S142 (only in four strains), L181, G184, and K217, were related to virus attenuation. However, two aa residues (N193 and E205), found in virulent DHAV-1 strains, were also observed in our strains. This study confirms the circulation of DHAV-1 (subclade B2) in Lower Egypt and elucidates the phylogenetic characters of the VP1 genes, which will be useful in following the local trends of DHAV-1 infections. Further studies are indicated to determine the correlation between these mutations and the virulence of the Egyptian DHAV-1 isolates.


Analytical Ultracentrifugation as an Approach to Characterize Recombinant Adeno-Associated Viral Vectors.
Recombinant adeno-associated viral (rAAV) vectors represent a novel class of biopharmaceutical drugs. The production of clinical-grade rAAV vectors for gene therapy would benefit from analytical methods that are able to monitor drug product quality with regard to homogeneity, purity, and manufacturing consistency. Here, we demonstrate the novel application of analytical ultracentrifugation (AUC) to characterize the homogeneity of preparations of rAAV vectors. We show that a single sedimentation velocity run of rAAV vectors detected and quantified a number of different viral species, such as vectors harboring an intact genome, lacking a vector genome (empty particles), and containing fragmented or incomplete vector genomes. This information is obtained by direct boundary modeling of the AUC data generated from refractometric or UV detection systems using the computer program SEDFIT. Using AUC, we show that multiple parameters contributed to vector quality, including the AAV genome form (i.e., self-complementary vs. single-stranded), vector genome size, and the production and purification methods. Hence, AUC is a critical tool for identifying optimal production and purification processes and for monitoring the physical attributes of rAAV vectors to ensure their quality.


Structure and driving factors of the soil microbial community associated with Alhagi sparsifolia in an arid desert.
Environmental properties are important factors in structuring soil microbial communities. The primary driving factors vary in different ecosystems. In the present work, we analyzed the microbial communities of rhizosphere and bulk soils associated with the halophyte Alhagi sparsifolia across three salt/water gradients in the desert area around Ebinur Lake Basin, China, using high-throughput sequencing technology. We found that there were significant differences in soil water content (SWC), soil salinity (SAL), total nitrogen (TN), and total phosphorus (TP) contents between the three water/salt gradients. In the L (low water and salt) plot, Actinobacteria was the most abundant bacterial phylum while Ascomycota was the dominant fungal phylum. The relative abundance of Actinobacteria was negatively correlated with soil pH, soil organic carbon (SOC), TP, and available phosphorus (AP). The abundance of Bacteroidetes was significantly positively correlated with soil SOC, SWC, SAL, pH, TN, and TP (P < 0.05). The abundance of fungal phylum Chytridiomycota was significantly positively correlated with pH (P < 0.01), SWC, AP, and sulfate ion (P < 0.05). SOC and nitrate nitrogen were the main factors impacting the bacterial community, while ammonium nitrogen (NH4+) and TP were the main driving forces for the fungal community. Soil nutrients were the main contributors to the dissimilarities in the bacterial and fungal communities, explaining 48.06% and 44.45% of the variation. SWC, SAL, and pH explained only a small percentage of the microbial community dissimilarity. In conclusion, soil microbial community structure was affected by SWC, SAL, pH, and soil nutrients, with soil nutrients as the main driving factors. Nitrogen has a differential effect on the different microbial communities: bacterial communities of Alhagi sparsifolia were mainly affected by nitrate nitrogen, while fungal communities were mainly driven by ammonium nitrogen.


Performance characteristics of aerobic/anoxic sludge digestion at elevated temperatures.
Laboratory experiments were conducted to study the performance of aerobic/anoxic digestion of mixed primary and waste activated sludge compared to aerobic digestion alone in terms of solids destruction, organic reduction, nutrient removal, filtrate quality and sludge dewaterability. The process performance was examined at different solids residence times (10 and 20 d), temperatures (20, 30 and 40 degrees C) and anoxic cycle length (0, 8, 12 and 16 h). Both modes of operation gave comparable solids destruction results. The volatile suspended solids (VSS) reduction was affected by temperature with the highest VSS reduction reported at 30 degrees C (42.4%), while solid retention time (SRT) did not seem to affect the process as indicated by the percent VSS removal. Biodegradable solids destruction followed a first-order kinetic model. Aerobic/anoxic sludge digestion is advantageous to mere aerobic digestion since it improves sludge dewaterability and filtrate quality. Alternating aerobic/anoxic operation can conserve most of the influent alkalinity and maintain near neutral pH conditions over prolonged periods. Optimum process performance was observed at 20 degrees C with SRT of 10 days and anoxic cycle length of 8 hours.


Nephron-sparing surgery for de novo renal cell carcinoma in allograft kidneys.
Renal cell carcinomas account for 4.6% of post-transplant cancers, 10% of which occur in allograft kidneys. We report three such cases among kidney grafts that were performed or followed from 1970 to 2004. In all patients, we performed a partial allograft nephrectomy after consideration of the tumor size, location, and absence of metastases and local extension. Renal function has remained stable, and there has been no sign of graft rejection, tumor recurrence or metastases. The surgery was technically feasible without exposing the patients to increased postoperative risks. The lateral, peripherally located tumor allowed excision without renal hilar dissection or entry into the collecting system. In agreement with data emerging from the literature, the present cases confirm that even in the setting of long-standing immunosuppression, de novo RCC of the kidney graft warrants a minimally invasive approach to spare patients graft loss and return to hemodialysis.


Urine TREM-1 as a marker of urinary tract infection in children.
Objective Triggering receptor expressed on myeloid cells (TREM)-1 is a receptor that is thought to improve recognition of patients with true infection. In this study, we investigated whether Triggering receptor expressed on myeloid cells (TREM-1) is present in urine samples from children with urinary tract infection (UTI) and in samples from healthy children. Methods A total of 128 samples met the inclusion criteria for the study. Urine samples were processed for culture and urinalysis as a regular protocol for patients with UTI. Samples were classified according to culture and urinalysis results. TREM-1 protein expression was detected with flow cytometry and sTREM-1 was assessed by ELISA. Results Flow cytometry showed detectable expression of TREM-1 in 100% of samples, UTI and non-UTI groups ( p < 0.001). Mean fluorescence intensity of TREM-1 was different between the groups ( p < 0.001). Levels of sTREM-1 were detected in patients with UTI, but not in non-UTI patients. Conclusions All of our patients (healthy and diseased) showed TREM-1 expression. However, TREM-1 levels in patients with UTI tend to be higher and are associated with increased neutrophils and cytokine activity induced by bacteria.


Low-dose Desmopressin and Tolterodine Combination Therapy for Treating Nocturia in Women with Overactive Bladder: A Double-blind, Randomized, Controlled Study.
Evaluation of safety and efficacy of desmopressin/tolterodine combination therapy in women. This double-blind, randomized, proof-of-concept study enrolled 106 patients (≥18 years), with overactive bladder (OAB) and nocturia, with ≥2 nocturnal voids, receiving a 3-month once-daily combination (desmopressin 25 µg, orally-disintegrating tablets [ODT]/tolterodine 4 mg [Detrol® LA]; n = 49) or monotherapy (tolterodine 4 mg/placebo ODT; n = 57). Primary endpoint was change from baseline in mean number of nocturnal voids. Secondary endpoints were change from baseline in nocturnal voided volume, time to first nocturnal void, and quality-of-life. Post-hoc exploratory analysis were performed for patients with and without baseline nocturnal polyuria (NP, n = 47 each). Overall population showed a non-significant reduction in mean number of nocturnal voids with combination versus monotherapy (full analysis set: adjusted treatment contrast [TC], -0.34; P = 0.112). Change in mean nocturnal void volume (TC, -64.16 mL; P = 0.103), mean time to first nocturnal void (TC, 18.00 min; P = 0.385) and Nocturia Impact (NI) Diary© scores were comparable. In post-hoc analysis, NP patients showed a benefit with combination versus monotherapy for nocturnal void volume (P = 0.034) and time to first nocturnal void (P = 0.045), and a non-significant improvement in NI Diary© scores. Safety profile was comparable between treatments. A single transient event of asymptomatic clinically significant hyponatremia in combination group resolved subsequently. Low-dose desmopressin could be safely combined with tolterodine for treating nocturia in women with OAB, with a significant benefit in women with NP. Further, prospective validation studies of combination therapy are warranted in mixed NP/OAB population, based on this favorable proof-of-concept finding.


[Traumatic luxation of the stapes: radiology and surgical outcome].
To describe the value of high resolution computed tomography scan (HRCT scan) in post traumatic hearing loss. HRCT scan of the temporal bone in millimetric cut with axial and coronal views was performed. CT scan confirmed pneumolabyrinth with intact stapes depressed deeply into the vestibule. Surgical exploration was performed and the stapes was gently removed from the vestibule. CT scan confirmed the diagnosis and studied the stapes integrity. Hearing deteriorated postoperatively is increased in case of stapes fracture. When a luxation of the stapes into the vestibule is suspected, it is important to determine how deeply and whether it is fractured. When such a case is encountered, high resolution CT scan of the temporal bone must be performed to confirm the diagnosis and to confirm integrity of the stapes.


High-dose bolus injection of urokinase. Use during cardiopulmonary resuscitation for massive pulmonary embolism.
Bolus administration of high-dose thrombolytic agents has been reported for the treatment of acute pulmonary embolism. We describe the case of a 60-year-old woman who suffered a massive pulmonary embolism with cardiopulmonary arrest 21 h after an exploratory laparotomy. After 20 min of unsuccessful cardiopulmonary resuscitation (CPR), a bolus of 2,000,000 U of urokinase was injected via a peripheral vein. Ten minutes later, the circulatory system stabilized, and the patient survived without subsequent bleeding. In our opinion, bolus lysis made a definitive contribution to the success of the resuscitation. Several other case reports and small series showed successful treatment of pulmonary embolism during similar circumstances using high-dose bolus injection of thrombolytic agents. Mechanical thrombus fragmentation using a pulmonary artery catheter or pulmonary embolectomy has not been shown to be more successful during resuscitation. We conclude that bolus administration of thrombolytic agents during CPR for massive pulmonary thromboembolism may be an acceptable and successful technique, which also is available even in the community hospital setting.


NECPAL Tool Aids Early Identification of Palliative Care Needs.
Background: A key issue in the development of population-based access to palliative care is identification of appropriate patients. Objective: To evaluate the NECPAL (NECesidades Paliativas) tool to identify unmet palliative care needs in the Czech Republic in regional hospitals of the Vysocina region. Methods: We used the End-of-Life care information system (ELFis) to evaluate prognostication to aid the identification of palliative care needs. The evaluation process was developed in cooperation with the regional government and central health care insurance agency as a step toward the development of a nation-wide palliative care program. Results: Our results demonstrate that the NECPAL tool successfully identified palliative care needs in specifically prepared clinical environment. An important part of this is a support of main stakeholders and an effective leadership. Conclusion: An unexpected finding was the role that leadership played in testing the tool, and very short time (10 months) needed for statistically visible changes in a regional system of care.


The dopamine paradox in lung and kidney epithelia: sharing the same target but operating different signaling networks.
Stimulation of dopamine receptors in the lung or kidney epithelia has distinct and opposite effects on the function of Na,K-ATPase, which results in increased Na(+) absorption across the alveolar epithelium and increased sodium excretion via the kidney epithelium. In the lung, dopamine increases Na,K-ATPase by increasing cell basolateral surface expression of Na(+),K(+)-ATPase molecules, whereas in the kidney epithelia it decreases Na(+),K(+)-ATPase activity by removing active units from the plasma membrane by endocytosis. The opposite effects of dopamine over the same target (the Na(+),K(+)-ATPase) involve the activation of a distinct signaling network that it is target specific, and has a different spatial resolution. Understanding the specific signaling pathways involved in these actions of dopamine and their hierarchical organization may facilitate the drug discovery process that could lead to the design of new therapeutic approaches to clear lung edema in patients with acute lung injury and to decrease fluid overload during congestive heart failure and hypertension.


Opiate receptor subtypes in the rat hypothalamus and neurointermediate lobe.
The potent opiate radioligands [3H]etorphine, [3H]ethylketocyclazocine (EKC), and [3H]naloxone, bound specifically and saturably to a single class of membrane-binding sites in rat neurointermediate lobe (NIL), with Kd values of 3.7, 24, and 51 nM, respectively. In the hypothalamus (Ht), [3H]etorphine bound to specific and saturable sites with a Kd of 2.9 nM. Binding-inhibition studies with [3H]etorphine and unlabeled etorphine-HCl as well as [3H]EKC and unlabeled EKC, revealed high and low affinity binding sites in rat Ht and NIL as well as in the neural lobe of the bovine pituitary gland. [3H]naloxone also bound specifically to two classes of sites in Ht membranes, but to only a single class of low affinity sites in NIL membranes. Specific binding represented 80-90% of total [3H]etorphine binding, about 75% of total [3H]EKC binding, and 45-55% of total [3H]naloxone binding at 22 C in NIL and Ht, respectively. Relative binding potencies derived from Ki values for binding-inhibition studies of [3H]etorphine with opioid peptides and opiates were: NIL, etorphine-HCl greater than dynorphin A greater than naloxone-HCl greater than dynorphin-(1-9) greater than beta-endorphin much greater than alpha-neoendorphin approximately (Leu5)enkephalin approximately DAGO (Tyr-D-Ala-Gly-NMe-Phe-Gly-ol); Ht, etorphine HCl greater than naloxone-HCl greater than beta-endorphin greater than dynorphin A much greater than DAGO greater than morphiceptin much greater than (Leu5)enkephalin. Specific [3H]etorphine binding was also demonstrable after preincubation of NIL membranes with DAGO and (Leu5)enkephalin and after preincubation of Ht membranes with morphiceptin and (Leu5)enkephalin; such binding could be displaced by nonradioactive dynorphin A. In addition, [3H]etorphine binding to bovine neural lobe was displaceable by naloxone-HCl, with an ED50 of 43 nM. Specific ligands for sigma-opiate receptors, such as (+)SKF 10,047 (N-allylnorcyclazocine), phencyclidine (PCP), and (-)cyclazocine, displaced specifically bound [3H]etorphine and [3H]EKC from NIL membranes only at high (micromolar) concentrations. However, specific [3H]PCP sites were of higher affinity in NIL and Ht membranes, with similar Kd values of 102 and 190 nM respectively, and different concentrations (0.15 and 1.32 pmol/mg protein, respectively). These data have revealed several differences in the opiate-binding properties of rat Ht and NIL membranes.(ABSTRACT TRUNCATED AT 400 WORDS)


Clinical evaluation of the zygoma implant: 3-year follow-up at 16 clinics.
The purpose of this clinical investigation was to evaluate the treatment outcome with zygoma implants with regard to implant survival, patient satisfaction, and function of prosthesis replacement after 3 years. The treatment outcome of 76 patients treated with 145 zygoma fixtures at 16 centers was evaluated with regard to implant survival. Status of peri-implant mucosa and amount of plaque were registered annually. Patients' and dentists' evaluations of the functional and esthetic outcome of the treatment were assessed at delivery of prosthesis and thereafter at each follow-up visit. Sixty of 76 patients were followed for 3 years after prosthetic delivery. Five of 145 placed zygoma implants failed during the course of the study resulting in an overall implant survival rate of 96.3%. At the 3-year follow-up, 75% of the implants sites were registered with normal peri-implant mucosa and 68% with no visible plaque. The patients were fully satisfied with the esthetic and functional outcome of the treatment in 86% and 71%, respectively, at the 3-year follow-up visit. All reported data from dentists scored from acceptable to excellent. The multicenter study showed a high predictability of the zygoma implant-supported rehabilitation.


Dry, damp, and wet: correlates and presumed consequences of local alcohol ordinances.
Local alcohol ordinances were studied in the state of Tennessee where 28% of the population resides in jurisdictions that forbid the sale of alcohol to the public. Local alcohol ordinances range from "dry" (total prohibition) to "wet" (sale of alcohol permitted through both liquor stores and bars). Two alcohol-related variables (type of alcohol ordinance and number of alcohol outlets per 100,000 population) and four population variables (population size, percent change, percent residing in urban areas, percent non-White) were studied in relationship to four dependent variables (mortality rates resulting from motor vehicle crashes, liver disease and cirrhosis, suicide, and homicide). The results of the analysis suggest that these alcohol availability measures do play a role, directly and indirectly, in causing some socially deleterious behaviors and conditions. However, we would point out that the correlations between our alcohol availability measures and some of the socially injurious behaviors were very weak. The analyses reveal that complex inter-relationships exist between the variables studied such that no easy generalizations are warranted as to the social desirability of one type of alcohol ordinance policy over another since various population and demographic variables strongly interact with the alcohol availability measures in determining their social impact.


Robotic distal pancreatectomy using a docking-free system (the hinotori™ Surgical Robot System).
Although robotic surgery has rapidly spread in pancreatectomy [1], the procedure is performed by the da Vinci™ Surgical System (Intuitive Surgical Inc., CA), the most common surgical robot in the world [2]. We herein present our first experience of robotic distal pancreatectomy using a new Japanese surgical robot named the hinotori™ Surgical Robot System (Medicaroid Corporation, Kobe, Japan). A 68-year-old man who was found to have the mass lesion in the pancreatic tail in a medical examination. Investigations, including various imaging studies suggested a diagnosis of pancreatic cancer (Fig. 1). The patient was considered for robotic pancreatectomy. Five trocars, including one port for the assistant surgeon, were placed at the upper abdomen. The operation unit was rolled in from the right side (Fig. 2). The patient successfully underwent robotic distal pancreatectomy combined with dissection of the regional lymph nodes using the hinotori™ system. The cockpit surgeon performed all procedures, excluding port placement, vessel clipping, and transection of the pancreas. There were no unrecoverable device errors in this operation. The total operation time was 473 minutes, and the estimated blood loss was 182 ml. The postoperative course was uneventful, and hospital length of stay was 10 days. Pathological diagnosis was pancreatic cancer, T1N1M0, Stage ⅡB. Adjuvant chemotherapy using S-1 was administered, and he has survived without recurrence for 3 months after the curative resection. This is the first report of robotic pancreatectomy using the hinotori™ system, which showed the favorable perioperative results. The accumulation of experience and further studies are required to confirm its clinical benefits.


Targeting Intracellular Ion Homeostasis for the Control of Respiratory Syncytial Virus.
Respiratory syncytial virus (RSV) is a leading cause of mortality in infants and young children. Despite the RSV disease burden, no vaccine is available, and treatment remains nonspecific. New drug candidates are needed to combat RSV. Toward this goal, we screened over 2,000 compounds to identify approved drugs with novel anti-RSV activity. Cardiac glycosides, inhibitors of the membrane-bound Na+/K+-ATPase, were identified to have anti-RSV activity. Cardiac glycosides diminished RSV infection in human epithelial type 2 cells and in primary human airway epithelial cells grown at an air-liquid interface. Digoxin, a U.S. Food and Drug Administration-approved cardiac glycoside, was also able to inhibit infection of primary nasal epithelial cells with community isolates of RSV. Our results suggest that the antiviral effects of cardiac glycosides may be dependent on changes in the intracellular Na+ and K+ composition. Consistent with this mechanism, we demonstrated that the ionophoric antibiotics salinomycin, valinomycin, and monensin inhibited RSV in human epithelial type 2 cells and primary nasal epithelial cells. Our data indicate that the K+/Na+-sensitive steps in the RSV life cycle occur within the initial 4 hours of viral infection but do not include virus binding/entry. Rather, our findings demonstrated a negative effect on the RSV transcription and/or replication process. Overall, this work suggests that targeting intracellular ion concentrations offers a novel antiviral strategy.


Interest of Urinary [TIMP-2] × [IGFBP-7] for Predicting the Occurrence of Acute Kidney Injury After Cardiac Surgery: A Gray Zone Approach.
This study assessed the ability of 3-hour postoperative urinary tissue inhibitor of metalloproteinases-2 × insulin-like growth factor binding protein-7 ([TIMP-2] × [IGFBP-7]) to predict postoperative acute kidney injury (AKI) in patients undergoing cardiopulmonary bypass during cardiac surgery. Patients undergoing cardiac surgery with cardiopulmonary bypass were eligible for this study. Patients with initial chronic renal insufficiency requiring renal replacement therapy, patients <18 years of age, and parturients were not included. Anesthesia and hemodynamic management followed current practices. Urinary [TIMP2] × [IGFBP-7] was measured in 3-hour postoperative period. The primary objective was the occurrence of AKI (Kidney Disease: Improving Global Outcome [KDIGO] stage >0) within the first 48 hours postoperatively. The ability of urinary [TIMP-2] × [IGFBP-7] to predict postoperative AKI was assessed by building a receiver operating characteristic curve (with 95% confidence interval [CI] and by a gray zone approach that allowed either the prediction or the exclusion of postoperative AKI with a sensitivity >0.90 and a specificity >0.90). AKI occurred in 34 of 93 patients included (37%). The area under the receiver operating characteristic curve of urinary [TIMP-2] × [IGFBP-7] was 0.73 (95% CI, 0.62-0.83). The best cutoff value for urinary [TIMP-2] × [IGFBP-7] in predicting AKI was 0.3 ng/mL/1000 [0.09-1.40] (sensitivity = 76%; 95% CI, 73-97, specificity = 64%; 95% CI, 42-69). Urinary [TIMP-2] × [IGFBP-7] of <0.09 ng/mL/1000 and >1.40 ng/mL/1000 had a sensitivity and specificity >90% in predicting postoperative AKI. Fifty-nine patients (63%) were within the gray zone. In patients undergoing cardiopulmonary bypass during cardiac surgery, urinary [TIMP-2] × [IGFBP-7] could not accurately predict the occurrence of postoperative AKI.