Euploidy in somatic cells from R6/2 transgenic Huntington's disease mice.
Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a CAG repeat expansion in the HD gene. The huntingtin protein expressed from HD has an unknown function but is suggested to interact with proteins involved in the cell division machinery. The R6/2 transgenic mouse is the most widely used model to study HD. In R6/2 fibroblast cultures, a reduced mitotic index and high frequencies of multiple centrosomes and aneuploid cells have recently been reported. Aneuploidy is normally a feature closely connected to neoplastic disease. To further explore this unexpected aspect of HD, we studied cultures derived from 6- and 12-week-old R6/2 fibroblasts, skeletal muscle cells, and liver cells. Cytogenetic analyses revealed a high frequency of polyploid cells in cultures from both R6/2 and wild-type mice with the greatest proportions of polyploid cells in cultures derived from skeletal muscle cells of both genotypes. The presence of polyploid cells in skeletal muscle in vivo was confirmed by fluorescence in situ hybridisation with centromeric probes. Enlarged and supernumerary centrosomes were found in cultures from both R6/2 and wild-type mice. However, no aneuploid cells could be found in any of the tissues. We conclude that polyploid cells are found in fibroblast and skeletal muscle cultures derived from both R6/2 and wild-type littermate mice and that aneuploidy is unlikely to be a hallmark of HD.


Community-acquired methicillin-resistant Staphylococcus aureus outbreak in a local high school football team unsuccessful interventions.
A retrospective review of an outbreak of community-acquired methicillin-resistant Staphylococcus aureus soft tissue infections in a high school football team was conducted. Thirteen players had 20 infections. Available community-acquired methicillin-resistant S. aureus isolates showed identical antibiotic susceptibility and field inversion gel electrophoresis analysis band patterns. Nasal cultures and mupirocin were ineffective at predicting and controlling infection, respectively. Infections treated with beta-lactam antibiotics were at risk for recurrence.


Comparison of endothelial vasodilator function, inflammatory markers, and N-terminal pro-brain natriuretic peptide in patients with or without chronotropic incompetence to exercise test.
To investigate the role of endothelial function, inflammatory markers, and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with impaired chronotropic response during exercise test. 86 subjects were enrolled. Treadmill exercise test was conducted according to the modified Bruce protocols. Brachial ultrasound was used to measure endothelium dependent flow mediated vasodilatation (FMD). Chronotropic incompetence was defined as either failure to achieve 85% of the age predicted maximum heart rate or a low chronotropic index (< 0.8). Of the 86 patients, 20 (23%) exhibited chronotropic incompetence. The patients were divided into three groups according to chronotropic index: group 1, < 0.8 (n = 20); group 2, 0.8-1.0 (n = 26); and group 3, > 1.0 (n = 40). Patients with impaired chronotropic response had significantly lower FMD than those with higher chronotropic response (mean (SD) 2.8 (1.9)% v 5.0 (2.8)% v 5.3 (2.5)%, p = 0.002, for groups 1, 2, and 3, respectively). Serum concentrations of high-sensitivity C reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), and NT-proBNP were significantly higher in group 1 than in groups 2 and 3 (hsCRP: 19 (12) v 9 (6) v 9 (6) mg/l, p < 0.05; MCP-1: 140 (51) v 133 (60) v 108 (46) pg/ml, p = 0.046; NT-proBNP: 4760 (1980) v 3710 (850) v 3910 (1060) mg/l, p = 0.019, respectively). In addition, chronotropic index was significantly related to FMD (r = 0.380, p = 0.001) and inversely related to hsCRP (r = -0.267, p = 0.013). By multivariate analysis, impaired chronotropic response was significantly related to endothelial dysfunction (p = 0.012). Patients with impaired chronotropic response to graded exercise had endothelial dysfunction, enhanced systemic inflammation, and higher NT-proBNP concentrations. These findings may partly explain the mechanism of chronotropic incompetence as a predictor of cardiovascular risk and increased mortality.


[Reproduction of asthma model in ovalbumin-sensitized mice by ovalbumin challenge and lipopolysaccharide induction.].
to reproduce an asthma model in ovalbumin (OVA)-sensitized Balb/C mice by OVA challenge and Lipopolysaccharide (LPS) induction. one hundred and twenty BALB/C mice were randomly divided into 6 groups: PBS control group (A group, PBS sensitization and PBS challenge), OVA group (B group, OVA sensitization and OVA challenge), low-dose LPS/LPS group (C1 group, 50 microg LPS sensitization and 50 microg LPS challenge), high-dose LPS/LPS group (C2 group, 100 microg LPS sensitization and 100 microg LPS challenge), low-dose OVA/LPS group (D1 group, OVA sensitization, OVA challenge and 50 microg LPS induction) and high-dose OVA/LPS group (D2 group, OVA sensitization. OVA challenge and 100 microg LPS induction). Asthmatic symptoms were observed. Airway responsiveness were assessed and lung resistance (R(L)) was calculated using a proprietary software program. Cells in bronchoalveolar lavage fluid (BALF) were counted and lung histopathology was evaluated by HE staining. (1) asthma symptoms in either D1 group or D2 group was more severe than other groups, especially in D2 group. (2) The level of total BALF cells, macrophages, lymphocytes, eosinophils, and neutrophils in either D1 group or D2 group was significantly higher than that in A group (P < 0.05, P < 0.01). The level of total BALF cells, lymphocytes, eosinophils, and neutrophils in D1 group was significantly higher than that in B group (P < 0.01, respectively). The level of total BALF cells, macrophages, lymphocytes, and neutrophils in D2 group was significantly higher than those in B group (P < 0.05, respectively). (3) When mice were stimulated by Ach (5.0 g/L), R(L) in either D1 group [(9.32 +/- 1.51) cm H2Oxml(-1)xs(-1) (1 cm H2O = 0.098 kPa)] or D2 group [(44.21 +/- 2.88) cm H2Oxml(-1)xs(-1)] was significantly higher than that in A group [(2.41 +/- 0.35) cm H2Oxml(-1)xs(-1)] and B group [(5.96 +/- 1.83) cm H2Oxml(-1)xs(-1)] (P < 0.01, respectively). (4) More marked and extensive asthma-specific changes in lung was observed in either D1 group or D2 group, especially in D2 group. LPS induction in OVA-sensitized Balb/C mice can lead to more severe airway inflammation and greater airway hyperresponsiveness.


Dietary intake and adequacy of vitamin K.
The current daily recommended dietary allowance for vitamin K is 1 microg/kg. Reliable measurements of vitamin K content in foods are now available, and data from 11 studies of vitamin K intake indicate that the mean intake of young adults is approximately 80 microg phylloquinone/d and that older adults consume approximately 150 microg/d. The vitamin K concentration in most foods is very low (<10 microg/100 g), and the majority of the vitamin is obtained from a few leafy green vegetables and four vegetable oils (soybean, cottonseed, canola and olive) that contain high amounts. Limited data indicate that absorption of phylloquinone from a food matrix is poor. Hydrogenated oils also contain appreciable amounts of 2', 3'-dihydrophylloquinone of unknown physiological importance. Menaquinones absorbed from the diet or the gut appear to provide only a minor portion of the human daily requirement. Measures of the extent to which plasma prothrombin or serum osteocalcin lack essential gamma-carboxyglutamic acid residues formed by vitamin K action, or the urinary excretion of this amino acid, provide more sensitive measures of vitamin K status than measures of plasma phylloquinone or insensitive clotting assays.


Soil-pH and cement influence the weathering kinetics of chrysotile asbestos in soils and its hydroxyl radical yield.
Chrysotile asbestos is a toxic and carcinogenic mineral that has been used in a variety of industrial and consumer applications. Much of the fiber- and cement-containing asbestos waste has ended up in terrestrial environments. Chrysotile weathering in soils and the potential for natural attenuation have, however, hardly been examined yet. Here we explored how soil properties influence the dissolution rate of chrysotile, the release of the carcinogenic metals chromium and nickel, and the hydroxyl radical (HO•) generation by chrysotile fibers. Chrysotile dissolution rates in soil suspensions decreased with increasing soil-pH and were lower than reported rates in soil-free systems. Dissolved organic carbon did not markedly accelerate dissolution at circumneutral pH, whereas cement mixed with soil inhibited dissolution because of its alkalinity. The HO•-yield of incubated fibers in non-amended soils eventually decreased by 60-75%. The decline was fastest in an acidic podzol soil, yet was followed by a small rebound. Cement amendment induced the largest HO•-yield reduction (∼90%), presumably due to surface coating of the fibers. Overall, this work demonstrates that the potential for natural attenuation of chrysotile asbestos in soils critically depends on soil chemical parameters and the presence of cement in association with the fibers.


The prophylactic use of polyvinylpyridine-N-oxide (PVNO) in baboons exposed to quartz dust.
Twelve baboons were exposed to a quartz dust cloud. Four of these were also given polyvinylpyridine-N-oxide (PVNO) by aerosol and four received PVNO by aerosol and injection. A prophylactic effect was demonstrated during the course of treatment, but when treatment stopped the silicosis progressed to the same degree of severity as in the untreated animals.


Factors influencing the readiness to tackle the burden of ischaemic heart disease in India: a systematic review protocol.
Ischaemic heart disease (IHD) is one of the leading causes of death and disease burden in India affecting all age groups. To reduce the deaths and tackle the burden of existing IHD, the government approach has been mostly through the National Health Policy (2017) and National Programme for Prevention and Control of Diabetes, Cardiovascular diseases and Stroke. This paper offers a protocol for the systematic review of studies exploring the factors influencing service readiness of the public health system of India to tackle the burden of IHD. Electronic databases of Embase (Ovid), AMED (Ovid), HMIC (Ovid), BNI (ProQuest), CINAHL (EBSCO), EMCARE (Ovid), PsycINFO (ProQuest), MEDLINE/PubMed and Web of Science (Clarivate Analytics) will be searched till 2020 for primary studies. Grey literature will be accessed through OpenGrey, TRIP Medical, WHO database, MoHFW website, Open Government Data (OGD) Platform of India and Google Scholar (between 2010 and 2020). Primary studies meeting the eligibility criteria and grey literature published in English between 2010 and 2020 will be included. Data will be analysed through a conceptual framework, and the primary outcome will constitute both quantitative and qualitative data. The quality of included studies will be assessed based on study design. Data will be managed on the COVIDENCE platform. All authors will be involved in data extraction, quality appraisal, data synthesis and formulation of the final draft. This study, being a systematic review, does not involve any clinical trial, primary data collection or empirical study involving humans or animals. Therefore, no ethical permissions were sought by reviewers. CRD42020219490.


[The sphenoid: tumoral pathology].
The interest and difficulty of sphenoid tumor imaging relate mainly to its great diversity. Detection may be difficult due to variable tumor size and often misleading clinical data. Because the sphenoid is located at the center of the skull base, tumor extension may be quite variable and difficult to assess, requiring sufficient knowledge of anatomy and imaging features to detect tumor spread, especially retrograde perineural spread, since this has a negative impact on prognosis.


Examining the Intervening Roles of Patient-Centered Care and Patient Activation in the Health Impacts of Offline Healthcare Obstacles and Online Health Consultations Among Deaf and Hard-of-Hearing Patients.
Deaf and hard-of-hearing (DHH) patients often encounter difficulties in effective communication with healthcare professionals and are less likely to receive quality medical care. However, DHH populations are understudied in health communication research. This study examined how offline healthcare obstacles and online health consultation impact DHH patients' health, and the mediating roles of patient-centered care (PCC) and patient activation. Data from 323 DHH patients were analyzed using structural equation modeling to test the hypothesized mediation pathway model. Results indicate that offline healthcare obstacles negatively affect DHH patients' perception of patient-centeredness, which reduces their ability and confidence in self-care (conceptualized as patient activation in this study). This reduced patient activation may jeopardize DHH patients' physical and psychological health. Meanwhile, online health consultation is positively associated with PCC, and higher levels of PCC can increase patient activation, contributing to better physical and psychological health. Testing the same model with hearing-abled participants (n = 3542) revealed significant differences in these intervening relationships. Overall, this study provides valuable insights into the relationship between DHH patients' healthcare experience and their health outcomes. The findings support interventions that focus on enhancing PCC and patient activation to improve the physical and psychological health outcomes of DHH patients.


[The evaluation of resource support and organization of medical care of patients of pulmonology profile].
The article presents the results of evaluation of resource support and organization of medical care of patients of pulmonological profile on the territory of the Amurskaia and Yaroslavskaia oblast. The data permits establishing the regional differences and reserves of the oblasts for increasing effectiveness of curative and preventive activities in the field of pulmonology. The analysis of study results testify necessity of implementing complex of organizational methodical activities targeted to development of medical care at the level of primary health care in accordance with acting regulations and standards.


Draft Genome Sequence of the Polysaccharide-Degrading Marine Bacterium Pseudoalteromonas sp. Strain A601.
Pseudoalteromonas sp. strain A601 is a marine bacterium with excellent polysaccharide-degrading capabilities. Here, we present a high-quality draft genome sequence of strain A601 with a size of approximately 4.89 Mb and a mean G+C content of 40.0%. Various putative polysaccharide-degrading genes were found in the draft genome.


Correlativity between blood measures related to blood stasis blocking collaterals and gene expression of angiotensin-converting enzyme of renal cortex in diabetic rats and effect of stasis removing and collaterals dredging.
To investigate the correlativity between the changes of blood measures related to blood stasis blocking collaterals and gene expression levels of angiotensin-converting enzyme (ACE) and ACE2 of renal cortex in diabetic rats with stasis blocking collaterals syndrome, as well as the effect of stasis removing and collaterals dredging. Male Sprague-Dawley rats were divided randomly into normal control group (C group), high-carbohydrate-fat control group (H group) and streptozotocin (STZ)-injecting group. The diabeticrats were induced from rats in the STZ-injecting, group by high-carbohydrate-fat diet combined with STZ intraperitoneal injection, with sustained high-carbohydrate-fat diet fed afterwards, and were further divided into model group (M group) and Chinese medicine of stasis removing and collaterals dredging group (Z group). Rats in the Z group were fed with stasis-removing-and-collaterals-dredging herbal granule suspension intragastrically daily for 16 weeks, while drinking water of corresponding volume was administrated to the rats in other groups. At the end of the 16th week after successful establishment of models, the ultrastructures of glomeruli in different groups were detected by a transmission electron microscopy; and blood measures related to blood stasis blocking collaterals, including lipid profile and blood viscosity measures, were tested, as well as the relative gene expressions of ACE and ACE2. Changes in ultrastructures of glomeruli in the M group were characterized by lack of clarity in structure and occasional thickening of glomerular basement membrane and extensive fusion in foot processes. The correlation analysis showed that there were positive correlations between lipid profile, blood viscosity, and the ACE mRNA expression levels in the M group (P < 0.05), except for cholesterol. And except for triglyceride, the blood measures were in negative correlation with the ACE2 mRNA expression levels in the M group (P < 0.05). Compared with the C and H groups, the lipid profile, plasma viscosity and blood viscosity were significantly higher (P < 0.01). All the above-mentioned measures were significantly improved in the Z group rats (P < 0.05). ACE mRNA expression was significantly higher in the M group than in the C group(P < 0.05). ACE2 mRNA level was significantly lower in the M group than in the C and H groups (P < 0.01); and its level in the Z group was higher than that in the M group (P < 0.01). Blood measures related to blood stasis blocking collaterals had positive linear correlations with ACE mRNA expression and negative linear correlations with ACE2 mRNA expression in the M group. Chinese recipe of stasis removing and collaterals dredging could play a renal protecting role for diabetic rats by reducing lipid profile and blood viscosity, down-regulating ACE mRNA expression and up-regulating ACE2 mRNA expression.


Five-year field results and long-term effectiveness of 20 mg/kg liposomal amphotericin B (Ambisome) for visceral leishmaniasis in Bihar, India.
Visceral Leishmaniasis (VL; also known as Kala-azar) is an ultimately fatal disease endemic in Bihar. A 2007 observational cohort study in Bihar of 251 patients with VL treated with 20 mg/Kg intravenous liposomal amphotericin B (Ambisome) demonstrated a 98% cure rate at 6-months. Between July 2007 and August 2012, Médecins Sans Frontières (MSF) and the Rajendra Memorial Research Institute (RMRI) implemented a VL treatment project in Bihar, India-an area highly endemic for Leishmania donovani-using this regimen as first-line treatment. Intravenous Ambisome 20 mg/kg was administered in four doses of 5 mg/kg over 4-10 days, depending on the severity of disease. Initial clinical cure at discharge was defined as improved symptoms, cessation of fever, and recession of spleen enlargement. This observational retrospective cohort study describes 8749 patients with laboratory-confirmed primary VL treated over a 5-year period: 1396 at primary healthcare centers, 7189 at hospital, and 164 at treatment camps. Initial clinical cure was achieved in 99.3% of patients (8692/8749); 0.3% of patients (26/8749) defaulted from treatment and 0.4% (31/8749) died. Overall, 1.8% of patients (161/8749) were co-infected with HIV and 0.6% (51/8749) with tuberculosis. Treatment was discontinued because of severe allergic reactions in 0.1% of patients (7/8749). Overall, 27 patients (0.3%) were readmitted with post Kala-azar dermal leishmaniasis (PKDL). Risk factors for late presentation included female sex, age >15 years and being from a scheduled caste. In 2012, a long-term efficacy survey in the same area of Bihar determined relapse rates of VL after 5 years' intervention with Ambisome. Of 984 immunocompetent patients discharged between September 2010 and December 2011, 827 (84.0%) were traced in order to determine their long-term outcomes. Of these, 20 patients (2.4%) had relapsed or received further treatment for VL. Of those completing 6, 12, and 15 month follow-up, 0.3% (2/767), 3.7% (14/383), and 2.4% (4/164), respectively, had relapsed. The mean ±SD time-to-relapse was 9.6±3.0 months. This is the largest cohort of VL patients treated with 20 mg/kg Ambisome worldwide. The drug has high initial and long-term efficacy, and a low rate of adverse reactions when administered under field conditions in Bihar, India. Although challenging, its use as first line treatment in rural settings in Bihar is safe and feasible.


In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is a disease characterized by microvascular thrombosis, often associated with deficiency of the vonWillebrand factor (VWF) cleaving protease ADAMTS13. We investigated the spectrum of ADAMTS13 gene mutations in patients with TTP and congenital ADAMTS13 deficiency to establish the consequences on ADAMTS13 processing and activity. We describe five missense (V88M, G1239V, R1060W, R1123C and R1219W), 1 nonsense (W1016Stop) and 1 insertion (82_83insT) mutations. In two patients no mutation was identified despite undetectable protease activity. Expression in HEK293 mammalian cells (V88M, G1239V, R1123C and R1219W) documented that three missense mutants were not secreted, whereas theV88M was secreted at low levels and with reduced activity. We also provide evidence that impaired secretion of ADAMTS13 mutants observed in vitro translates into severely reduced ADAMTS13 antigen levels in patients in vivo. To evaluate whether the small amounts of mutant protease present in the circulation of patients had VWF cleaving activity, WT and mutant rADAMTS13 were stably expressed in Drosophila S2 cells under the influence of the Drosophila BiP protein signal sequence, which allows protein secretion. Drosophila expression system showed a 40-60% protease activity in the mutants. Several single nucleotide polymorphisms (SNPs) within exons and intron boundaries were found in patients, suggesting that the interplay of SNPs could at least in part account for ADAMTS13 functional abnormalities in patients without mutations. In conclusion, defective secretion and impaired activity of the mutants concur to determine an almost complete deficiency of ADAMTS13 activity in patients with a homozygous or two heterozygous ADAMTS13 mutations.


Retrospective Analysis of a New Prognostic Score for Diffuse Large B-Cell Lymphoma Based on Interim Positron Emission Tomography-Computed Tomography.
The International Prognostic Index (IPI) scoring system is the most widely used prognostic tool for diffuse large B-cell lymphoma (DLBCL); however, it fails to consistently identify patients with poor outcomes. This retrospective study was undertaken to confirm the clinical value of a new prognostic score and compare it with the IPI. The aim of this single-center study was to confirm the clinical value of a new prognostic score and its association with various clinical features, disease progression, and death in 70 patients with DLBCL who had undergone at least 6 cycles of chemotherapy. The IPI and the new prognostic index were both associated with 3-year mortality (p ≤ 0.032); however, only the new prognostic index was associated with 3-year progression (p ≤ 0.036). Multivariate analysis showed that the new prognostic index was associated with 3-year progression but not overall survival. The new prognostic score also distinguished 3-year progression-free survival and overall survival in the low- and low-intermediate-risk groups as well as in the low-intermediate- and high-intermediate-risk groups. The new prognostic score represents a comprehensive prognostic model superior to the IPI. Prospective studies are necessary to explore whether treatment strategies may be adjusted using this new prognostic score.


[Medical teaching in the middle age].
History of medical teaching during the Middle Age is an interesting field of study and research; medicine, at least from XIII century, is largely based on the way in which every other kind of knowledge is transmitted into the Scholastic philosophy. Medieval medical studies are deeply different from the standard offered by classical antiquity or by university teaching of Modern Age.


Synthesis, structure, and magnetic properties of the NaCoXO4F·2H2O phases where X = S and Se.
A novel hydrated fluoroselenate NaCoSeO(4)F·2H(2)O has been synthesized, and its structure determined. Like its sulfate homologue, NaCoSO(4)F·2H(2)O, the structure contains one-dimensional chains of corner-sharing MO(4)F(2) octahedra linked together through F atoms sitting in a trans configuration with respect to each other. The magnetic properties of the two phases have been investigated using powder neutron diffraction and susceptibility measurements which indicate antiferromagnetic ordering along the length of the chains and result in a G-type antiferromagnetic ground state. Both compounds exhibit a Néel temperature near 4 K, and undergo a field-induced magnetic phase transition in fields greater than 3 kOe.


Structural characterization of photodegradation products of enalapril and its metabolite enalaprilat obtained under simulated environmental conditions by hybrid quadrupole-linear ion trap-MS and quadrupole-time-of-flight-MS.
In the environment, organic micropollutants such as pharmaceuticals can be degraded via various biotic and abiotic transformation routes. In surface waters, for example, photodegradation may constitute a relevant natural attenuation process for drug residues that have been discharged from sewage treatment facilities. In the present work, the photochemical fate of the prodrug enalapril (376 Da, C20H28N2O5) and its active metabolite enalaprilat (348 Da, C18H24N2O5), a hypotensive cardioprotector previously reported to occur in contaminated rivers, was investigated in aqueous media under the influence of irradiation generated by a sunlight simulator. The experiments yielded three detectable photodegradates for enalapril (346 Da, 2 x 207 Da) whereas the photolysis of enalaprilat went hand in hand with the intermittent buildup of one photodegradate (304 Da). Fragmentation patterns of the parent compounds were established on a hybrid quadrupole-linear ion trap-mass spectrometer exploiting its MS3 capabilities. Accurate mass measurements recorded on a hybrid quadrupole-time-of-flight instrument in MS/MS mode allowed us to propose elemental compositions for the molecular ions of the degradates (346 Da, C19H26N2O4; 207 Da, C12H17NO2; 304 Da, C17H24N2O3) as well as of their fragment ions. Based on these complementary data sets from the two distinct mass spectrometric instruments, plausible structures were postulated for the four photodegradates. The compounds formed by enalapril corresponded to the loss of formaldehyde out of the proline residue (346 Da), cleavage of the central amide bond (207 Da) followed by migration of the ethylester side chain (207 Da) while decarboxylation of the free carboxylic acid was described for enalaprilat (304 Da). The study emphasized the potential of sunlight for breaking down an environmentally relevant drug and its metabolite.


Notch Suppression Collaborates with Ascl1 and Lin28 to Unleash a Regenerative Response in Fish Retina, But Not in Mice.
Müller glial (MG) cells in the zebrafish retina respond to injury by acquiring retinal stem-cell characteristics. Thousands of gene expression changes are associated with this event. Key among these changes is the induction of Ascl1a and Lin28a, two reprogramming factors whose expression is necessary for retina regeneration. Whether these factors are sufficient to drive MG proliferation and subsequent neuronal-fate specification remains unknown. To test this, we conditionally expressed Ascl1a and Lin28a in the uninjured retina of male and female fish. We found that together, their forced expression only stimulates sparse MG proliferation. However, in combination with Notch signaling inhibition, widespread MG proliferation and neuron regeneration ensued. Remarkably, Ascl1 and Lin28a expression in the retina of male and female mice also stimulated sparse MG proliferation, although this was not enhanced when combined with inhibitors of Notch signaling. Lineage tracing in both fish and mice suggested that the proliferating MG generated multipotent progenitors; however, this process was much more efficient in fish than mice. Overall, our studies suggest that the overexpression of Ascl1a and Lin28a in zebrafish, in combination with inhibition of Notch signaling, can phenocopy the effects of retinal injury in Müller glia. Interestingly, Ascl1 and Lin28a seem to have similar effects in fish and mice, whereas Notch signaling may differ. Understanding the different consequences of Notch signaling inhibition in fish and mice, may suggest additional strategies for enhancing retina regeneration in mammals.SIGNIFICANCE STATEMENT Mechanisms underlying retina regeneration in fish may suggest strategies for stimulating this process in mammals. Here we report that forced expression of Ascl1 and Lin28a can stimulate sparse MG proliferation in fish and mice; however, only in fish does Notch signaling inhibition collaborate with Ascl1a and Lin28a to stimulate widespread MG proliferation in the uninjured retina. Discerning differences in Notch signaling between fish and mice MG may reveal strategies for stimulating retina regeneration in mammals.


The detection value of PD-L1 expression in biopsy specimens and surgical resection specimens in non-small cell lung cancer: a meta-analysis.
The detection value of different types of specimens for programmed death ligand-1 (PD-L1) expression remains controversial. As such, the purpose of this meta-analysis was to compare the detection value of biopsy specimens and surgical resection specimens for PD-L1 expression in patients with non-small cell lung cancer (NSCLC). PubMed and Web of Science were searched prior to December 2020 to identify studies that compared the detection value of biopsy specimens and surgical resection specimens for PD-L1 expression in NSCLC. Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 scale was used to evaluate the quality of the literature included. The detection value of different types of specimens for PD-L1 expression was then assessed. Besides, the relative risk (RR) with 95% CI were pooled using Review Manager 5.3 software and Stata 14.0 software. The meta-analysis involved 12 articles and included 877 patients. There was no significant difference in the detection rate of PD-L1 at the 1% cutoff between biopsy specimens and surgical resection specimens (RR =0.89, 95% CI: 0.70-1.12, P=0.33). However, there was a significant difference between two groups when the cutoff is 50% (RR =0.69, 95% CI: 0.58-0.83, P<0.01). In addition, a subgroup analysis of the type of biopsy specimens and the PD-L1 qualitative immunohistochemistry (IHC) assays showed that the detection rate of PD-L1 in small biopsies and using the SP142 antibody were lower than in surgical specimens and using other antibodies for both the 1% and 50% cut-offs (P<0.01). Current evidence suggests that caution must be taken when using biopsy specimens from patients with advanced NSCLC to evaluate PD-L1 status eligible for immunotherapy, additional biopsy specimens sampling may be needed to minimize the risk of tumor misclassification. In addition, PD-L1 qualitative IHC assays and the type of biopsy specimens related to PD-L1 expression detection.


A new applicability of the suppressive Nauta method in the early phase of neuronal damage.
A new applicability of the suppressive Nauta impregnation method was tested allowing the detailed mapping of early neuronal damage expressed in the form of somatodendritic argyrophilia. Two spinal cord ischemia-reperfusion models of rabbit and dog, a model of canine global brain ischemia-reperfusion, involving cardiac arrest followed by resuscitation, and a canine spinal cord compression-decompression model were used. Early phases of neuronal damage are characterized by conspicuous somatodendritic argyrophilia permitting an exact evaluation of acute neuronal damage according to soma size, dendritic ramifications and localization of the affected neuronal neuronal pool. By its high sensitivity to somatodendritic damage the suppressive Nauta method appears to be a valuable neuropathological technique.


Software tools that facilitate kinetic modelling with large data sets: an example using growth modelling in sugarcane.
A solution to manage cumbersome data sets associated with large modelling projects is described. A kinetic model of sucrose accumulation in sugarcane is used to predict changes in sucrose metabolism with sugarcane internode maturity. This results in large amounts of output data to be analysed. Growth is simulated by reassigning maximal activity values, specific to each internode of the sugarcane plant, to parameter attributes of a model object. From a programming perspective, only one model definition file is required for the simulation software used; however, the amount of input data increases with each extra interrnode that is modelled, and likewise the amount of output data that is generated also increases. To store, manipulate and analyse these data, the modelling was performed from within a spreadsheet. This was made possible by the scripting language Python and the modelling software PySCeS through an embedded Python interpreter available in the Gnumeric spreadsheet program.


Contrast-enhanced ultrasound of the pancreas.
The introduction of contrast-enhanced ultrasonography (CEUS) has led to major improvements in the diagnostic capabilities of ultrasound (US). The innovative use of CEUS for study of the pancreas has created the need for a definition of the most frequent dynamic features of solid and cystic masses. CEUS is less expensive compared to computed tomography and magnetic resonance imaging and is able to significantly improve the accuracy of US, allowing better characterization and staging of pancreatic pathologies.


Defining human-AI teaming the human-centered way: a scoping review and network analysis.
With the advancement of technology and the increasing utilization of AI, the nature of human work is evolving, requiring individuals to collaborate not only with other humans but also with AI technologies to accomplish complex goals. This requires a shift in perspective from technology-driven questions to a human-centered research and design agenda putting people and evolving teams in the center of attention. A socio-technical approach is needed to view AI as more than just a technological tool, but as a team member, leading to the emergence of human-AI teaming (HAIT). In this new form of work, humans and AI synergistically combine their respective capabilities to accomplish shared goals. The aim of our work is to uncover current research streams on HAIT and derive a unified understanding of the construct through a bibliometric network analysis, a scoping review and synthetization of a definition from a socio-technical point of view. In addition, antecedents and outcomes examined in the literature are extracted to guide future research in this field. Through network analysis, five clusters with different research focuses on HAIT were identified. These clusters revolve around (1) human and (2) task-dependent variables, (3) AI explainability, (4) AI-driven robotic systems, and (5) the effects of AI performance on human perception. Despite these diverse research focuses, the current body of literature is predominantly driven by a technology-centric and engineering perspective, with no consistent definition or terminology of HAIT emerging to date. We propose a unifying definition combining a human-centered and team-oriented perspective as well as summarize what is still needed in future research regarding HAIT. Thus, this work contributes to support the idea of the Frontiers Research Topic of a theoretical and conceptual basis for human work with AI systems.


[Clinical analysis of 12 cases of long bone ossifying fibromas].
Twelve cases of ossifying fibroma of long bones, the lesions in 11 cases were resected with their sclerotic margin. Inactivation of the tumor cells within bone cavity was applied 50% Zinc Chloride, and autogenous bone grafts were applied with or without a few man-made bones. One case was treated by en bloc resection of the lesion. Follow-up for 3-14 years revealed that 2 cases recurred, and secondary operation was performed. After that follow-up for 5-14 years revealed no-recurrence. Recurrence rate of these cases was low and the effect of treatment was satisfactory. This kind of lesion showed the features of its aggressive growth and proneness to recur after operation. The authors consider that resection of the lesion including its sclerotic margin was effective to prevent recurrence.


Incidental vascular findings on brain magnetic resonance angiography.
Given the ever-increasing utilization of magnetic resonance angiography, incidental vascular findings are increasingly discovered on exams performed for unconnected indications. Some incidental lesions represent pathology and require further intervention and surveillance, such as aneurysm, certain vascular malformations, and arterial stenoses or occlusions. Others are benign or represent normal anatomic variation, and may warrant description, but not further work-up. This review describes the most commonly encountered incidental findings on magnetic resonance angiography, their prevalence, clinical implications, and any available management recommendations.


[Pharmacokinetic and clinical evaluations of ceftriaxone in perinatal infections in obstetrics and gynecology].
Ceftriaxone (CTRX), an injectable cephem antibiotic agent, was studied for its pharmacokinetic properties and clinical usefulness in perinatal infections in obstetrics and gynecology on a multicenter basis. The study results are summarized below. 1. Following the one-shot intravenous injection of CTRX 1 g to pregnant women before labor, the maternal serum level of CTRX reached a peak at 131.8 micrograms/ml soon after the injection then it began to decrease gradually. T 1/2 was 6.7 hours. The umbilical serum level reached a peak at 16.0 micrograms/ml at 4.9 hours post-dose and decreased gradually with a half-life of 8.1 hours. The umbilical serum level was higher than the maternal serum level at about 12 hours post-dose. The amniotic fluid level reached a peak of 9.6 micrograms/ml at 12.8 hours post-dose. T 1/2 was 15.2 hours. The amniotic fluid level at about 15 hours post-dose or later exceeded the maternal serum level and was almost equal to the umbilical serum level at 24 hours post-dose. 2. Clinical usefulness was evaluated in 79 evaluable cases out of 89 treated for various infections at puerperium or for prophylaxis of infections at cesarean section or premature rupture of membranes (PROM). The efficacy rate was 100% in 7 cases of prenatal infections such as urinary tract infection and 30 cases of postnatal infections such as puerperal intrauterine infections. In 42 cases treated for prophylaxis in cases of cesarean section or PROM, the efficacy rate was 92.9%. Bacteriologically, 29 strains of pathogens were isolated from 26 cases. The disappearance rate of the pathogens was 96.0% as 23 strains were eradicated, 1 strain was substituted and no change was observed in 1 strain with unknown results in 4 strain. Skin rash and itching appeared in 1 patient as an adverse effect (1.1%). There were 10 cases of abnormal clinical laboratory test results such as elevated transaminase level were observed in 7 patients (7.9%). From the results, CTRX was considered to be a useful drug for the perinatal infection in the obstetrics and gynecology fields.


A strip-type microthrottle pump: modeling, design and fabrication.
A novel design for a strip-type microthrottle pump with a rectangular actuator geometry is proposed, with more efficient chip surface consumption compared to existing micropumps with circular actuators. Due to the complex structure and operation of the proposed device, determination of detailed structural parameters is essential. Therefore, we developed an advanced, fully coupled 3D electro-fluid-solid mechanics simulation model in COMSOL that includes fluid inertial effects and a hyperelastic model for PDMS and no-slip boundary condition in fluid-wall interface. Numerical simulation resulted in accurate virtual prototyping of the proposed device only after inclusion of all mentioned effects. Here, we provide analysis of device operation at various frequencies which describes the basic pumping effects, role of excitation amplitude and backpressure and provides optimization of critical design parameters such as optimal position and height of the microthrottles. Micropump prototypes were then fabricated and characterized. Measured characteristics proved expected micropump operation, achieving maximal flow-rate 0.43 mL·min(-1) and maximal backpressure 12.4 kPa at 300 V excitation. Good agreement between simulation and measurements on fabricated devices confirmed the correctness of the developed simulation model.


Diversity of Astroviruses Circulating in Humans, Bats, and Wild Birds in Egypt.
Astroviruses belong to Astroviridae family which includes two main genera: Mamastroviruses that infect mammals, and Avastroviruses that infect avian hosts. Bats and wild birds are considered among the natural reservoirs for astroviruses. Infections in humans are associated with severe gastroenteritis, especially among children. We conducted surveillance for astroviruses in bats, wild birds, and humans in Egypt. Our results indicated relatively high prevalence of astroviruses in those hosts. Phylogenetic analysis revealed diversity of these viruses within hosts. Detected human viruses showed similarity with classic and variant human astroviruses, as well as similarity with animal-origin viruses. Viruses in bats were dispersed, with similarities to other bat viruses as well as other mammalian, including human, viruses. Wild bird viruses varied and were related to other avastroviruses, as well as human astroviruses. Our results indicate that astroviruses are common in bats, wild birds, and humans in Egypt, with a wide gene pool. Potential cross-species transmission may be occurring but should be verified by further surveillance and molecular studies.


Cardiac implantable electronic device and vascular access: Strategies to overcome problems.
For arrhythmia treatment or sudden cardiac death prevention in hemodialysis patients, there is a frequent need for placement of a cardiac implantable electronic device (pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization device). Leads from a cardiac implantable electronic device can cause central vein stenosis and carry the risk of tricuspid regurgitation or contribute to infective endocarditis. In patients with end-stage kidney disease requiring vascular access and cardiac implantable electronic device, the best strategy is to create an arteriovenous fistula on the contralateral upper limb for a cardiac implantable electronic device and avoidance of central vein catheter. Fortunately, cardiac electrotherapy is moving toward miniaturization and less transvenous wires. Whenever feasible, one should avoid transvenous leads and choose alternative options such as subcutaneous implantable cardioverter defibrillator, epicardial leads, and leadless pacemaker. Based on recent reports on the leadless pacemaker/implantable cardioverter defibrillator effectiveness, in patients with rapid progression of chronic kidney disease (high risk of renal failure) or glomerular filtration rate <20 mL/min/1.73 m2, this option should be considered by the implanting cardiologist for future access protection.


Asynchrony, fragmentation, and scale determine benefits of landscape heterogeneity to mobile herbivores.
Understanding the ways that resource heterogeneity shapes the performance of individuals and the dynamics of populations offers a central challenge in contemporary ecology. Emerging evidence shows that herbivores track heterogeneity in nutritional quality of vegetation by responding to phenological differences in plants, differences that result from spatial and temporal variation in conditions favoring plant growth. Theory predicts that when spatial variation in temperature, nutrients, or moisture results in spatially asynchronous pulses of plant growth, herbivores are able to prolong the period during which they have access to forage of peak nutritional value. Although this idea has substantial support from observational and modeling studies, it has not been examined experimentally. We hypothesized that access to asynchronous resources enhances nutritional status and growth of herbivores and that the magnitude of this effect depends on the scale of access relative to the grain of resources. We tested these hypotheses in mesocosm experiment using the migratory grasshopper, Melanoplus sanguinipes, feeding on young wheat and protein-rich bran as a model system. We demonstrated access to asynchronous pulses in resources enhanced the efficiency of use of high quality resource use and increased growth of individuals by 13%. Disruption of this mechanism when landscapes were fragmented lowered efficiency of resource use and caused growth of individuals to decline by 15%. However, the strength of the effects of fragmentation on herbivore performance depended on the spatial extent of fragmentation relative to the spatial and temporal grain of resource emergence. Our findings add experimental support to modeling and observational studies that have linked herbivore performance to spatial and temporal variation in plant phenology. We also offer evidence that fragmentation can impair herbivore performance, even when the total amount and quality of resources on landscapes remains unchanged.


Congenital mitral stenosis. A review of 20 years' experience.
The clinical course of 38 patients with congenital mitral stenosis (MS) is reviewed. Associated cardiac defects were present in 28 patients, including tetralogy of Fallot in five. In all but one of the eight patients with supravalvar mitral ring (SVR), there were concomitant abnormalities of the mitral valve. Delay in the diagnosis of MS was common. Serial cardiac catheterizations and pulmonary pathologic examination indicated that pulmonary vascular obstructive disease develops during childhood. Mitral valve surgery was performed in 19 of 38 patients: valvotomy alone in eight, excision of SVR in five (two ofwhom also had valvotomy) and mitral valve replacemtnt in seven. Additional non-mitral cardiac surgery was performed in 18 patients. Overall surgical mortality was 49%; mortality for surgery on the mitral valve was 26%. Only patients having mitral valve replacement or with isolated SVR which was then resected became asymptomatic and had normal hemodynamics on postoperative catheterization.


Thromboembolic and bleeding complications during oral anticoagulation therapy in cancer patients with atrial fibrillation: a Danish nationwide population-based cohort study.
Coexisting cancer in patients with atrial fibrillation (AF) has been associated with thromboembolism and bleeding. We used Danish population-based medical databases to conduct a population-based cohort study that included all AF patients who redeemed a prescription for vitamin K antagonists (VKA) or non-VKA oral anticoagulant (NOAC) between July 2004 and December 2013. We characterized these patients according to the presence (N = 11,855) or absence (N = 56,264) of a cancer diagnosis before redemption of their oral anticoagulant prescription, and then examined their 1-year risk of thromboembolic or bleeding complications or death. We next used Cox regression to compare the hazard ratios for complications among VKA- or NOAC-treated AF patients with versus without a cancer diagnosis, after adjusting for sex, age, and CHA2 DS2 VASc score. One-year risks of thromboembolic complications in AF patients who redeemed a VKA prescription were similar in those with (6.5%) and without (5.8%) cancer [hazard ratio (HR) 1.0 (95% confidence interval (CI): 0.93, 1.1)]. This also was found for bleeding complications (5.4% vs. 4.3%, HR 1.1 [95% CI: 1.0, 1.2]). For AF patients with cancer who redeemed a NOAC prescription, risks were also similar for thromboembolic complications (4.9% of cancer patients vs. 5.1% of noncancer patients, HR 0.80 [95% CI: 0.61, 1.1]), and for bleeding complications (4.4% vs. 3.1%, HR 1.2 [95% CI: 0.92, 1.7]). The absolute risks of thromboembolic or bleeding complications were nearly the same in patients with and without cancer who redeemed prescription for VKAs or NOACs.


Fatherless adolescents' feelings about their mothers--a pilot study.
Data from a study on feelings of Jerusalem high school students about their parents were used to explore fatherless adolescents' feelings about their mothers. Only eighteen such cases were found in this population and they were divided into two groups: twelve girls and six boys. The boys and the girls from two-parent families served as control groups. Statistical evaluation showed that fatherless adolescent girls perceived their mothers as significantly less benevolent (p less than 0.01) than girls from two-parent families of similar sociodemographic background. In the smaller group of boys no differences were found.


Inflammation Effects on Glutamate as a Pathway to Neuroprogression in Mood Disorders.
Neuroprogression is a term used to describe worsening psychopathology, poor treatment response, and declining cognitive and functional outcomes among patients with chronic mental disorders. Chronic inflammatory activation and glutamate-mediated excitotoxicity are two key etiological factors implicated in the development of neuroprogression. In this chapter, we hypothesize that the association between chronic inflammatory activation, neuroprogression, and glutamate dysregulation might be mediated by glial dysfunction. The role played by other mechanisms that increase glutamatergic activity, including oxidative stress and kynurenine pathway activation, will also be discussed, albeit briefly. We will conclude by providing a mechanistic model that draws upon our previous research, to link neuroimmune/neurotransmitter dysregulation to disrupted local neural activity and brain network connectivity eventually leading to a neuroprogressive course and associated clinical outcomes.


Kaposi Sarcoma of Childhood: Inborn or Acquired Immunodeficiency to Oncogenic HHV-8.
Kaposi sarcoma (KS) is an endothelial malignancy caused by human herpes virus-8 (HHV-8) infection. The epidemic and iatrogenic forms of childhood KS result from a profound and acquired T cell deficiency. Recent studies have shown that classic KS of childhood can result from rare single-gene inborn errors of immunity, with mutations in WAS, IFNGR1, STIM1, and TNFRSF4. The pathogenesis of the endemic form of childhood KS has remained elusive. We review childhood KS pathogenesis and its relationship to inherited and acquired immunodeficiency to oncogenic HHV-8.


[Suffering and death from a philosopher's perspective].
Death is a paradox. Without death we would not be. Heraclitus already knew that we exist because all that lives, ''lives of death and dies of life''. Without death the great chain of being would not exist. The Greeks called humans mortals, but Hegel taught us that to suffer means to undergo a gradual development. Pain is fight and competition, and every individual has his own threshold for pain.


Metabolic interaction between cyclosporine and sirolimus.
When the immunosuppressants cyclosporine (CsA) and sirolimus (SRL) are co-administered to transplant patients, lower doses are used than when either drug is given alone. Since both drugs share similar transport and metabolic pathways, there is the potential for an interaction leading to unpredictable effects. Furthermore, both drugs affect the activity of cytochrome P450 3A1/2 (CYP3A1/2), the rat parallel to human CYP3A4, and the multidrug transporter P-glycoprotein (Pgp). To clarify the role of metabolic enzymes and membrane transporters involved in the disposition of both drugs, we examined hepatic CYP3A1/2, Pgp, and multidrug resistance gene (mdr) mRNA during chronic therapy with CsA and SRL in salt-depleted rats. Specifically, rats were given intravenous doses of CsA 2.5 mg/kg and SRL 1 mg/kg, alone or in combination, for two weeks via constant rate intravenous infusion. CsA treatment inhibited hepatic CYP3A1/2 protein expression, catalytic activity, and mRNA levels. SRL dosing suppressed CYP3A1/2 protein expression and catalytic activity, without affecting mRNA. With combined dosing, however, there was a much greater reduction. Hepatic Pgp protein levels were elevated after treatment with either drug alone, as well as with combined dosing. Compared to controls, there were significant increases in mdr1a and mdr1b mRNA levels in all treatment groups, with the combined drugs causing the greatest increase. Both CYP3A1/2 and Pgp participate in the disposition of CsA and SRL in rats. Changes in the individual activities of CYP3A1/2 and Pgp may contribute to an interaction between CsA and SRL resulting in unanticipated effects during chronic therapy.


From combinatorial chemistry to chemical microarray.
Combinatorial chemistry was first applied to the generation of peptide arrays in 1984. Since then, the field of combinatorial chemistry has evolved rapidly into a new discipline. There is a great need for the development of methods to examine the proteome functionally at a global level. Using many of the techniques and instruments developed for DNA microarrays, chemical microarray methods have advanced significantly in the past three years. High-density chemical microarrays can now be synthesized in situ on glass slides or be printed through covalent linkage or non-specific adsorption to the surface of the solid-support with fully automatic arrayers. Microfabrication methods enable one to generate arrays of microsensors at the end of optical fibers or arrays of microwells on a flat surface. In conjunction with the one-bead one-compound combinatorial library method, chemical microarrays have proven to be very useful in lead identification and optimization. High-throughput protein expression systems, robust high-density protein, peptide and small-molecule microarray systems, and automatic mass spectrometers are critical tools for the field of functional proteomics.


No Evidence to Favor 99mTc-HMPAO or 99mTc-ECD for Ictal Brain Perfusion SPECT for Identification of the Seizure Onset Zone.
Ictal brain perfusion SPECT with the tracer 99mTc-HMPAO or 99mTc-ECD is widely used for identification of the epileptic seizure onset zone (SOZ) in presurgical evaluation if standard pointers are uncertain or inconsistent. For both tracers, there are theoretical arguments to favor it over the other for this task. The aim of this study was to compare the performance of ictal brain perfusion SPECT between 99mTc-HMPAO and 99mTc-ECD in a rather large patient sample. The study retrospectively included 196 patients from clinical routine in whom ictal perfusion SPECT had been performed with stabilized 99mTc-HMPAO (n = 110) or 99mTc-ECD (n = 86). Lateralization and localization of the SOZ were obtained by the consensus of 2 independent readers based on visual inspection of the SPECT images. The 99mTc-HMPAO group and the 99mTc-ECD group were well matched with respect to age, sex, age at first seizure, duration of disease, seizure frequency, history of previous brain surgery, and findings of presurgical MRI. The proportion of lateralizing ictal SPECT did not differ significantly between 99mTc-HMPAO and 99mTc-ECD (65.5% vs 72.1%, P = 0.36). Sensitivity of ictal perfusion SPECT (independent of the tracer) for correct localization of the SOZ in 62 patients with temporal lobe epilepsy and at least worthwhile improvement (Engel scale ≤ III) 12 months after temporal epilepsy surgery was 63%. This study does not provide evidence to favor 99mTc-HMPAO or 99mTc-ECD for identification of the SOZ by ictal perfusion SPECT.


Anomalous origin of right coronary artery from pulmonary artery and severe mitral regurgitation due to myxomatous mitral valve disease: a case report and literature review.
Anomalous origin of the right coronary artery from the pulmonary artery (ARCAPA) is an uncommon congenital coronary artery anomaly. In contrast to anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA), most of the patients with ARCAPA remain asymptomatic. However, few cases of angina, heart failure and sudden cardiac death depicting the malignant nature of the disease are described in the literature. We report an unusual case of ARCAPA with severe mitral valve regurgitation and pulmonary hypertension. Echocardiography and angiography were utilized for the diagnosis. Surgical correction was provided to our patient and should be considered for all patients with this potentially fatal disease.


Exploration of fluorescence behavior of an imidazolium-based chemosensor in solution and in the solid state and its turn-on response to Al3+ in pure aqueous medium.
An imidazolium-based quinoline Schiff base ImSB was developed and fully characterized by FT-IR, 1H and 13C NMR spectroscopy, mass spectrometry, and X-ray crystallography. The fluorescence behaviour of ImSB in solution and in the solid state, keto-enol stability at different concentrations and pH in aqueous medium were investigated. The UV-visible and fluorescence studies were performed to determine the response of ImSB towards different ions in aqueous medium. ImSB showed a turn-on fluorescence behaviour with high selectivity towards Al3+ over various cations and anions due to chelation-enhanced fluorescence (CHEF), inhibition of photoinduced electron transfer (PET) and restriction of C[double bond, length as m-dash]N isomerization. The low detection limit for Al3+ was 54 nM and Job's plot confirmed 1 : 1 stoichiometry between ImSB and Al3+ with a high binding constant value of 4.16 × 106 M-1. Monitoring of Al3+ was also demonstrated in real water samples (mineral, river and tap water). The structural and electronic parameters of ImSB and ImSB-Al3+ were also studied theoretically.


Silver(I) N-heterocyclic carbene-bridged calix[4]arene analogues as efficient [60]fullerene receptors.
Two silver(I) N-heterocyclic carbene-bridged calix[4]arene analogues 4 and 5 were synthesized by a fragment-coupling approach; the preliminary inclusion properties of 5 with [60]fullerene shows that it is a novel efficient [60]fullerene fluorescent sensor.


Phytoestrogenic isoflavonoids in epidemiologic and clinical research.
Isoflavones (IFLs) are natural products to which humans have been traditionally exposed predominantly through soy foods; more recently humans are also exposed to them through soy protein addition to processed foods or through supplements. They are structurally similar to steroidal estrogens and can exert estrogenic or antiestrogenic effects depending on their concentrations and on the tissue considered. These properties qualify IFLs to be classified as phytoestrogens and are believed to account for many of the biological effects observed for soy and/or IFL exposure including benefits for bone and heart health or prevention of menopausal symptoms and certain types of cancer. In order to evaluate the function of IFLs, alone or when exposure happens through soy intake, pharmacokinetics and bioavailability are critical issues to be considered in epidemiologic and clinical research. For this purpose precise, accurate, robust, fast, and affordable techniques for IFL analyses are required.


Estradiol modulation of neurotrophin receptor expression in female mouse basal forebrain cholinergic neurons in vivo.
The neuroprotective effect of estradiol (E2) on basal forebrain cholinergic neurons (BFCNs) has been suggested to occur as a result of E2 modulation of the neurotrophin system on these neurons. The present study provides a comprehensive examination of the relationship between E2 and neurotrophin signaling on BFCNs by investigating the effect of E2 deficiency on the expression levels of neurotrophin receptors (NRs), TrkA, TrkB, and p75 on BFCNs. The number of TrkA receptor-expressing choline acetyltransferase-positive neurons was significantly reduced in the medial septum (MS) in the absence of E2. A significant reduction in TrkB-expressing choline acetyltransferase-positive cells was also observed in ovariectomized mice in the MS and nucleus basalis magnocellularis (NBM). p75 receptor expression was reduced in the NBM and striatum but not in the MS. We also showed that estrogen receptor (ER)-α was expressed by a small percentage of TrkA- and TrkB-positive neurons in the MS (12%) and NBM (19%) and by a high percentage of TrkB-positive neurons in the striatum (69%). Similarly, ERα was expressed at low levels by p75 neurons in the MS (6%) and NBM (9%) but was not expressed on striatal neurons. Finally, ERα knockout using neuron-specific estrogen receptor-α knockout transgenic mice abolished all E2-mediated changes in the NR expression on BFCNs. These results indicate that E2 differentially regulates NR expression on BFCNs, with effects depending on the NR type and neuroanatomical location, and also provide some evidence that alterations in the NR expression are, at least in part, mediated via ERα.


Salsalate ameliorates metabolic disturbances by reducing inflammation in spontaneously hypertensive rats expressing human C-reactive protein and by activating brown adipose tissue in nontransgenic controls.
Chronic low-grade inflammation plays an important role in the pathogenesis of insulin resistance. In the current study, we tested the effects of salsalate, a non-steroidal anti-inflammatory drug, in an animal model of inflammation and metabolic syndrome using spontaneously hypertensive rats (SHR) that transgenically express human C-reactive protein (SHR-CRP rats). We treated 15-month-old male transgenic SHR-CRP rats and nontransgenic SHR with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP and SHR rats were fed a standard diet without salsalate. In the SHR-CRP transgenic strain, salsalate treatment decreased circulating concentrations of the inflammatory markers TNF-α and MCP-1, reduced oxidative stress in the liver and kidney, increased sensitivity of skeletal muscles to insulin action and improved tolerance to glucose. In SHR controls with no CRP-induced inflammation, salsalate treatment reduced body weight, decreased concentrations of serum free fatty acids and total and HDL cholesterol and increased palmitate oxidation and incorporation in brown adipose tissue. Salsalate regulated inflammation by affecting the expression of genes from MAPK signalling and NOD-like receptor signalling pathways and lipid metabolism by affecting hepatic expression of genes that favour lipid oxidation from PPAR-α signalling pathways. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.


Selective extra levator versus conventional abdomino perineal resection: experience from a tertiary-care center.
To compare extra levator abdomino perineal resection (ELAPER) with conventional abdominoperineal resection (APER) in terms of short-term oncological and clinical outcomes. This is a retrospective review of a prospectively maintained database including all the patients of rectal cancer who underwent APER at Tata Memorial Center between July 1, 2013, and January 31, 2015. Short-term oncological parameters evaluated included circumferential resection margin involvement (CRM), tumor site perforation, and number of nodes harvested. Peri operative outcomes included blood loss, length of hospital stay, postoperative perineal wound complications, and 30-day mortality. The χ(2)-test was used to compare the results between the two groups. Forty-two cases of ELAPER and 78 cases of conventional APER were included in the study. Levator involvement was significantly higher in the ELAPER compared with the conventional group; otherwise, the two groups were comparable in all the aspects. CRM involvement was seen in seven patients (8.9%) in the conventional group compared with three patients (7.14%) in the ELAPER group. Median hospital stay was significantly longer with ELAPER. The univariate analysis of the factors influencing CRM positivity did not show any significance. ELAPER should be the preferred approach for low rectal tumors with involvement of levators. For those cases in which levators are not involved, as shown in preoperative magnetic resonance imaging (MRI), the current evidence is insufficient to recommend ELAPER over conventional APER. This stresses the importance of preoperative MRI in determining the best approach for an individual patient.


Oxoisoaporphine alkaloid derivative 8-1 reduces Aβ1-42 secretion and toxicity in human cell and Caenorhabditis elegans models of Alzheimer's disease.
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease and a growing health problem worldwide. Because the drugs currently used to treat AD have certain drawbacks such as single targeting, there is a need to develop novel multi-target compounds, among which oxoisoaporphine alkaloid derivatives are promising candidates. In this study, the possible anti-AD activities of 14 novel oxoisoaporphine alkaloid derivatives that we synthesized were screened and evaluated. We found that, in the 14 novel derivatives, compound 8-1 significantly reduced Aβ1-42 secretion in SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw). Next, we found that compound 8-1 could down-regulate the expression level of β-amyloid precursor protein (APP) in APPsw cells. Moreover, compound 8-1 significantly delayed paralysis in the Aβ1-42-transgenic Caenorhabditis elegans strain GMC101, which could be explained by the fact that compound 8-1 down-regulated acetylcholinesterase activity, protected against H2O2-induced acute oxidative stress and paraquat-induced chronic oxidative stress, and enhanced autophagy activity. Taken together, our data suggest that compound 8-1 could attenuate the onset and development of AD.


[Diagnostic criteria and differential diagnosis of neuromyelitis optica].
Neuromyelitis optica (NMO) is an autoimmune central nervous system disease associated with anti-aquaporin 4 (AQP4) antibody. Although the current diagnostic criteria requires both optic neuritis and myelitis, many of the patients with anti-AQP4 antibody do not fulfil the criteria, so that they have a chance to be misdiagnosed as having multiple sclerosis (MS). To avoid the misdiagnosis, a sensitive method to detect anti-AQP4 antibody is required although widely used kits has lower sensitivity. Although MS is one of the most important differential diagnosis of NMO, diseases associated with anti-myelin oligodendrocyte glycoprotein antibody may mimic NMO clinical features and should be considered as differential diagnosis.


Diurnal Tracking of Blink and Relationship to Signs and Symptoms of Dry Eye.
To assess diurnal changes in the signs and symptoms of dry eyes and their relationship to diurnal interblink interval (IBI) in normal subjects and in subjects with dry eye. Blink data were collected from 9:00 AM to 8:00 PM during 2 days of normal activity using an electrocardiogram monitoring device. All subjects recorded ocular discomfort (0-5 scale) and primary activity hourly each day in a diary. Inferior and central fluorescein staining was graded by slit lamp (0-4) at the start and end of each day. Blink activity was detected using an algorithm based on recognition of the waveform corresponding to the kinematic properties of the blink signal. Normal subjects (N = 12) reported negligible symptoms, and results did not show a diurnal change in group hourly IBI. Mean daily IBI for the group with dry eye (N = 15) (4.63 ± 1.63 s) was shorter than that for the normal group (5.28 ± 1.48 s) (P = 0.0483). Correlation of diurnal symptoms and mean hourly IBI was relatively weak (r = -0.248). A repeated-measures model found IBI to be significantly associated with the time of day (P = 0.0028). Inferior corneal staining showed a small but significant diurnal increase for both normal group and group with dry eyes. Diurnal blink tracking reveals significant trending with symptoms. Diurnal change in IBI may be an appropriate surrogate for symptoms in the study of dry eye.


Development of a Hemagglutination Inhibition Assay for Duck Tembusu Virus.
The HB strain of duck Tembusu virus (DTMUV) propagated in the brains of newborn mice was used to prepare antigens for use in the hemagglutination inhibition (HI) test. Results showed that such prepared antigens are highly specific to the serum samples derived from DTMUV-infected animals. No spurious hemagglutination reactions against serum samples specific to avian influenza virus H5, H7, H9 subtypes, Newcastle disease virus, egg drop syndrome virus, duck plague virus, and duck hepatitis A virus were observed. The HI test can detect specific antibodies in the serum samples as early as day 4 after experimental infection of ducks with DTMUV. When compared to a virus neutralization test, the sensitivity is 100%. Overall, the HI test developed is highly specific to DTMUV and can be used in clinical diagnosis of diseases and in vaccine studies to monitor the kinetics of antibody response.


ERK1/2 pathway regulates coxsackie and adenovirus receptor expression in mouse cardiac stem cells.
Cardiac stem cells (CSCs) are the most promising and effective candidates for the therapy of cardiac regenerative diseases; however, they have marked limitations. For instance, the implantation of CSCs is hampered by factors such as their sustainability and long-term durability. Gene modification appears to be the most effective method of optimizing CSCs and gene therapy trials have demonstrated that efficient gene transfer is key to achieving therapeutic efficacy. However, the transduction ability of adenovirus (Ad) is limited. Previous studies have reported that low expression of coxsackie and adenovirus receptor (CAR) in target cells decreases the transduction efficiency. A promising method for improving Ad-mediated gene transfer is to increase CAR expression in target cells. The present study investigated the effect of the Raf-mitogen-associated protein kinase (MAPK) kinase (MEK)-extracellular signal-associated protein kinase (ERK) signaling pathway on the expression of CAR on CSCs, as this pathway decreases cell-cell adhesion via cell surface molecules. The results demonstrated that interference with the Raf-MEK-ERK signaling pathway by knockdown of ERK1/2 upregulated the expression of CAR. The entry of the Ad into the cells was increased following inhibition of ERK1/2. Moreover, following knockdown of CAR, the entry of Ad into cells was decreased. However, knockdown of c-Jun N-terminal kinase and p38 as other components of the MAPK pathway did not affect CAR expression. Therefore, CAR expression in CSCs may be mediated via the Raf-MEK-ERK signaling pathway. Upregulation of CAR by knockdown of ERK1/2 may significantly improve Ad-mediated genetic modification of CSCs in the treatment of cardiovascular diseases.


Electrical responses of pineal cells to pineal indoles and putative transmitters in intact and blinded pigeons.
The effects of micro-electrophoretically applied pineal indoles, melatonin (MEL), 5-methoxytryptophol (MTL) and 5-hydroxytryptophol (HTL) and of the neurotransmitters, noradrenaline (NOR), acetylcholine (ACH) and gamma-aminobutyric acid (GABA) on the electrical activity of pineal cells were studied in anaesthetized pigeons. Recordings were made from both sighted and blinded birds during both the day- and night-time. Both excitatory and inhibitory responses to the application of all substances tested were observed, while in all cases unresponsive cells were also found. The pattern of responses to MEL, MTL and to NOR varied significantly depending on whether the cells in the sighted pigeons were tested during the day or at night. This day/night rhythm of responses to MEL and to MTL also occurred in the blinded pigeons, although this was not the case for the effects of NOR. Units which were orthodromically excited by electrical stimulation of the habenular complex were also excited by application of GABA. The activity of these units was also likely to be enhanced by application of ACH. The results suggest that the pigeon pineal organ exhibits intrinsic circadian rhythmicity which does not require entrainment signals from the retina. They also indicate that the activity of pineal cells could be influenced by neurotransmitter input provided from within the gland or via its innervation.


The Incidence of Venous Thromboembolism Following Pelvic and Lower Extremity Trauma Despite Adherence to Modern Prophylactic Protocols.
Describe the incidence of venous thromboembolism (VTE) in patients with pelvic and lower extremity long bone trauma in the setting of modern prophylaxis. Retrospective health-system database study. Multi-center health care system. Database query from 2010 to 2017 identified 11,313 adult trauma patients who received open reduction internal fixation of pelvic, acetabular, femoral neck, or intertrochanteric fractures, or received intramedullary nailing (IMN) of the femoral or tibial shaft. Patients with incomplete prophylaxis, prior history of VTE, coagulopathy, or concomitant lower extremity fracture were excluded. Mechanical and chemical VTE prophylaxis following pelvic or lower extremity fracture fixation. VTE rates. The overall VTE rate was 0.82% [0.39% deep venous thromboses (DVT); 0.43% pulmonary emboli (PE)]. By procedure, pelvic open reduction and internal fixation (ORIF) and femoral IMN had the highest VTE rates 1.70% (0.98% DVT; 0.78% PE) and 1.33% (0.75% DVT; 0.58% PE), whereas tibial IMN had the lowest incidence of VTE 0.34% (0.17% DVT; 0.17% PE). Among hip fractures, femoral neck ORIF had a VTE rate of 0.98% (0.59% DVT; 0.39% PE), whereas intertrochanteric ORIF had lower rates of 0.59% (0.20% DVT; 0.39% PE). Despite adherence to modern VTEp protocols, nonpreventable VTE occur in 0.82% of pelvic and lower extremity orthopaedic trauma patients. Incidence ranged between 0.34% and 1.70% depending on injury/fixation method with the highest rate observed in pelvis ORIF followed by femoral IMN. In the era of pay for quality performance, it is important for health systems and auditing agencies to reconcile the difference between preventable and nonpreventable VTEs. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Inversion Reveals Perceptual Asymmetries in the Configural Processing of Human Body.
Ambiguous human bodies performing unimanual/unipedal actions are perceived more frequently as right-handed/footed rather than left-handed/footed, which suggests a perceptual and attentional bias toward the right side of others' body. A bias toward the right arm of human bodies could be adaptive in social life, most social interactions occurring with right-handed individuals, and the implicit knowledge that the dominant hand of humans is usually placed on their right side might also be included in body configural information. Given that inversion disrupts configural processing for human bodies, we investigated whether inversion reduces the bias toward the right side of human bodies. Consistent with our hypothesis, when presented with ambiguous stimuli depicting humans performing lateralized actions or movements, participants perceived a greater proportion of right-handed figures when the stimuli were shown upright than when the stimuli were shown inverted. The present findings seem to confirm our hypothesis that body configural information may include some form of knowledge about the probable handedness of other individuals, although alternative accounts involving the role of experience cannot be ruled out.


Papules in the auricular concha: lichen amyloidosus in a case of biphasic amyloidosis.
We present a patient with lichen amyloidosus on the ears and macular amyloidosis on the back. These diagnoses were supported by histological, histochemical and immunohistochemical studies. This is to the best of our knowledge the first reported case of a biphasic form of amyloidosis whose lichenoid counterpart consists of papules on the ears. This suggests that primary cutaneous localized amyloidosis may have peculiar clinical manifestations depending on the location of the lesion.


High prevalence of alcohol use disorders in patients with inflammatory skin diseases.
There is a known association between psoriasis and heavy alcohol consumption. The association between heavy alcohol consumption and other inflammatory skin diseases remains to be defined. To examine the prevalence of heavy drinking using the Alcohol Use Disorders Identification Test (AUDIT) in patients with inflammatory skin disease. We conducted an observational cross-sectional study in a single hospital outpatient department. We recruited 609 patients with either psoriasis, eczema, cutaneous lupus or other inflammatory disorders, and a reference population with skin lesions. Primary outcome was the proportion of patients in each group with an alcohol use disorder (AUD). The observed prevalence of AUD was 30·6% in patients with psoriasis, 33·3% in those with eczema, 12·3% in those with cutaneous lupus, 21·8% in those with other inflammatory disease and 14·3% in those with non-inflammatory disease. Odds ratios (OR) for AUD in patients in the inflammatory groups compared with those in the noninflammatory groups, adjusted for age and sex, were as follows: psoriasis 1·65 [95% confidence interval (CI) 0·86-3·17], eczema 2·00 (95% CI 1·03-3·85), lupus 1·03 (95% CI 0·39-2·71), other inflammatory disease 1·32 (95% CI 0·68-2·56). ORs were reduced if also adjusted for Dermatology Life Quality Index (DLQI). The prevalence of DLQI ≥ 11 was 31·1% for psoriasis, 43·7% for eczema, 17·5% for cutaneous lupus, 17·2% for other inflammatory disease and 2·8% for noninflammatory disease. Patients with eczema attending a hospital clinic have been shown to have high levels of AUD of a similar level to patients with psoriasis and higher than patients with noninflammatory skin diseases.


Pemphigus vulgaris and pregnancy.
The management and counseling of patients with pemphigus vulgaris during pregnancy is a challenge. The frequency of the association is very low and the current knowledge is based only on case reports or small series. The authors report 2 cases ofpemphigus vulgaris and pregnancy that differed from each other in the time of occurrence and clinical course but had similar favorable outcomes. Based on a literature review and their personal observations, the authors discuss the characteristics of this association, the therapeutic behavior, patients' followup, and fetal prognosis.


[Clinical significance of different assesment methods of myocardial fibrosis in patients with hypertrophic cardiomyopathy.]
Objective To evaluate prospects for clinical use of circulating biomarkers for characterizing fibrotic changes in the myocardium of patients with hypertrophic cardiomyopathy (HCMP) with left ventricular (LV) outflow tract obstruction.Materials and Methods This was a prospective study with a 12-month follow-up period. The study included 47 patients (29 females and 18 males) with obstructive HCMP who were selected for septal reduction. Echocardiography (EchoCG), cardiac magnetic resonance imaging (MRI) and measurements of serum C-reactive protein, N-terminal pro-brain natriuretic peptide, and relevant circulating markers of fibrosis (TGF-β1, MMP-2,-9, TIMP-1, galectin-3, sST2, CITP, PICP, and PIIINP) were performed for all patients. All patients were evaluated at baseline and at 7 days, 6 and 12 months following surgical treatment. Morphometrical analysis of intraoperative biopsy samples was performed for evaluation of the degree of fibrotic changes. Patients received beta-blockers (95.7%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (34%), loop diuretics (68.1%), aldosterone antagonists (34%), and statins (66%).Results Women with HCMP were older and more frequently had additional risk factors (arterial hypertension). Men had a higher risk of sudden cardiac death. Histological study of intraoperative myocardial biopsy samples showed that the area of fibrotic changes was 13.9±6.9%. According to cardiac MRI mean area of delayed contrast enhancement was 8.7±3.3% of LV myocardial mass. No association was established between traditional cardiovascular risk factors and severity of myocardial fibrotic changes or levels of circulating fibrosis markers. Perhaps that was due to the modifying effect of the drug therapy received by HCMP patients. According to EchoCG maximum pressure gradient in the LV outflow tract before the surgical treatment was 88 (55; 192) mm Hg, and interventricular septal thickness was 22 (16; 32) mm. A considerable decrease (p=0.0002) in the LV outflow tract gradient was observed after myectomy in all patients. At the same time, the left ventricular dimension, which tended to decrease in the early postoperative period, returned to baseline values by the 6th month of follow-up.Conclusion The study confirmed the increase in relevant circulating markers of fibrosis in patients with obstructive HCMP. At the same time, no correlation was observed between levels of circulating biomarkers and severity of fibrosis according to data of histology and cardiac MRI, which was probably due to the modifying effect of drug therapy and limited sampling.


Efficient transfection of Xenobiotic Responsive Element-biosensor plasmid using diether lipid and phosphatidylcholine liposomes in differentiated HepaRG cells.
In this study, we evaluated cationic liposomes prepared from diether-NH2 and egg phosphatidylcholine (EPC) for in vitro gene delivery. The impact of the lipid composition, i.e. the EPC and Diether-NH2 molar ratio, on in vitro transfection efficiency and cytotoxicity was investigated using the human HEK293T and hepatoma HepaRG cells known to be permissive and poorly permissive cells for liposome-mediated gene transfer, respectively. Here, we report that EPC/Diether-NH2-based liposomes enabled a very efficient transfection with low cytotoxicity compared to commercial transfection reagents in both HEK293T and proliferating progenitor HepaRG cells. Taking advantage of these non-toxic EPC/Diether-NH2-based liposomes, we developed a method to efficiently transfect differentiated hepatocyte-like HepaRG cells and a biosensor plasmid containing a Xenobiotic Responsive Element and a minimal promoter driving the transcription of the luciferase reporter gene. We demonstrated that the luciferase activity was induced by a canonical inducer of cytochrome P450 genes, the benzo[a]pyrene, and two environmental contaminants, the fluoranthene, a polycyclic aromatic hydrocarbon, and the endosulfan, an organochlorine insecticide, known to induce toxicity and genotoxicity in differentiated HepaRG cells. In conclusion, we established a new efficient lipofection-mediated gene transfer in hepatocyte-like HepaRG cells opening new perspectives in drug evaluation relying on xenobiotic inducible biosensor plasmids.


Characterization of the B Cell Receptor Repertoire in the Intestinal Mucosa and of Tumor-Infiltrating Lymphocytes in Colorectal Adenoma and Carcinoma.
The B cells inhabited in mucosa play a vital role in mediating homeostasis with autoantigens and external Ags. Tumor-infiltrating lymphocytes are potential prognostic markers and therapeutic agents for cancer. However, the spatial heterogeneity of the B cell repertoire in intestinal mucosa and the tumor-infiltrating lymphocytes in colorectal cancer (CRC) remain poorly understood. In this study, we developed an unbiased method to amplify the IgH repertoire, as well as a bioinformatic pipeline to process these high-throughput sequencing data. With biopsies from seven intestinal mucosal segments, we uncovered their strong spatial homogeneity among the large intestine, where the clone overlap rate was up to 62.21%. The heterogeneity between terminal ileum and large intestine was also observed, including discrepant isotype distribution and low clone overlap rate. With tumor and adjacent normal mucosal tissues from CRC and colorectal advanced adenoma (AD) patients, we observed a similar IgH profile between tumor and adjacent normal mucosal tissues in AD, as well as a slight difference in CRC. Interestingly, we found distinct repertoire properties in the CRC tumor from AD and normal mucosa. Finally, we identified 1445 public clones for the normal mucosa, and 22 public clones for the CRC tumor with characteristic features. These data may be of potential use in clinical prognosis, diagnosis, and treatment of CRC.


The influence of the operating surgeon's specialisation on patient survival in ovarian carcinoma.
A retrospective analysis of ovarian cancer patients registered with the West Midlands Cancer Registry from 1 January 1985 to 31 December 1987 was undertaken to examine the variables associated with survival patterns, with particular reference to the specialty of the surgeon. A total of 1,654 patients were registered, of whom 1,184 had histologically confirmed ovarian cancer, with the operator identified. This consisted of 870 patients operated on by gynaecologists and 314 operated on by general surgeons. A significantly older population and a greater number of patients with stage III/IV disease were operated on by general surgeons. The median survival of patients under the general surgeons' care was 9.87 months, significantly lower (P < 0.0001) than the survival of the gynaecologists' patients (median survival = 29.1 months). Univariate and multivariate analysis correlated poor prognosis with advanced stage disease, older age, the presence of bulky residual tumour and a general surgeon as the operator. Stepwise Cox's proportional hazard analysis confirmed the general surgeon as an independent adverse prognostic factor with a relative hazard ratio of 1.34 (95% confidence interval = 1.05-1.71). Accepting the limitations of retrospective reviews, these findings suggest that every attempt be made to ensure that a gynaecologist is involved in the treatment of patients with ovarian pathology.


Combined cervical and vaginal reconstruction with prefabricated pudendal thigh flap in a case with cervical and vaginal agenesis (MURCS syndrome): a new and original technique.
In the presence of functional endometrium, in addition to the construction of anatomically, functionally normal and sensitive neovagina and cervix, the preservation of the uterus for future possible pregnancies must also be considered as the main goal in this process. So far, hysterectomy was the general treatment modality in such cases. For maintaining cervical patency, there were no reports in the literature related to cervical prefabrication using flaps. In this report we present a case with cervical and vaginal agenesis (MURCS syndrome). In this case combined cervical and vaginal reconstructions were successfully performed by using bilateral pudendal thigh flaps; a real-like cervix and cervical canal had been previously prefabricated on the distal part of one of the pudendal thigh flaps. Sensitivity and function were both preserved and maintained at the end of this operation.


Renal thromboxane synthesis in excised kidney distal to renovascular lesions.
Excision of a kidney with three distinct zones of perfusion was required in a patient with renovascular hypertension. One third of the kidney was normal, one third was ischemic from a stenotic artery, and one third was severely ischemic from a completely occluded artery. This provided a unique opportunity to study renal prostaglandin production in hypoperfused and control tissue by radioimmunoassays of incubated tissue slices. The thromboxane-prostacyclin synthesis ratio for the outer cortex increased from 2.2 in control tissue to 5.8 in moderately ischemic tissue and 11.3 in severely ischemic tissue; for the inner cortex, 2.1 to 6.3 and 8.8; and for the medulla, 0.4 to 1.2 and 3.0, respectively . Similar ratios were noted for thromboxane-prostaglandin E2. This correlates, for the first time in man, absolute and relative increases in renal thromboxane synthesis with renovascular hypertension.


Properties and malignant transformation of established rat liver parenchymal cells in culture.
Epithelioid cells from the livers of normal and genetically impaired (Gunn) rats were established in long-term cultures in vitro. These cells grew as flat, epithelioid cobble-stone-type monolayers and showed a diploid karyotype. They secreted rat serum albumin and proteins into their growth media and contained aryl hydrocarbon hydroxylase. Such cells were transformed by treatment with methylazoxymethanol acetate; they then exhibited an irregular, piling growth pattern, acquired the ability to grow in soft agar, and thereafter grew as tumors in hamsters given cortisone and in nude mice. These malignant spindle-cell tumors were reestablished in culture and still secreted serum albumin. The transformed cells became highly multinucleate when exposed to cytochalasin B and thus behaved like tumor cells. This behavior was not shown by the original cells. Cells transformed by benzo[a]pyrene failed to grow in soft agar culture or as tumor in animals. Cells were not affected by diethylnitrosamine.


Loss of function of Trp53, but not Apc, leads to the development of esophageal adenocarcinoma in mice with jejunoesophageal reflux.
APC and TP53 are tumor suppressor genes known to be altered frequently in human esophageal adenocarcinoma (EAC), which arises as a complication of reflux disease. To determine the functional role of these genes in the development of EAC, we have created reflux in mice gene-targeted for either Trp53 or Apc. Wild-type (WT), p53-knockout (Trp53-/-), or Apc-mutated (ApcMin/+) mice were generated in our breeding colony. Total gastrectomy with esophagojejunostomy was performed at 6 weeks of age, creating jejunoesophageal reflux. Unoperated control mice were maintained under identical conditions. Mice were sacrificed at 30 weeks of age. Histology of the esophagus and jejunal anastamosis or gastroesophageal junction was reviewed by a single pathologist blinded to the genotype of the animal. The esophagus was normal in all of the unoperated mice (6 ApcMin/+, 6 WT, and 6 Trp53-/-). All operated mice (6 ApcMin/+, 12 WT, and 4 Trp53-/-) had esophagitis, with squamous hyperplasia and early focal ulceration. Barrett's metaplasia was identified in 33% of the operated ApcMin/+ (2/6) and 25% of the Trp53-/- (1/4) mice, but not in the WT mice. Of 4 operated Trp53-/- mice, all developed severe dysplasia of the squamous epithelium and 2 (50%) had EAC on histology, although no gross tumors were seen. No severe dysplasia or carcinoma was identified in any of the ApcMin/+ or WT mice. Loss of either Trp53 or Apc leads to the development of columnar metaplasia, whereas loss of Trp53, but not Apc, leads to development of cancer in mice with jejunoesophageal reflux.


Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation.
Th cell access to primary B cell follicles is dependent on CXCR5. However, whether CXCR5 induction on T cells is sufficient in determining their follicular positioning has been unclear. In this study, we find that transgenic CXCR5 overexpression is not sufficient to promote follicular entry of naive T cells unless the counterbalancing influence of CCR7 ligands is removed. In contrast, the positioning of Ag-engaged T cells at the B/T boundary could occur in the absence of CXCR5. The germinal center (GC) response was 2-fold reduced when T cells lacked CXCR5, although these T cells were able to access the GC. Finally, CXCR5(high)CCR7(low) T cells were found to have elevated IL-4 transcript and programmed cell death gene-1 (PD-1) expression, and PD-1(high) cells were reduced in the absence of T cell CXCR5 or in mice compromised in GC formation. Overall, these findings provide further understanding of how the changes in CXCR5 and CCR7 expression regulate Th cell positioning during Ab responses, and they suggest that development and/or maintenance of a PD-1(high) follicular Th cell subset is dependent on appropriate interaction with GC B cells.


Secular change in menarche in women in Madrid.
The age at menarche was estimated by recollection in 1617 women between the ages of 18 and 60 in Madrid and a nearby suburb, Pinto. The population of Pinto is working-class and the Madrid group, taken from residential neighbourhoods , belongs to the upper middle class. In both groups we found a diminution in average age at menarche, from 14.04 to 13.02 years in Madrid and from 14.55 to 13.16 years from about 1935 to about 1965 in Pinto. These changes have been more intense in the group which is less well-off economically, where living conditions have varied much more drastically.


Phase-selective synthesis of lead-free CsMnBr3 and Cs3MnBr5 nanocrystals dependent on solvent concentration.
We demonstrate the crystal phase-selective synthesis for lead-free cesium manganese bromine perovskite nanocrystals synthesized by the modified hot-injection method due to changing the concentration of solvent (trioctylphosphine; TOP). The compositions synthesized were determined by the amount of TOP solvent, and the structure phase of the nanocrystals was selected from hexagonal CsMnBr3 to tetragonal Cs3MnBr5 as the amount of TOP solvent increased. The emission peaks of CsMnBr3 and Cs3MnBr5 nanocrystals were observed at 650 nm (red) and 520 nm (green), respectively. After a durability test at 85°C and 85% humidity for 24 h, the lead-free perovskite CsMnBr3 nanocrystal powder maintained its initial emission intensity, and the metal halide Cs3MnBr5 nanocrystal powder exhibited an increase in red emission due to the post-synthesis of CsMnBr3 nanocrystals.


Role of the red blood cell in drug metabolism.
Contrary to the belief that the RBC is not metabolically active towards pharmacologically active endogenous and exogenous substances, it is evident that the RBC contains moderate cytochrome P-450-like activity, in addition to the ability to catalyse various other transformations of a range of drugs. The list of drugs for which there is evidence of metabolism by RBC (Table 1) contains examples from several drug classes. However some major classes of drugs which are principally cleared in vivo by metabolism are missing (for example, benzodiazepines). Moreover, there is as yet no evidence for the RBC having the capacity for the more important drug conjugation reactions (glucuronidation, sulphation) although there is evidence of other conjugation reactions (methylation, acetylation, glutathione conjugation). It is conceivable that the RBC could be used as a convenient tissue to add to other metabolism screening procedures used in drug development. Already use has been made of the RBC in identifying fast and slow acetylators. Others have used RBC to identify a possible sex-based difference in drug metabolism. Hopefully, this review has stimulated interest in the ability of the RBC to metabolize drugs and this interest will result in further discoveries.


[Clinical and laboratory tests characteristics in children with nephrolithiasis: case control study].
To evaluate the clinical and laboratory findings in pediatric patients with urolithiasis in a case control study and to obtain variables predicting a low risk of having urolithiasis. Retrospective analysis of 24 cases of children with urolithiasis (age range 3 to 17 years old) admitted to the pediatric emergency room or the hospital ward. Clinical and laboratory information was obtained from the clinical charts and compared with a control group of 29 patients with history of abdominal pain admitted to the hospital. Binary logistic regression and recursive partitioning analysis were used to obtain variables predicting a low risk of having urolithiasis. There was no difference in age, gender, dysuria or nausea (p > 0. 2) between groups. A difference regarding the presence of fever (p = 0.007), haematuria (p = 0.001), costovertebral angle tenderness (p = 0.004), family history (p = 0.007) and abdominal pain lasting more than 48 hs (p = 0.04) was detected. After logistic regression and using recursive partitioning, the presence or history of fever, absence of gross haematuria and no family history of urolithiasis showed a 100% negative predictive value and sensitivity (95% CI 84.7 to 100 and 89.2 to 100 respectively). Children with abdominal pain present a low risk of having urolithiasis if there is a history or presence of fever, absence of gross haematuria and a negative family history of urolithiasis in a first degree relative.


[Measurement of ADF/thioredoxin in human serum and its clinical significance].
The adult T cell leukemia (ATL)-derived factor (ADF) was first described as an interleukin 2 receptor alpha chain (IL-2R alpha) inducing factor which is produced by an HTLV-I infected cell line. Subsequent purification and gene cloning proved that it is a human homologue of a bacterial reducing coenzyme, thioredoxin (TRX). ADF/human TRX (hTRX) has multiple functions both in the extracellular and intracellular compartments, such as cytokine activity, dithiol-reducing activity and radical scavenging activity. ADF/hTRX can facilitate the interactions between the transcriptional factors and its target DNA sequences, which may result in the overexpression of IL -2R alpha in HTLV-I infected cells. Recently, we have detected the presence of ADF/hTRX in human serum (sADF) obtained from healthy volunteers using the insulin reducing assay and Western blotting analysis. Another endogenous redox regulator, glutathione (GSH) system, has long been studied for its relation to cell proliferation and activation. Our recent data showed that thiol compounds such as L-cysteine and GSH may be involved in the activation and cell cycle progression of stimulated lymphocytes. We have also found that ADF/hTRX promotes L-cysteine transport into the cells and increases intracellular GSH content, indicating the close association between ADF/hTRX and GSH systems. Redox regulation by ADF/hTRX and GSH systems seems to play an important role in regulating cell proliferation and activation. To assess the possible alteration of the sADF level in pathological conditions, such as viral infections, an ELISA system for ADF/hTRX was recently established using two different monoclonal antibodies against rADF.(ABSTRACT TRUNCATED AT 250 WORDS)