Role of omentin-1 in susceptibility to anxiety and depression like behaviors.
Neuro-inflammation and blood-brain barrier (BBB) dysfunction are associated with depression. Evidence shows that adipokines enter the brain from the circulation, which regulates depressive behaviors. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about its role in neuro-inflammation and mood-relevant behavior. Our results showed omentin-1 knockout mice (Omentin-1-/-) increased susceptibility to anxiety and depressive-like behaviors, which are associated with abnormalities of cerebral blood flow (CBF) and impaired BBB permeability. Moreover, omentin-1 depletion significantly increased hippocampal pro-inflammatory cytokines (IL-1β, TNFα, IL-6), caused microglial activation, inhibited hippocampus neurogenesis, and resulted in autophagy impairment by dysregulating ATG genes. Omentin-1 deficiency also sensitized mice to the behavioral changes induced by lipopolysaccharide (LPS), suggesting that omentin-1 could rescue neuro-inflammation by acting as an anti-depressant. Our in vitro microglia cell culture data confirmed that recombinant omentin-1 suppresses microglial activation and pro-inflammatory cytokine expression induced by LPS. Our study suggests that omentin-1 can be used as a promising therapeutic agent for the prevention or treatment of depression by providing a barrier-promoting effect and an endogenous anti-inflammatory balance to downregulate the proinflammatory cytokines.


Analysis of unsaturated fatty acids of endoneurium and perineurium from normal and degenerating rat sciatic nerve. Morphological correlations.
The major portion of the endoneurial lipids is found in myelin. Since perineurial cells differ morphologically from endoneurial cell components, we attempted to determine whether these morphological differences also extended to a difference in fatty acid (FA) composition. Under normal circumstances, unsaturated FAs are more abundant than saturated ones (55-60% of total FAs) in endoneurium and perineurium. A characteristic biochemical difference between these two structures lies in the distribution of linoleic acid (C18:2(n-6)) which represents 20% of total FAs in perineurium and only 2% in endoneurium. Wallerian degeneration takes place after injection of pure glycerol into the endoneurium. This is followed by regeneration characterized by a proliferation of perineurial cells infiltrating the center of the nerve fascicule forming microcompartments. The changes in linoleic acid content reflect these morphological changes. A marked increase in linoleic acid is detected in the endoneurial fraction in parallel with the observed infiltration of perineurial cells into the nerve fascicule.


Analytical studies on illicit heroin. V. Efficacy of volatilization during heroin smoking.
The recovery of heroin in fumes was investigated. In the Netherlands the common mode of heroin smoking is the 'chasing the dragon' procedure: heroin is heated on an aluminium foil by a lighter and the fumes are inhaled. The efficiency of the volatilization of heroin using this procedure was studied under laboratory conditions using thin layer chromatography, gas chromatography and high pressure liquid chromatography. A considerable influence of the form (salt or base) of the heroin was found as well as strong influences of other substances that may be present in illicit heroin samples as diluents. The danger of the inhalation of fumes containing unknown pyrolysis products is mentioned and a hypothesis is given for the phenomenon of 'heroin'-leucoencephalopathy that was observed in heroin smokers in Amsterdam in 1981. The types of heroin encountered in the Netherlands are discussed with regard to their suitability for smoking.


Differential dependence of eosinophil chemotactic responses on phosphoinositide 3-kinase (PI3K).
Control of eosinophil migration to sites of inflammatory responses is a potentially therapeutic intervention in diseases such as bronchial asthma. Chemoattractants, their receptors and the associated signalling pathways may, therefore, be important targets for novel therapeutics. While several potentially important chemoattractants have been identified, the signalling pathways mediating their actions are incompletely understood. The role of phosphoinositide 3-kinase (PI3K) in responses of human eosinophils to two important eosinophil chemoattractants -- platelet-activating factor (PAF) and eotaxin (CCL11) -- was studied to determine whether this enzyme activity might be crucial for eosinophil migration. Eosinophils were isolated from atopic donor blood by immunomagnetic selection. Chemotaxis was assayed in a 96-well blind-chamber cell fluorescence assay. Respiratory burst and leukotriene C(4) secretion were also assayed. Two PI3K inhibitors, wortmannin and LY294002, caused concentration-dependent inhibition of PAF-induced eosinophil chemotaxis (IC(50) = 0.54 nM and 0.15 microM, respectively) but exhibited at least 100-fold lower potency against eotaxin-induced responses (IC(50) = 48 nM and >100 microM, respectively), indicating that these responses were not dependent upon PI3K. Wortmannin and LY294002 also inhibited PAF induced respiratory burst but not PAF-induced LTC(4) secretion. We conclude that PI3K-dependence varies with stimulus and response, and that eotaxin-induced eosinophil migration is not controlled by PI3K. This may indicate a limit to the potential of PI3K inhibitors to suppress tissue eosinophilia in diseases such as asthma.


GAP-43 is critical for normal development of the serotonergic innervation in forebrain.
Serotonergic (5-HT) axons from the raphe nuclei are among the earliest afferents to innervate the developing forebrain. The present study examined whether GAP-43, a growth-associated protein expressed on growing 5-HT axons, is necessary for normal 5-HT axonal outgrowth and terminal arborization during the perinatal period. We found a nearly complete failure of 5-HT immunoreactive axons to innervate the cortex and hippocampus in GAP-43-null (GAP43-/-) mice. Abnormal ingrowth of 5-HT axons was apparent on postnatal day 0 (P0); quantitative analysis of P7 brains revealed significant reductions in the density of 5-HT axons in the cortex and hippocampus of GAP43-/- mice relative to wild-type (WT) controls. In contrast, 5-HT axon density was normal in the striatum, septum, and amygdala and dramatically higher than normal in the thalamus of GAP43-/- mice. Concentrations of serotonin and its metabolite, 5-hydroxyindolacetic acid, and norepinephrine were decreased markedly in the anterior and posterior cerebrum but increased in the brainstem of GAP43-/- mice. Cell loss could not account for these abnormalities, because unbiased stereological analysis showed no significant difference in the number of 5-HT dorsal raphe neurons in P7 GAP43-/- versus WT mice. The aberrant 5-HT innervation pattern persisted at P21, indicating a long-term alteration of 5-HT projections to forebrain in the absence of GAP-43. In heterozygotes, the density and morphology of 5-HT axons was intermediate between WT and homozygous GAP43-/- mice. These results suggest that GAP-43 is a key regulator in normal pathfinding and arborization of 5-HT axons during early brain development.


Biosynthesis of rhodiocyanosides in Lotus japonicus: rhodiocyanoside A is synthesized from (Z)-2-methylbutanaloxime via 2-methyl-2-butenenitrile.
Lotus japonicus contains the two cyanogenic glucosides, linamarin and lotaustralin, and the non cyanogenic hydroxynitriles, rhodiocyanoside A and D, with rhodiocyanoside A as the major rhodiocyanoside. Rhodiocyanosides are structurally related to cyanogenic glucosides but are not cyanogenic. In vitro administration of intermediates of the lotaustralin pathway to microsomes prepared from selected L. japonicus accessions identified 2-methyl-2-butenenitrile as an intermediate in the rhodiocyanoside biosynthetic pathway. In vitro inhibitory studies with carbon monoxide and tetcyclacis indicate that the conversion of (Z)-2-methylbutanal oxime to 2-methyl-2-butenenitrile is catalyzed by cytochrome P450(s). Carbon monoxide inhibited cyanogenic glucosides as well as rhodiocyanosides synthesis, but inhibition of the latter pathway was much stronger. These results demonstrate that the cyanogenic glucoside and rhodiocyanosides pathways share CYP79Ds to obtain (Z)-2-methylbutanaloxime from l-isoleucine, whereas the subsequent conversions are catalyzed by different P450s. The aglycon of rhodiocyanoside A forms the cyclic product 3-methyl-2(5H)-furanone. Furanones are known to possess antimicrobial properties indicating that rhodiocyanoside A may have evolved to serve as a phytoanticipin that following β-glucosidase activation and cyclization of the aglycone formed, give rise to a potent defense compound.


Association of tumorigenic and nontumorigenic (immunogenic) variants in a mouse T-cell lymphoma with two distinct p53 mutations.
An in vitro model system for xenogenization has been developed in which an immunogenic, nonmalignant phenotype was selected from a highly malignant T-cell line (S49). We showed by single-strand conformation polymorphism and DNA sequence analysis that specific point mutations in the p53 tumor suppressor gene correlated with a change from a tumorigenic to a nontumorigenic (immunogenic) phenotype. Specifically, we found that the highly malignant S49 cell line T-60 contains an Arg-->Gln substitution at residue 246 in exon 7 of p53. In contrast, nontumorigenic (immunogenic) variants (T-25-Adh and Rev-1) exhibited a Gly-->Ser substitution at residue 242 of p53. In two subsequent tumorigenic revertants derived from Rev-1, we again found the Arg-->Gln substitution at residue 246 that was found initially in the T-60 cells. Thus, mutation at residue 246 of p53 was associated with a highly malignant phenotype, whereas a novel mutation at residue 242 of p53 appeared to be associated with a nonmalignant phenotype and may have actually protected the host through immunization. We conclude that mutation of residue 242 may represent a new class of permissive (nonmalignant) mutations in the mouse that are analogous to the Li-Fraumeni mutation in humans.


Interferon gamma, interferon-gamma-induced-protein 10, and tuberculin responses of children at high risk of tuberculosis infection.
Children in contact with adults with pulmonary tuberculosis (TB) are at risk for infection and disease progression, and chemoprophylaxis may reduce this risk. The identification of infection is based on the tuberculin skin test (TST) and interferon-gamma (INF-gamma) release assays. Other biomarkers such as interferon-gamma-induced-protein 10 (IP-10) may have potential for the diagnosis of latent TB infections. To describe IP-10 concentrations and their association to TST and INF-gamma responses in children recently exposed to adults with smear-positive TB in Brazil and Nepal. : Two surveys using the same design were undertaken to describe TST, INF-gamma, and IP-10 responses in 146 children in Nepal and 113 children in Brazil. The concordance of TST and QuantiFERON-TB gold in-tube (QFT-IT) was high (kappa 0.73 in Brazil and 0.80 in Nepal). IP-10 responses were higher in children with both positive TST and positive QFT-IT (medians 1434 pg/mL in Brazil and 1402 pg/mL in Nepal) and lowest in children with both negative TST and negative QFT-IT (medians 206 pg/mL in Brazil and 81 pg/mL in Nepal). Children with negative TST and positive QFT-IT had higher IP-10 concentrations than children with positive TST but negative QFT-IT. IP-10 is a potential marker to identify latent TB infections that is expressed in large quantities and with good agreement with QFT-IT. The reasons for the discrepant results observed are discussed.


Polyphosphate-crosslinked collagen scaffolds for hemostasis and alveolar bone regeneration after tooth extraction.
Post-extraction bleeding and alveolar bone resorption are the two frequently encountered complications after tooth extraction that result in poor healing and rehabilitation difficulties. The present study covalently bonded polyphosphate onto a collagen scaffold (P-CS) by crosslinking. The P-CS demonstrated improved hemostatic property in a healthy rat model and an anticoagulant-treated rat model. This improvement is attributed to the increase in hydrophilicity, increased thrombin generation, platelet activation and stimulation of the intrinsic coagulation pathway. In addition, the P-CS promoted the in-situ bone regeneration and alveolar ridge preservation in a rat alveolar bone defect model. The promotion is attributed to enhanced osteogenic differentiation of bone marrow stromal cells. Osteogenesis was improved by both polyphosphate and blood clots. Taken together, P-CS possesses favorable hemostasis and alveolar ridge preservation capability. It may be used as an effective treatment option for post-extraction bleeding and alveolar bone loss. Collagen scaffold is commonly used for the treatment of post-extraction bleeding and alveolar bone loss after tooth extraction. However, its application is hampered by insufficient hemostatic and osteoinductive property. Crosslinking polyphosphate with collagen produces a modified collagen scaffold that possesses improved hemostatic performance and augmented bone regeneration potential.


Searching biomarker candidates in serum using multidimensional native chromatography. II Method evaluation with Alport syndrome and severe inflammation.
Biomarker search using multidimensional native liquid fractionation of serum in microplates was evaluated. From different donors, homologous sample fractions with UV absorbance depending on state of illness were selected, and their constituents were identified and quantitated by MS. Analysis of sera of patients with Alport syndrome and severe inflammation proved the reliability of the method by confirming characteristic alterations. Moreover, 23 new marker candidates were detected for Alport syndrome, some of them being involved in matrix degradation and repair, and 33 new candidates for severe inflammation, among them alpha1B-glycoprotein cysteine-rich secretory protein and an apparently low molecular-weight albumin variant.


Different binding thermodynamics of Ni2+, Cu2+, and Zn2+ to bacitracin A1 determined by capillary electrophoresis.
Thermodynamics of the binding of Ni(2+), Cu(2+) and Zn(2+) to bacitracin A(1) was studied by capillary electrophoresis measuring the peptide effective mobility at different pH in the presence of increasing concentration of the three ligands. The affinity follows the order Ni(2+) > Cu(2+) > Zn(2+), with association constant values of (2.3 +/- 0.1)x10(4), (4.9 +/- 0.2)x10(3), and (1.5 +/- 0.1)x10(3) M(-1), respectively. The only model able to rationalize mobility data implies that metal ion binds to the P(0) peptide form. Moreover, mobility values indicated a change of bacitracin A(1) acidic properties on Ni(2+) and Cu(2+) binding, with a shift of the pK(a) of N-terminal Ile-1 from 7.6 to about 5 and of the pK(a) of the delta-amino group of D-Orn-7 from 9.7 to about 7. Even though on Zn(2+) binding a shift of the N-terminal Ile-1 pK(a) was observed, restrictions in the pH range suitable for investigation, due to precipitation phenomena, did not allow establish if the shift of D-Orn-7 lateral chain pK(a) also occurred. Nonetheless, if present, the shift should be limited to the 7.8-9.7 range. Mobility data indicated that the Stokes radius of the complexes is ca. 3 A lower than that of the free peptide. The present results indicate that metal-ion binding to bacitracin A(1) is more complex than previously assumed.


A new species of Kentropyxia Baker, 1982 parasitic in the small intestine of Osteocephalus taurinus Steindachner (Anura: Hylidae) from the Brazilian Eastern Amazon.
Kentropyxia hylae n. sp. is described based on material from small intestine of Osteocephalus taurinus Steindachner from Caxiuanã National Forest, municipality of Melgaço, state of Pará, Brazil. The new species is easily distinguished from the type-species and only species of the genus, Kentropyxia sauria Baker, 1982, by its smaller dimensions, the presence of cervical alae, spicules divided into three parts: a robust, single pointed outer processes ending with small finger-like projections and latero-dorsal and latero-ventral processes branching at final portion of spicule into six main branches, each ending with 14 projections in the latero-dorsal process and 15 projections in the latero-ventral process and by the presence of a middle groove in bursa ray 4. This is the second species parasitic in hylids from the Brazilian Amazon and a new parasite for O. taurinus.


The effects of four different crystalloid bypass pump-priming fluids upon the metabolic response to cardiac operation.
The crystalloid solutions used to prime cardiopulmonary bypass pumps frequently contain metabolically active substrates. However, there is a lack of controlled studies to investigate the metabolic response to cardiac operations using different pump primes. We have carried out a prospective, randomized study of 24 patients divided into four groups, each group receiving a different crystalloid prime. The primes contained glucose, lactate, glucose and lactate, or neither glucose nor lactate. Using identical anesthetic, surgical, and perfusion techniques, we estimated the metabolic response to cardiac operation in all patients by frequent blood sampling for measurement of hormone (insulin, glucagon, cortisol, and growth hormone) and metabolite concentrations (glucose, lactate, pyruvate, glycerol, alanine, and 3-hydroxybutyrate) from the day before operation to the seventh postoperative day. The results demonstrated that, after 4 hours postoperatively, the endocrine and metabolic response to cardiac operation was unaffected by the nature of the priming fluid. However, major endocrine and metabolic changes occurred before that time, which were related directly to the glucose and lactate contents of the prime. Very high concentrations of both glucose and lactate were observed at the end of bypass if they were induced in the prime. Given the known dangers of hyperglycemia in cerebral ischemia and the potential gluconeogenic effects of infused lactate, we suggest that glucose-free and lactate-free primes be employed in the extracorporeal circuit.


Platelet activity and aspirin efficacy after off-pump compared with on-pump coronary artery bypass surgery: results from the prospective randomized trial PRAGUE 11-Coronary Artery Bypass and REactivity of Thrombocytes (CABARET).
Changes in hemostasis after off-pump coronary artery bypass grafting are still being discussed. There is a lack of information about platelet activity and aspirin efficacy after coronary artery bypass grafting. The aim of this study was to assess and compare platelet activity and aspirin efficacy early and late after off-pump and on-pump coronary artery bypass grafting. Eighty patients were enrolled in a prospective randomized study. Platelet activity was determined based on membrane expression of antigen CD62P (P-selectin) by means of flow cytometric analysis. Aspirin efficacy was assessed by using arachidonic acid-induced platelet aggregation. Blood samples were collected before the operation, immediately postoperatively, and on days 1, 2, 5, and 30. In the off-pump group expression of P-selectin was markedly increased in comparison with preoperative values, with a maximum difference observed on day 2 (+53%, P = .02), and it was significantly higher compared with that seen in the on-pump group on days 2 and 5 (+53% vs +4%, P = .004, and +20% vs -16%, P = .005). On day 30, P-selectin expression was similar both between the groups and in comparison with the preoperative values. Arachidonic acid-induced platelet aggregation was gradually decreasing until day 30, but on day 2, there was an unexpected increase in aggregation that was more expressed in the off-pump group. The platelet activity is higher in the early postoperative period in off-pump compared with on-pump coronary artery bypass grafting. The present aspirin strategy seems to be insufficient in the early postoperative period, irrespective of the surgical technique used.


Autophagy modulates the stability of Wee1 and cell cycle G2/M transition.
The mammalian cell cycle is divided into four sequential phases, namely G1 (Gap 1), S (synthesis), G2 (Gap 2), and M (mitosis). Wee1, whose turnover is tightly and finely regulated, is a well-known kinase serving as a gatekeeper for the G2/M transition. However, the mechanism underlying the turnover of Wee1 is not fully understood. Autophagy, a highly conserved cellular process, maintains cellular homeostasis by eliminating intracellular aggregations, damaged organelles, and individual proteins. In the present study, we found autophagy deficiency in mouse liver caused G2/M arrest in two mouse models, namely Fip200 and Atg7 liver-specific knockout mice. To uncover the link between autophagy deficiency and G2/M transition, we combined transcriptomic and proteomic analysis for liver samples from control and Atg7 liver-specific knockout mice. The data suggest that the inhibition of autophagy increases the protein level of Wee1 without any alteration of its mRNA abundance. Serum starvation, an autophagy stimulus, downregulates the protein level of Wee1 in vitro. In addition, the half-life of Wee1 is extended by the addition of chloroquine, an autophagy inhibitor. LC3, a central autophagic protein functioning in autophagy substrate selection and autophagosome biogenesis, interacts with Wee1 as assessed by co-immunoprecipitation assay. Furthermore, overexpression of Wee1 leads to G2/M arrest both in vitro and in vivo. Collectively, our data indicate that autophagy could degrade Wee1-a gatekeeper of the G2/M transition, whereas the inhibition of autophagy leads to the accumulation of Wee1 and causes G2/M arrest in mouse liver.


Telemedicine in ophthalmology in view of the emerging COVID-19 outbreak.
Technological advances in recent years have resulted in the development and implementation of various modalities and techniques enabling medical professionals to remotely diagnose and treat numerous medical conditions in diverse medical fields, including ophthalmology. Patients who require prolonged isolation until recovery, such as those who suffer from COVID-19, present multiple therapeutic dilemmas to their caregivers. Therefore, utilizing remote care in the daily workflow would be a valuable tool for the diagnosis and treatment of acute and chronic ocular conditions in this challenging clinical setting. Our aim is to review the latest technological and methodical advances in teleophthalmology and highlight their implementation in screening and managing various ocular conditions. We present them as well as potential diagnostic and treatment applications in view of the recent SARS-CoV-2 virus outbreak. A computerized search from January 2017 up to March 2020 of the online electronic database PubMed was performed, using the following search strings: "telemedicine," "telehealth," and "ophthalmology." More generalized complementary contemporary research data regarding the COVID-19 pandemic was also obtained from the PubMed database. A total of 312 records, including COVID-19-focused studies, were initially identified. After exclusion of non-relevant, non-English, and duplicate studies, a total of 138 records were found eligible. Ninety records were included in the final qualitative analysis. Teleophthalmology is an effective screening and management tool for a range of adult and pediatric acute and chronic ocular conditions. It is mostly utilized in screening of retinal conditions such as retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration; in diagnosing anterior segment condition; and in managing glaucoma. With improvements in image processing, and better integration of the patient's medical record, teleophthalmology should become a more accepted modality, all the more so in circumstances where social distancing is inflicted upon us.


Characterization and antioxidant activity in vitro and in vivo of polysaccharide purified from Rana chensinensis skin.
Preliminary characterization and antioxidant activity in vitro and in vivo investigation of the polysaccharide fraction named as RCSP II, which was extracted from Rana chensinensis skin, were performed. Results indicated that RCSP II comprised glucose, galactose, and mannose in a molar ratio of 87.82:2.77:1.54 with a molecular weight of 12.8 kDa. Antioxidant activity assay in vitro showed that RCSP II exhibited 75.2% scavenging activity against 2,2'-azino-bis(3-ethylbenz-thiazoline-6-sulfonic acid) radicals at the concentration of 2500 mg/L and 85.1% against chelated ferrous ion at 4000 mg/L. Antioxidant activity assay in vivo further showed that RCSP II increased the activities of antioxidant enzymes, decreased the levels of malondialodehyde, and enhanced total antioxidant capabilities in livers and sera of d-galactose induced mice. These results suggested that RCSP II could have potential antioxidant applications as medicine or functional food.


Glaucoma progression in patients receiving intravitreal anti-VEGF treatment for neovascular age-related macular degeneration.
The purpose of this study was to investigate how often glaucoma and neovascular age-related macular degeneration (nAMD) occur in the same patient and to evaluate whether glaucoma progression is faster in eyes treated with intravitreal anti-VEGF medications for nAMD. This single-centre retrospective real-world data (RWD) consists of medical records of 6314 glaucoma and 2166 nAMD patients treated in 2008-2017 in Tays Eye Centre, Finland. To study glaucoma progression, changes in visual fields (mean deviation [MD], dB/year), IOP (mmHg/year) and fundus photographs (progression, yes/no) were compared in glaucoma eyes with and without anti-VEGF treatment for nAMD and ≥1 year follow-up. During the 10-year period, 147 patients with glaucoma received intravitreal anti-VEGF treatment for nAMD corresponding to 2% of glaucoma and 7% of nAMD patients. The mean change in MD was -0.70 dB/year (SD 1.8) vs. -0.27 dB/year (SD 1.7) (p = 0.027) in glaucoma eyes with (n = 37) and without (n = 4304) anti-VEGF injections, respectively. In patients with bilateral glaucoma and unilateral nAMD treated with anti-VEGF injections (n = 20), MD declined at -0.62 dB/year (SD 1.9) vs 0.33 dB/year (SD 1.5) (p = 0.654), and glaucoma progression was detected in 14/20 vs 10/20 (p = 0.219) fundus photographs in eyes with anti-VEGF treatment compared with their untreated fellow eyes. nAMD and glaucoma were found co-existing in the same eye at rates that were similar to the age-corrected prevalence of the two diseases in the general population. Our results suggest that intravitreal anti-VEGF treatment for nAMD may accelerate glaucoma progression.


Disparities in breast and cervical cancer screening in women with mental illness: a systematic literature review.
Breast and cervical cancer screening rates have improved substantially in the U.S. during the past decade. Cancer screening and other health outcomes in patients with mental illnesses, such as major depression and schizophrenia, remain suboptimal. Understanding the prevalence and root causes of these disparities is an essential first step toward developing effective interventions. This paper presents a systematic literature review of current evidence on breast and cervical cancer screening disparities in women with mental illness. A systematic PubMed/MEDLINE and PsycINFO search completed in May 2012 retrieved articles pertaining to cancer screening and mentally ill patients using pertinent search terms. Articles that met the inclusion criteria were appraised critically for evidence quality related to screening disparities using defined criteria. Articles that reported cancer screening rates in patients with mental illness were reviewed to determine whether any barriers to screening or factors that promote screening were identified. Nineteen studies met the inclusion criteria. Many articles contributed to more than one of the identified areas of interest (i.e., screening utilization, barriers to screening, and factors that encourage screening). Substantial evidence in the current literature confirms disparities in breast and cervical cancer screening rates among women with mental illness. However, the mentally ill population is more complex and diverse than many studies imply. Using a global functional indicator that measures the overall impact of mental illness may yield a more useful categorization of influences on cancer screening.


Prophylactic oral nystatin and fungal infections in very-low-birthweight infants.
Prevention of systemic fungal infection in the very-low-birthweight infant is important since it is associated with a high morbidity and mortality. To determine if oral nystatin administration could prevent fungal colonization and infection, we evaluated 67 preterm infants with birthweights less than 1250 gm. Thirty-three infants received 1 ml (100,000 units/ml) of nystatin inside the mouth every 8 hours until 1 week after extubation. Oropharyngeal, rectal, blood, and urine cultures were obtained on the 1st day of life and weekly. Endotracheal cultures were obtained three times a week from intubated infants. Four (12%) of the 33 nystatin-treated infants had positive cultures, two (6%) developed systemic infection. The control group consisted of 34 infants, 15 (44%) had positive fungal cultures and 11 (32%) developed systemic infection. Fungi isolated were Candida species and Torulopsis glabrata. Colonized infants were dependent on the respirator (P less than 0.001), had indwelling catheters (P less than 0.01), and received antibiotics (P less than 0.05) for a longer period than infants free from fungi and their mortality was significantly higher (P less than 0.05). We conclude that prophylactic administration of oral nystatin reduces fungal colonization and infection in very-low-birthweight infants.


Involving stakeholders in building integrated fisheries models using Bayesian methods.
A participatory Bayesian approach was used to investigate how the views of stakeholders could be utilized to develop models to help understand the Central Baltic herring fishery. In task one, we applied the Bayesian belief network methodology to elicit the causal assumptions of six stakeholders on factors that influence natural mortality, growth, and egg survival of the herring stock in probabilistic terms. We also integrated the expressed views into a meta-model using the Bayesian model averaging (BMA) method. In task two, we used influence diagrams to study qualitatively how the stakeholders frame the management problem of the herring fishery and elucidate what kind of causalities the different views involve. The paper combines these two tasks to assess the suitability of the methodological choices to participatory modeling in terms of both a modeling tool and participation mode. The paper also assesses the potential of the study to contribute to the development of participatory modeling practices. It is concluded that the subjective perspective to knowledge, that is fundamental in Bayesian theory, suits participatory modeling better than a positivist paradigm that seeks the objective truth. The methodology provides a flexible tool that can be adapted to different kinds of needs and challenges of participatory modeling. The ability of the approach to deal with small data sets makes it cost-effective in participatory contexts. However, the BMA methodology used in modeling the biological uncertainties is so complex that it needs further development before it can be introduced to wider use in participatory contexts.


Comparison of the validity of the criteria for gestational diabetes mellitus by WHO and by the Japan Society of Obstetrics and Gynecology by the outcomes of pregnancy.
Data for 416 Japanese pregnant women who received a 75g oral glucose tolerance test (OGTT) for determination of gestational diabetes mellitus (GDM) in 13 hospitals in Japan were analyzed retrospectively. Comparison of the diagnostic criteria of the World Health Organization (WHO) and the Japan Society of Obstetrics and Gynecology (JSOG) revealed pregnant women who met the latter criteria for GDM to have significantly higher incidences of low Apgar scores, respiratory problems, neonatal hypoglycemia, preterm delivery and requirements for insulin therapy and cesarean section. The women who met the WHO criteria but not the JSOG criteria had minor complications. These observations suggest that the GDM criteria of the JSOG are more appropriate than the WHO criteria from the standpoint of therapeutic intervention for pregnant women.


Biological effects of 2,4-pentadiene-1-ol.
The biological effects of 2,4-pentadiene-1-ol (CH2 = CH--CH = CH--CH2--OH) the starting monomer in the preparation of a biocompatible polymer were studied. The experiments in rats revealed both a high local (oedema, necrosis) and systemic toxicity. Within 5-10 min after dermal application of 0.2 ml the compound evoked intensive hyperaemia of acral parts (ears, snout, paws) and induced severe breathing difficulties which led to death in half of the animals after a single administration. The most evident macroscopic and microscopic pathologic changes were found in the place of application and in the lungs (haemorrhage in alveolae). Both clinical and histological findings indicated that the toxicity is due to an increased permeability of capillaries.


A note on the projections of pars compacta neurons within pars reticulata of the substantia nigra in the rat.
The ascending projections of pars compacta (SNc) neurons displaced within the pars reticulata (SNr) of the substantia nigra in the rat were examined using a fluorescent retrograde tracing. Following unilateral injections of a tracer into the striatum, SNc cells within the SNr were retrogradely labeled predominantly in the caudal parts, and to a lesser extent in the rostral portions of the nucleus. These nigrostriatal projections arising from the SNc cells within the SNr were only ipsilateral. Injections of a tracer into the nucleus accumbens (Acc) did not produce any labeling of these displaced SNc cells in contrast with cells in the SNc proper. Given that the SNc neurons within the SNr project only to the striatum but not to the Acc, and that they contain dopamine but not cholecystokinin, they might be involved in the motor but not in the limbic function.


Lifetime and regeneration of immobilized titania for photocatalytic removal of aqueous hexavalent chromium.
Immobilized titania (TiO2) batch reactors reduced hexavalent chromium (Cr(VI)) in the form of potassium dichromate (K2Cr2O7) to trivalent chromium (Cr(III)) in aqueous solution at pH 3 under 171 W/m2 light intensity. The light source was a 125-W ultraviolet (UV) lamp. The Cr(VI) reduction showed zero-order kinetics (k0), while the Cr(VI) adsorption fitted with first-order kinetics (k(1st)). Adsorption capacity increased with increasing initial Cr(VI) concentration, and the area of immobilized TiO2 limited the reduction efficiency. The lifetime of fresh immobilized TiO2 was approximately 14 h. In addition, the regeneration of TiO2 with 3M sodium hydroxide (NaOH) was necessary to improve adsorption reaction.


Margin placement of esthetic veneer crowns. Part IV: Postoperative patient attitudes.
Ninety-one subjects with a total of 196 esthetic veneer crowns with visible gingival margins were surveyed. An esthetic analysis of crown margins showing with a normal smile and an exaggerated smile was performed and recorded. Patient satisfaction or dissatisfaction with the esthetic veneer crowns was assessed. The conclusions of this study support the results reported in the first three parts of this study, indicate that satisfactory results can be obtained on many individuals when the crown margins of esthetic veneer crowns are placed supragingivally, and support the philosophy that individual patient education and analysis are essential to the selection of optimum margin placement when esthetic veneer crowns are the treatment of choice.


The effect of quadriceps kinesiotaping on the dynamic balance of young healthy women after fatigue: A randomized controlled trial.
Balance is a key factor in performing daily activities and the quadriceps muscle plays an important role in regaining balance following imbalance. Quadriceps fatigue may cause disruption in sending proprioception signals to the central nervous system and may, ultimately, lead to motor dysfunction and increased fluctuating dynamic and static balance which is followed by an increased risk of falling. Based on conclusions from previous studies it is proposed that kinesiotaping (KT) might be effective in the reduction of muscle fatigue and eventually balance. To investigate the effect of quadriceps KT on the dynamic balance of young healthy non-athlete women following local fatigue. A Single-blind parallel randomized clinical trial. 28 healthy women aged from 18 to 30 years were selected using the convenience sampling method. They were thoroughly evaluated with regard to the inclusion and exclusion criteria and randomly divided into two groups of kinesiotaping (n = 14) and non-tape (n = 14) using coin tossing. Balance measurement was performed on both groups before and after fatigue using the Y balance test. Both groups performed the fatigue protocol, but only the KT group was taped. Results demonstrated that, the mean of normalized reach distances at anterior (KT: 1.014 ± 0.073, non-tape: 0.964 ± 0.097), posteromedial (KT: 0.816 ± 0.125, non-tape: 0.809 ± 0.076) and posterolateral (KT: 0.794 ± 0.102, non-tape: 0.753 ± 0.093) directions in the Y balance test had no significant difference between both groups after fatigue (p > 0.05). Our findings indicated no significant effect of quadriceps KT on the dynamic balance of young healthy women after fatigue.


An Overview of the Recent Developments and Patents in the Field of Pharmaceutical Nanotechnology.
Compared to traditional dosage methods, the Novel Drug Delivery Systems (NDDS) provide various advantages. In the last few years, the interest shifted to works focused on the novel drug delivery methods for small and large molecular drug carriers utilizing particulate drug delivery systems as well. It is evident from the last decade as observed in increased number of patents in this field that the technology has evolved tremendously. Drug carriers utilized by this novel technology include liposomes, dendrimers, polymeric nanoparticles, magnetic nanoparticles, solid lipid nanoparticles, and carbon nanomaterials. Various forms of polymers have been used in the production of nanocarriers. Nanocarriers are colloidal systems varying in size from 10 to 1000 nm. This technology is now used to identify, manage and monitor numerous diseases and physical methods to alter and enhance the pharmacokinetic and pharmacodynamic properties of specific types of drug molecules. Nanoparticles can be formulated by a number of techniques including ionic gelation, crosslinking, coacervation/precipitation, nanoprecipitation, spray drying, emulsion- droplet coalescence, nano sonication techniques, etc. Several methods are used with which these nanoparticles can be characterized. These methods include nuclear magnetic resonance, optical microscopy, atomic force microscopy, photon correlation spectroscopy and electron microscopy, surface charge, in-vitro drug release, etc. Conclusion: In the present review, the authors have tried to summarize recent advances in the field of pharmaceutical nanotechnology and also focused on the application and new patents in the area related to NDDS.


Kidney Tertiary Lymphoid Structures in Lupus Nephritis Develop into Large Interconnected Networks and Resemble Lymph Nodes in Gene Signature.
Immune aggregates organized as tertiary lymphoid structures (TLS) are observed within the kidneys of patients with systemic lupus erythematosus and lupus nephritis (LN). Renal TLS was characterized in lupus-prone New Zealand black × New Zealand white F1 mice analyzing cell composition and vessel formation. RNA sequencing was performed on transcriptomes isolated from lymph nodes, macrodissected TLS from kidneys, and total kidneys of mice at different disease stages by using a personal genome machine and RNA sequencing. Formation of TLS was found in anti-double-stranded DNA antibody-positive mice, and the structures were organized as interconnected large networks with distinct T/B cell zones with adjacent dendritic cells, macrophages, plasma cells, high endothelial venules, supporting follicular dendritic cells network, and functional germinal centers. Comparison of gene profiles of whole kidney, renal TLS, and lymph nodes revealed a similar gene signature of TLS and lymph nodes. The up-regulated genes within the kidneys of lupus-prone mice during LN development reflected TLS formation, whereas the down-regulated genes were involved in metabolic processes of the kidney cells. A comparison with human LN gene expression revealed similar up-regulated genes as observed during the development of murine LN and TLS. In conclusion, kidney TLS have a similar cell composition, structure, and gene signature as lymph nodes and therefore may function as a kidney-specific type of lymph node.


Association of baseline white blood cell counts with tuberculosis treatment outcome: a prospective multicentered cohort study.
Tuberculosis (TB) is the leading infectious cause of death in the world. Cheaper and more accessible TB treatment monitoring methods are needed. Here, we evaluated white blood cell (WBC) absolute counts, lymphocyte, and monocyte proportions during TB treatment, and characterized their association with treatment failure. This multicentered prospective cohort study was based in Bangladesh, Georgia, Lebanon, Madagascar, and Paraguay. Adult, non-immunocompromised patients with culture-confirmed pulmonary TB were included and followed up after two months of treatment and at the end of therapy. Blood counts were compared to treatment outcome using descriptive statistics, logistic regression, and Receiver Operating Characteristic (ROC) analyses. Between December 2017 and August 2020, 198 participants were enrolled, and 152 completed treatment, including 28 (18.5%) drug-resistant patients. The rate of cure at the end of treatment was 90.8% (138/152). WBC absolute counts decreased, and lymphocyte proportions increased throughout treatment. In multivariate analyses, baseline high WBC counts and low lymphocyte proportions were associated with positive sputum culture results at the end of treatment (WBC > 11,450 cells/mm3: p = 0.048; lymphocytes <16.0%: p = 0.039; WBC > 11,450 cells/mm3 and lymphocytes <16.0%: p = 0.024). High WBC counts and low lymphocyte proportions at baseline are significantly associated with the risk of TB treatment failure.


The effects of race and class on community-level stigmatization of opioid use and policy preferences.
With opioid use and overdose rates continuing to plague minority communities in the U.S., we explored whether a geographic community's racial composition and social class affect how opioid use in the community is stigmatized and what policy preferences arise in response. We use case vignettes in a randomized, between-subjects study (N = 1478) with a nation-wide survey. The vignettes describe a community where opioids are harmfully used, varying whether the community was (1) wealthy or poor, (2) predominantly Black or White and (3) facing prevalent use of painkillers or heroin. We tested how these variables affect public stigmatization of opioid use (measured with ratings of responsibility, dangerousness, sympathy, concern, anger, and disappointment) preferred levels of social distance from communities with opioid use (measured with responses to questions about living, working, and interacting in the community), and policy preferences for responding to opioid use (measured with levels of support for providing a safe-consumption site in the community, treating drug use in the community punitively, treating drug use in the community as an illness, and funding drug treatment in the community through income redistribution). Compared to wealthy communities with opioid use, poor communities with opioid use were less stigmatized in terms of responsibility, sympathy, concern, anger, and disappointment; they were also met with less support for punitiveness, more support for treating drug use as an illness, and preferences for greater social distance. Compared to White communities with opioid use, Black communities with opioid use were less stigmatized in terms of responsibility, and they were met with stronger preferences to not live and work there and with reduced support for using income redistribution to provide drug treatment for people in the community. Poor-Black communities with opioid use were also perceived to be more dangerous than both poor-White and wealthy-Black communities with opioid use. These results point to class- and race-based territorial stigma affecting how communities with opioid use are judged and whether policies for providing communities with treatment are supported.


Importance of the lateral parabrachial nucleus to sodium balance in fluid-depleted rats.
The lateral parabrachial nucleus (LPBN) exerts an important inhibitory influence for the control of sodium and water intake. However, the importance of LPBN on renal responses and cardiovascular changes during extracellular dehydration are still unknown. Here we investigated the effects of bilateral injections of moxonidine (alpha2-adrenergic and imidazoline receptor agonist) on renal and cardiovascular changes in fluid-depleted rats. Male Wistar rats (n=4-8 per group) with bilateral stainless steel guide-cannulas implanted into the LPBN were treated with subcutaneous furosemide (10mg/kg)+captopril (5mg/kg) to induce fluid depletion. Forty-five min later vehicle or moxonidine (0.5nmol/0.2μl) were bilaterally injected into the LPBN. In fluid-depleted rats, moxonidine produced strong 0.3M NaCl and water intake without noticeable changes in cardiovascular parameters. Moxonidine did not change sodium excretion (488±135, vs. vehicle: 376±75μEq/1h) or urinary volume (2.5±0.7, vs. vehicle: 2.5±0.3ml/1h) in fluid-depleted rats without access to fluids for rehydration. However, moxonidine decreased natriuresis (462±127, vs. vehicle: 888±122μEq/1h) and diuresis (2.5±0.5, vs. vehicle: 4.5±0.5ml/1h) in fluid-depleted rats submitted to i.g. rehydration. These data suggest that alpha2-adrenergic mechanism of the LPBN facilitates sodium/water retention and body fluid volume expansion during extracellular dehydration.


The coding of information by spiking neurons: an analytical study.
We analyse analytically the coding of information by a spiking neuron. The emphasis is on the question of how many spikes are necessary for the reliable discrimination of two different input signals. The discrimination ability is measured by the second-order Rényi mutual information between the random variable describing the name of the signal and a sequence of n output spikes. Analysing this measure as a function of n, we study the coding strategy of a single spiking neuron, with the following main results. A small number of output spikes is required for efficient discrimination of input signals, i.e. for encoding them, if the separation is easy; a large number of output spikes is required in the difficult case of separation of very similar input signals. Three different versions of the spike response model of a single neuron are studied. The approach presented can be regarded as a non-parametric version of the reconstruction method of Bialek.


HbAlc--an indicator of diabetic control.
Hemoglobin Alc levels were determined on 16 nondiabetic and 115 diabetic subjects. Twelve of the diabetic patients were newly diagnosed and 12 were in the remission phase. The mean percentage of HbAlc in the nondiabetic subjects was 4.33 +/- 0.39 (SE), in those with long-standing diabetes 8.34 +/- 0.23 SE, in newly diagnosed diabetic patients 8.99 +/- 0.50 SE, and in those undergoing partial remission 5.16 +/- 0.18 SE. The mean HbAlc levels of these four groups differed significantly (0.001 less than P less than 0.025). Among the diabetic subjects there was a good correlation between HbAlc level and such measures as fasting blood sugar, urinary sugar, and degree of diabetic control, whereas the correlations between HbAlc and age, sex, or duration of the disease were not significant. The obtained data show that HbAlc measurement can serve as an objective measure of glucose control in diabetic subjects.


Seeking the optimal schedule for chickenpox vaccination in Canada: Using an agent-based model to explore the impact of dose timing, coverage and waning of immunity on disease outcomes.
Many countries continue to consider implementing a universal chickenpox vaccine program; however, there is no consensus on the most appropriate and effective timing between vaccine doses. The chickenpox vaccine schedule debate is highlighted in Canada, where there are currently eight different vaccine schedules across the country. The objective of this study was to test the overall effectiveness of chickenpox vaccination, as well as the specific impact of two different vaccine schedules, on chickenpox disease outcomes in Alberta over 75 years. Using an agent-based model of chickenpox disease, we tested the impact of three vaccination scenarios including: baseline (no vaccination), a long dosing interval-Schedule LDI (1st dose - 12 months; 2nd dose - 4-6 years) and a short dosing interval-Schedule SDI (1st dose - 12 months; 2nd dose - 18 months) on chickenpox and shingles disease outcomes. Chickenpox vaccination led to a substantial decrease in chickenpox incidence over 75 years post-vaccine implementation. Compared to Schedule LDI, Schedule SDI resulted in a significantly lower chickenpox incidence, a higher age of chickenpox infection, a lower chickenpox breakthrough rate and a higher shingles incidence rate. Our model findings suggest that the chickenpox vaccine is effective over a long period of time and the dose timing of the vaccine may impact disease outcomes and vaccine effectiveness. However, the effectiveness of the vaccine dose timing is only one consideration for policy-makers who are implementing a chickenpox vaccine program, with others including risk of adverse events, the impact of the schedule on other antigens in a combination vaccine, parental acceptance and the cost associated with different schedules.


The engineering of spatially linked microbial consortia - potential and perspectives.
Traditional biotechnological applications of microorganisms employ mono-cultivation or co-cultivation in well-mixed vessels disregarding the potential of spatially organized cultures. Metabolic specialization and guided species interactions facilitated through spatial isolation would enable consortia of microbes to accomplish more complex functions than currently possible, for bioproduction as well as biodegradation processes. Here, we review concepts of spatially linked microbial consortia in which spatial arrangement is optimized to increase control and facilitate new species combinations. We highlight that genome-scale metabolic network models can inform the design and tuning of synthetic microbial consortia and suggest that a standardized assembly of such systems allows the combination of 'incompatibles', potentially leading to countless novel applications.


An antibody-free dual-biomarker rapid enrichment workflow (AnDREW) improves the sensitivity of malaria rapid diagnostic tests.
Rapid diagnostic tests (RDTs) are critical to the success of malaria elimination campaigns. These tests are rapid, user-friendly, and field-deployable to resource-limited regions. However, RDTs demonstrate poor sensitivity because they can only tolerate a small (5 μL) volume of blood, which limits the amount of protein biomarker delivered to the test. We have developed the Antibody-free Dual-biomarker Rapid Enrichment Workflow (AnDREW) for purifying histidine-rich protein 2 (HRP2) and Plasmodium lactate dehydrogenase (PLDH) from large volume (150 μL) blood samples. We used Zn(II)NTA and aptamer-conjugated magnetic beads to capture HRP2 and PLDH, respectively. Both biomarkers were then eluted into RDT-compatible volumes using ethylene diamine tetraacetic acid (EDTA). We optimized both bead conjugates individually by enzyme-linked immunosorbent assays (ELISAs) and then combined the optimized capture and elution assays for both biomarkers to produce the AnDREW. The AnDREW-enhanced RDTs exhibited a 11-fold and 9-fold improvement in analytical sensitivity for detection of HRP2 and PLDH, respectively, when compared to unenhanced RDTs. Moreover, the limit of detection for PLDH was improved 11-fold for the AnDREW-enhanced RDTs (3.80 parasites/μL) compared to unenhanced RDTs (42.31 parasites/μL). Importantly, the AnDREW utilizes a pan-specific PLDH aptamer and improves upon existing methods by eluting both biomarkers without complexed antibodies.


Stress responses of testicular development, inflammatory and apoptotic activities in male zebrafish (Danio rerio) under starvation.
Food deprivation is a severe stress across multiple fields and challenged to organismal development and immune system. Here, adult male zebrafish were used to investigate the starvation stress on organismal development, spermatogenesis, testicular inflammation and apoptosis. Results showed that the biological indexes, blood parameters, and RNA/DNA ratio in testis dramatically decreased after 1-3 weeks of starvation. The testicular architecture was impaired and the spermatogenesis was retarded with increased proportions of spermatogonia and spermatocytes, and decreased proportion of spermatozoa in the starved fish. The mRNA expressions of amh and sycp3 were downregulated, the retinoic acid content increased at later stage of starvation through the transcriptional regulation of aldh1a2 and cyp26a1. Besides, the immune response was elevated with upregulated mRNA and protein expressions of TNF-α, IL-6, and IL-1β, which indicated the inflammation of opportunistic risk in testis. The apoptotic activity was stimulated, accompanied by differentially upregulated expressions of baxa, casp9, casp3, casp2, and decreased ratio of Bcl-2/Bax in the attenuate testis. Taken together, our findings revealed that the stress responses of testicular development, inflammatory and apoptotic activities in male zebrafish under starvation and pointed out the susceptibility of fish gonad to food fluctuation.


The Blalock-Taussig shunt. Low risk, effective palliation, and pulmonary artery growth.
The Blalock-Taussig shunt has been used at our institution in 64 infants with cyanotic congenital heart disease who required palliation. Thirty-one of these children were less than 2 months of age at the time of operation. There were no early shunt closures. There were two hospital deaths (3%). There was only one hospital death in the 31 patients less than 60 days old. According to a life-table analysis, 87% +/- 9% (+/- 95% confidence limits) of the shunts were functioning at 1 year and 78% +/- 12% at 2 years. Results are similar in the subgroup of children less than 60 days of age at the time of operation or in the subgroup of children weighing less than 3,999 gm at operation. In infants with small pulmonary arteries, pulmonary arterial growth was excellent (ipsilateral pulmonary artery/descending aorta ratio 0.70 leads to 0.95 in 550 days, p less than 0.001; contralateral ratio 0.73 leads to 0.99 in 550 days, p less than 0.001). The Blalock-Taussig shunt can be performed with low risk, provides excellent palliation, and is associated with excellent pulmonary artery growth.


Matched-pair analysis of postoperative morbidity and mortality for pancreaticogastrostomy and pancreaticojejunostomy using mattress sutures in soft pancreatic tissue remnants.
After pancreaticoduodenectomy, the incidence of postoperative pancreatic fistula remains high, especially in patients with "soft" pancreatic tissue remnants. No "gold standard" surgical technique for pancreaticoenteric anastomosis has been established. This study aimed to compare the postoperative morbidity and mortality of pancreaticogastrostomy and pancreaticojejunostomy for "soft" pancreatic tissue remnants using modified mattress sutures. Seventy-five patients who had undergone pancreaticogastrostomy and 75 who had undergone pancreaticojejunostomy after pancreaticoduodenectomy between 2002 and 2008 were retrospectively compared using matched-pair analysis. A modified mattress suture technique was used for the pancreaticoenteric anastomosis. Patients with an underlying "hard" pancreatic tissue remnant, as in chronic pancreatitis, were excluded. Both groups were homogeneous for age, gender, and underlying disease. Postoperative morbidity, mortality, and preoperative and operative data were analyzed. There were no significant differences between the groups for the incidence of postoperative pancreatic fistula (10.7% in both). Postoperative morbidity and mortality, median operation time, median length of hospital stay, intraoperative blood loss, and the amount of intraoperatively transfused erythrocyte concentrates also did not significantly differ between the groups. Patient age >65 years (P=0.017), operation time >350 minutes (P=0.001), and intraoperative transfusion of erythrocyte concentrates (P=0.038) were identified as risk factors for postoperative morbidity. Our results showed no significant differences between the groups in the pancreaticogastrostomy and pancreaticojejunostomy anastomosis techniques using mattress sutures for "soft" pancreatic tissue remnants. In our experience, the mattress sutures are safe and simple to use, and pancreaticogastrostomy in particular is feasible and easy to learn, with good endoscopic accessibility to the anastomosis region. However, the location of the anastomosis and the surgical technique need to be individually evaluated to further reduce the incidence of postoperative pancreatic fistula.


Ghrelin promotes the differentiation of human embryonic stem cells in infarcted cardiac microenvironment.
Ghrelin is broadly expressed in myocardial tissues, where it exerts different functions. It also has been found to have a wide variety of biological functions on cell differentiation and tissue development. The aim of this study was to investigate the effect of ghrelin on human embryonic stem cell (hESC) differentiation in infarcted cardiac microenvironment. The hESCs grown on feeder layers expressed several pluripotential markers including alkaline phosphatase (AKP). Four weeks after transplantation into rat infarcted hearts, the hESCs and their progeny cells survived and formed intracardiac grafts were 54.7% and 19.6% respectively in ghrelin- and phosphate-buffered saline (PBS)-treated groups. Double immunostaining with anti-human Sox9 and anti-HNA or anti-human fetal liver kinase-1 (Flk1) and anti β-tubulin showed that the human grafts were in development. However, double positive stains were only found in the ghrelin-treated group. In addition, the hESC injection protocol was insufficient to restore heart function of the acute myocardial infarction model. Our study, therefore, provides a new insight of ghrelin on promoting hESC survival and differentiation in rat infarcted cardiac microenvironment. This may give a clue for therapy for myocardial infarction by hESCs or progeny cells.


Open ankle fractures: Factors influencing unplanned reoperation.
Ankle fractures are amongst the most common open fracture injuries presenting to major trauma centres (MTC) and their management remains a topic of debate. Incidence is increasing particularly in the elderly population however the optimal surgical approach and risk factors for unplanned reoperation remain scarce. We therefore conducted a retrospective case study to analyse our institution's outcomes as well as identify risk factors for early unplanned reoperation. Sixty-five consecutive open ankle fractures were identified using our institutional database between July 2016 and July 2020. Medical records and operation notes were reviewed to identify patient age at injury, Sex, co-morbidities and other co-morbidities, fracture configuration, extent of soft tissue injury, fixation type and post-operative complications. The data was categorised into four groups for analysis, 1) age, 2) AO-OTA classification 3) Sex 4) Gustilo-Anderson grade. Statistical analysis was undertaken to identify predictors of unplanned reoperation. The mean age of patients at the time of injury was 60.8. Unplanned reoperation rate was 17.5%. Age and Gustilo-Anderson classification grade were both statistically significant predictors of unplanned reoperation. AO-OTA classification, Sex and Diabetes were not statistically significant factors associated with unplanned reoperation. Age and quality of soft tissue envelope are significant risk factors for unplanned reoperation. Patients with these risk factors may benefit from an alternative surgical approach.


Smile attractiveness of patients treated for congenitally missing maxillary lateral incisors as rated by dentists, laypersons, and the patients themselves.
Esthetic judgments can help dental professionals better understand how attentive people are to their own smiles and those of others. The purpose of this study was to evaluate the smile attractiveness of patients treated for maxillary lateral incisor agenesis compared with that of individuals with a complete dentition. Photographs were made of the smiles of patients with maxillary lateral incisor agenesis who were treated with space closure and teeth recontouring (n=26) or space opening and implants (n=20) and of a control group with a complete dentition (n=22). Both laypersons and dentists assessed smile attractiveness by using a visual analog scale. Patients and controls also assessed the level of satisfaction with their own smile. Assessments were performed twice, and the reliability of the method was determined with Cronbach α and intraclass correlation. Multifactorial and 1-way ANOVA were used to analyze smile attractiveness and participant satisfaction, followed by the Bonferroni post hoc test (α=.05). Attractiveness ratings by dentists and laypersons did not differ significantly among the study groups (P=.64). The ratings of male dentists and female laypersons differed significantly from those of other evaluators (P=.01). Patients with space closure and teeth recontouring were significantly more satisfied than controls (P=.002). No significant differences were found between the patients with implants and controls or between the patients with implants and those with space closure and teeth recontouring. The smiles of patients with maxillary lateral incisor agenesis were judged to be as attractive as those of the controls. Male dentists were the most critical raters, closely followed by female laypersons. All participants had high levels of satisfaction with their own smile; patients treated with space closure and teeth recontouring were the most satisfied.


Engineering allosteric communication.
Protein allostery is a vitally important protein function that has proven to be a vexing problem to understand at the molecular level. Allosteric communication is a hallmark of many protein functions. However, despite more than four decades of study the details regarding allosteric communication in protein systems are still being developed. Engineering of LacI and related homologues to confer alternate allosteric communication has shed light on the pre-requisites for the de novo design of allosteric communication. While the de novo design of an allosteric pathway and complementary functional surfaces has not been realized, this review highlights recent advances that set the stage for true predictive design for a given protein topology.


The impact of smoking on recurrence and progression of non-muscle invasive bladder cancer: a systematic review and meta-analysis.
Although smoking is a well-recognized causative factor of urothelial bladder cancer and accounts for 50% of cases, less is known about the prognostic significance of smoking on non-muscle invasive bladder cancer (NMIBC) prognosis. This systematic review and meta-analysis aimed to evaluate the effect of smoking on the risk of NMIBC recurrence and progression. We systematically searched Medline, Web of Science and Scopus databases for original articles published before October 2021 regarding the effect of smoking on NMIBC recurrence and progression. Information about smoking status and the number of events or odds ratio or hazard ratio for event-free survival must have been reported to include the study in the analysis. Quality In Prognosis Studies tool was utilized for the risk of bias assessment. We selected 64 eligible studies, including 28 617 patients with NMIBC with available data on smoking status. In a meta-analysis of 28 studies with 7885 patients, we found that smokers (current/former) were at higher risk for recurrence (OR = 1.68; 95% CI 1.34-2.09; P < 0.0001) compared to never smokers. Subgroup analysis of 2967 patients revealed that current smokers were at a 1.24 higher risk of recurrence (OR = 1.24; 95% CI 1.02-1.50; P = 0.03) compared to former smokers. A meta-analysis of the hazard ratio revealed that smokers are at higher risk of recurrence (HR = 1.31; 95%CI 1.15-1.48; P < 0.0001) and progression (HR = 1.18; 95%CI 1.08-1.29; P < 0.001) compared to never smokers. Detrimental prognostic effect of smoking on progression, but not for recurrence risk was also noted in the subgroup analysis of high-risk patients (HR = 1.30; 95%CI 1.09-1.55; P = 0.004) and BCG-treated ones (HR = 1.15; 95%CI 1.06-1.25; P < 0.001). In conclusion, patients with non-muscle invasive bladder cancer and a history of smoking have a worse prognosis regarding recurrence-free and progression-free survival compared to non-smokers.


Ureteral obstruction caused by a duplicated anomaly of inferior vena cava.
Developmental anomalies of inferior vena cava are a rare cause of ureteral obstruction. We report a case that presented with right upper ureteral obstruction that radiologically simulated a retrocaval ureter. An aberrant vessel, which caused obstruction of the right ureter was identified at operation and surgical relief of ureteral obstruction was performed. Inferior venocavography was performed postoperatively and disclosed an unusual incomplete duplication of inferior vena cava. Our findings suggested that ureteral obstruction by incompletely duplicated anomaly of the inferior vena cava should be included in the differential diagnosis of extrinsic ureteral obstruction.


Inappropriate antidiuretic hormone in children with viral meningitis.
Urinary excretion rates of antidiuretic hormone were determined by radioimmunoassay in children with bacterial (6) and viral (11) meningitis, and in children with other febrile illnesses (7). These values were compared to normal data obtained from 50 healthy, normally hydrated children ranging in age from 1 week to 9 years. Plasma sodium concentrations were measured in the sick children; urine osmolality and creatinine concentrations were measured in all children. Upon admission, all children with bacterial meningitis and 64% of those with viral meningitis had urinary antidiuretic hormone excretion rates greater than 2 S.D. above values obtained from age-matched controls. Fifty-seven percent of children with other febrile illnesses had similarly elevated antidiuretic hormone values; however, only in the bacterial and viral meningitis groups were antidiuretic hormone excretion rates inappropriate because they occurred when serum sodium concentrations were found to be normal or low normal (i.e., 136 +/- 2 mEq/L and 137 +/- 1 mEq/L, respectively). The average serum sodium in the group with other febrile illnesses was higher (146 +/- 5 mEq/L; p less than 0.05) and could represent an appropriate stimulus for antidiuretic hormone release. In spite of high levels of antidiuretic hormone, most viral meningitis patients did not concentrate their urine, probably because all except 2 were younger than 2 months of age. We conclude that viral meningitis, like bacterial meningitis, frequently is associated with inappropriate antidiuretic hormone secretion; however, most children with viral meningitis may be protected from developing hyponatremia because of their inability to concentrate their urine.


Elevated neutral protease activity in myelin from brains of patients with multiple sclerosis.
Incubation of human myelin at neutral pH resulted in the proteolytic conversion of the myelin-associated glycoprotein to a lower molecular weight derivative (dMAG) and the degradation of basic protein. The formation of dMAG occurred much more rapidly than the degradation of basic protein. The formation of dMAG and the degradation of basic protein both occurred significantly more rapidly in myelin preparations purified from brains of patients with multiple sclerosis than in preparations from control brain. The results suggest that this neutral protease associated with myelin may function in the pathogenesis of demyelinating diseases such as multiple sclerosis.


Purinergic signaling mediates oxidative stress in UVA-exposed THP-1 cells.
Ultraviolet A (UVA) radiation, the major UV component of solar radiation, can penetrate easily to the dermis, where it causes significant damage to cellular components by inducing formation of reactive oxygen species (ROS). On the other hand, extracellular ATP is released in response to various stimuli, and activates purinergic P2X7 receptor, triggering ROS production and cell death. Here, we examined the hypothesis that ATP release followed by activation of P2X7 receptor plays a role in UVA-induced oxidative cell damage, using human acute monocytic leukemia cell line THP-1. Indeed, UVA irradiation of THP-1 cells induced ATP release and activation of P2X7 receptor. Irradiated cells showed a rapid increase of both p67 phox in membrane fraction and intracellular ROS. Pretreatment with ecto-nucleotidase or P2X7 receptor antagonist blocked the UVA-initiated membrane translocation of p67 phox and ROS production. Furthermore, pretreatment with antioxidant or P2X7 receptor antagonist efficiently protected UVA-irradiated cells from caspase-dependent cell death. These findings show that autocrine signaling through release of ATP and activation of P2X7 receptor is required for UVA-induced stimulation of oxidative stress in monocytes.


The potential role of serum angiotensin-converting enzyme in coronavirus disease 2019.
To explore the clinical significance of serum angiotensin-converting enzyme (ACE) activity in coronavirus disease 2019 (COVID-19). In this retrospective study, a total of 136 consecutive patients with confirmed COVID-19 were recruited. Demographic and clinical data were recorded. The serum ACE activity was measured at baseline and during the recovery phase, and its relationship with clinical condition was analyzed. Of the 136 patients with confirmed COVID-19, the 16 severe patients were older and had a higher body mass index (BMI) and proportion of hypertension than the 120 nonsevere patients. In comparison to those of normal controls, the baseline serum ACE activities of subjects in the severe group and nonsevere group were decreased, with the lowest level in the severe group. However, the serum ACE activity increased in the recovery phase, and there were no significant differences among the severe group, nonsevere group and normal control group. Serum ACE activity could be used as a marker to reflect the clinical condition of COVID-19 since low activity was associated with the severity of COVID-19 at baseline, and the activity increased with the remission of the disease.


A Canadian experiment: the Institute of Neurosciences, Mental Health and Addiction. How to link up the brain via a virtual institute.
In June 2000, the Canadian government abolished the Medical Research Council of Canada, creating the Canadian Institutes of Health Research (CIHR) and appointing the internationally renowned geneticist Alan Bernstein as its first president. Bernstein and the CIHR Governing Council then elaborated the novel concept of 13 'virtual' CIHR institutes (see http://www.cihr.ca for further information). These institutes are not physical entities, but virtual organizations aiming to support researchers located in universities, hospitals and research centres across Canada. Following an open competition, December 2000 saw the appointment of a scientific director to lead the development of each institute. Rémi Quirion, a neuroscientist and Professor of Psychiatry based at the Douglas Hospital Research Centre of McGill University (Montreal, Canada) is the first Scientific Director of the Institute of Neurosciences, Mental Health and Addiction (INMHA). Here he summarizes the early developments and initiatives undertaken by his institute.


The role of fiber durability/biopersistence of silica-based synthetic vitreous fibers and their influence on toxicology.
This work summarizes what is known about the role of fiber durability/biopersistence of silica-based synthetic vitreous fibers (SVFs) and their influence on toxicology. The article describes the key processes leading from exposure to biological effect, including exposure, pulmonary deposition, clearance by various mechanisms, accumulation in the lung, and finally possible biological effects. The dose-dimension-durability paradigm is used to explain the key determinants of SVF toxicology. In particular, the key role played by the durability/biopersistence of long (>20microm) fibers is highlighted. Relevant literature on the prediction of in-vitro dissolution rates from chemical composition is summarized. Data from in-vitro and in-vivo durability/biopersistence tests show that these measures are highly correlated for long fibers. Both durability and biopersistence are correlated with the outcome of chronic inhalation bioassays. A schematic approach is presented for the design and testing of new SVFs with lower biopersistence.


The structure and function of presynaptic endosomes.
The function of endosomes and of endosome-like structures in the presynaptic compartment is still controversial. This is in part due to the absence of a consensus on definitions and markers for these compartments. Synaptic endosomes are sometimes seen as stable organelles, permanently present in the synapse. Alternatively, they are seen as short-lived intermediates in synaptic vesicle recycling, arising from the endocytosis of large vesicles from the plasma membrane, or from homotypic fusion of small vesicles. In addition, the potential function of the endosome is largely unknown in the synapse. Some groups have proposed that the endosome is involved in the sorting of synaptic vesicle proteins, albeit others have produced data that deny this possibility. In this review, we present the existing evidence for synaptic endosomes, we discuss their potential functions, and we highlight frequent technical pitfalls in the analysis of this elusive compartment. We also sketch a roadmap to definitely determine the role of synaptic endosomes for the synaptic vesicle cycle. Finally, we propose a common definition of synaptic endosome-like structures.


Pre-depletion of TRBC1+ T cells promotes the therapeutic efficacy of anti-TRBC1 CAR-T for T-cell malignancies.
Targeting T cell receptor β-chain constant region 1 (TRBC1) CAR-T could specifically kill TRBC1+ T-cell malignancies. However, over-expressed CARs on anti-TRBC1 CAR transduced TRBC1+ T cells (CAR-C1) bound to autologous TRBC1, masking TRBC1 from identification by other anti-TRBC1 CAR-T, and moreover only the remaining unoccupied CARs recognized TRBC1+ cells, considerably reducing therapeutic potency of CAR-C1. In addition, co-culture of anti-TRBC1 CAR-T and TRBC1+ cells could promote exhaustion and terminal differentiation of CAR-T. These findings provide a rationale for pre-depleting TRBC1+ T cells before anti-TRBC1 CAR-T manufacturing.


Evodia alkaloids suppress gluconeogenesis and lipogenesis by activating the constitutive androstane receptor.
The constitutive androstane receptor (CAR) is a key sensor in xenobiotic detoxification and endobiotic metabolism. Increasing evidence suggests that CAR also plays a role in energy metabolism by suppressing the hepatic gluconeogenesis and lipogenesis. In this study, we investigated the effects of two evodia alkaloids, rutaecarpine (Rut) and evodiamine (Evo), on gluconeogenesis and lipogenesis through their activation of the human CAR (hCAR). We found that both Rut and Evo exhibited anti-lipogenic and anti-gluconeogenic effects in the hyperlipidemic HepG2 cells. Both compounds can potently activate hCAR, and treatment of cells with hCAR antagonists reversed the anti-lipogenic and anti-gluconeogenic effects of Rut and Evo. The anti-gluconeogenic effect of Rut and Evo was due to the CAR-mediated inhibition of the recruitment of forkhead box O1 (FoxO1) and hepatocyte nuclear factor 4α (HNF4α) onto the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene promoters. In vivo, we showed that treatment of mice with Rut improved glucose tolerance in a CAR-dependent manner. Our results suggest that the evodia alkaloids Rut and Evo may have a therapeutic potential for the treatment of hyperglycemia and type 2 diabetes. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.


Interaction between P2Y and NMDA receptors in layer V pyramidal neurons of the rat prefrontal cortex.
In the first part of this study, monosynaptic excitatory postsynaptic potentials (EPSPs) in layer V of the rat prefrontal cortex were evoked by electrical stimulation of layer I. Recordings by intracellular sharp microelectrodes showed that EPSPs were concentration-dependently facilitated by the P2 receptor antagonistic ATP analogue 2-methylthio ATP (2-MeSATP), while ATP itself depressed the synaptic potentials. The inhibitory effect of ATP turned into facilitation in the presence of the adenosine A(1) receptor antagonist DPCPX. The 2-MeSATP-induced potentiation of EPSP amplitudes were prevented by the P2 receptor antagonists PPADS and Suramin. The EPSP was almost abolished by coapplication of the NMDA receptor antagonist AP-5 and the AMPA/kainate receptor antagonist CNQX. After blockade of the NMDA receptor-mediated part of the EPSP by AP-5, the stimulatory effect of 2-MeSATP disappeared. When NMDA or AMPA were pressure-applied onto pyramidal cells, only the NMDA-induced depolarization was potentiated by 2-MeSATP. In the second part of the study, NMDA-induced currents were measured by whole-cell patch-clamp pipettes. ATP, 2-MeSATP, UDP and UTP potentiated the response to NMDA, while ADP-beta-S was inactive. PPADS antagonized the effect of ATP. Synaptic isolation of pyramidal neurons by a Ca(2+)-free medium or tetrodotoxin did not alter the effect of ATP which, however, was markedly depressed when GTP in the micropipette was replaced by GDP-beta-S. These observations suggest that in layer V pyramidal neurons of the prefrontal cortex postsynaptically localized P2Y receptors interact with NMDA receptor-channels.


Electroporation-delivered transdermal neostigmine in rats: equivalent action to intravenous administration.
Transdermal electroporation has become one of the most promising noninvasive methods for drug administration, with greatly increased transport of macromolecules through the skin. The cecal-contracting effects of repeated transdermal electroporation delivery and intravenous administration of neostigmine were compared in anesthetized rats. The cecal contractions were detected with implantable strain gauge sensors, and the plasma levels of neostigmine were followed by high-performance liquid chromatography. Both intravenously and EP-administered neostigmine (0.2-66.7 μg/kg) increased the cecal contractions in a dose-dependent manner. For both the low doses and the highest dose, the neostigmine plasma concentrations were the same after the two modes of administration, while an insignificantly higher level was observed at a dose of 20 μg/kg after intravenous administration as compared with the electroporation route. The contractile responses did not differ significantly after the two administration routes. The results suggest that electroporation-delivered neostigmine elicits action equivalent to that observed after intravenous administration as concerning both time and intensity. Electroporation permits the delivery of even lower doses of water-soluble compounds through the skin, which is very promising for clinical practice.


Gallbladder wall thickening in dengue hemorrhagic fever: an ultrasonographic study.
This study attempts to investigate whether gallbladder wall thickening (GBWT) measured by ultrasonography can be used in children as a reliable criterion to predict the onset of severe dengue hemorrhage fever (DHF). In this prospective study, we performed ultrasound examinations focusing on the gallbladder wall and the presence of intraperitoneal free fluid in 48 mild DHF cases (grades I-II) and 48 severe cases (grades III-IV). GBWT varied between 1 mm and 8 mm with a mean of 3.77 mm +/- 2.04 mm. The mean value of DHF grades I and II (2.39 mm +/- 1.48 mm) is significantly lower than that of grades III and IV (5.14 mm +/- 1.54 mm), p < 0.001. GBWT exceeded 3 mm in only 16 of 48 (33.3%) grade I-II patients and in 45 of 48 (93.8%) grade III-IV patients. A significant positive correlation was apparent between GBWT and the severity of illness, p < 0.001. Patients with ascites have significantly thicker gallbladder walls than those without, p < 0.01. In clinically confirmed DHF cases, the sonographic finding of GBWT > 3 mm to 5 mm, with 93.8% sensitivity, can be used as a criterion indicating the need for admission and monitoring. A GBWT of > or = 5 mm, with 91.7% specificity, is useful as a criterion for identifying DHF patients at high risk of developing hypovolemic shock.


Antiproliferative homoscalarane sesterterpenes from two Madagascan sponges.
Dereplication of the antiproliferative ethyl acetate fraction of the Madagascan sponge Carteriospongia sp. led to the detection and isolation of the two known homoscalarane-type sesterterpenes 1 and 2. Investigation of a similar sponge containing closely related compounds afforded the four new antiproliferative homoscalarane sesterterpenes (3 and 5-7). The structures of all isolated compounds were elucidated by spectroscopic methods, including UV, IR and 1D and 2D NMR. Compounds 1, 3 and 5 displayed submicromolar antiproliferative activity against the A2780 ovarian cell line with IC50 values of 0.65, 0.26 and 0.28 μM, respectively, while compounds 6 and 7 showed moderate activity (4.5 and 8.7 μM, respectively). Compounds 3 and 5 also displayed anti-proliferative activity against the H522-T1 non-small cell lung and A2058 human melanoma cancer cell lines.


Severity, satisfaction and symptom resolution in patients of emergency medicine residents.
Emergency department patients treated by first and second year emergency medicine residents were compared with those treated by surgical interns and residents and medical interns and residents to see if emergency medicine residents are exposed to patients with problems that aid in teaching and whether there is a suitable correspondence between patient severity and clinical training level. The Emergency Department Surveillance System at The Johns Hopkins Health Services Research and Development Center was used to gather data. Results indicated emergency medicine residents were exposed to fewer severe medical causes than medical housestaff but saw a significantly greater number of severe surgical cases than surgical interns and residents. Patients reported greater satisfaction with nonemergency medicine residents. Regarding outcome, there was no significant difference among the clinician groups. For all the patients, pain and anxiety levels improved significantly. Although the findings may be specific to The Johns Hopkins Adult Emergency Department, they demonstrate the methods and motivation for examining the training experience offered emergency medicine residents.


Intravenous tacrolimus is a superior induction therapy for acute severe ulcerative colitis compared to oral tacrolimus.
Intravenous corticosteroid is the mainstay for managing acute severe ulcerative colitis, but one-third of patients do not respond to intravenous corticosteroid. Tacrolimus, a salvage therapy before colectomy, is usually orally administered, though its bioavailability is low compared intravenous administration. The efficacy of intravenous tacrolimus has not been widely studied. To determine the efficacy and safety of intravenous tacrolimus for the treatment of acute severe ulcerative colitis. Eighty-seven hospitalized acute severe ulcerative colitis patients were enrolled for a prospective cohort study between 2009 and 2017. Sixty-five patients received intravenous tacrolimus and 22 received oral tacrolimus. The primary outcome was the achievement of clinical remission within 2 weeks. Relapse and colectomy incidence and adverse events were assessed at 24 weeks. Response rates of both treatments exceeded 50% but were not significantly different. The remission rate was higher in intravenous tacrolimus compared with oral tacrolimus. At 24 weeks, oral and intravenous tacrolimus showed similar relapse-free survival rates; however, colectomy-free survival rates were higher in intravenous tacrolimus compared with oral tacrolimus. Patients receiving intravenous tacrolimus achieved superior remission and colectomy-free survival rates compared with patients receiving oral tacrolimus. Safety was similar between the two treatments.


Patient safety in the rehabilitation of children with spinal cord injuries, spina bifida, neuromuscular disorders, and amputations.
Pediatric patient safety continues to challenge both pediatricians and pediatric physiatrists. While there is a trend toward developing general patient safety initiatives, there is little research on pediatric patient safety. This article identifies major areas of general safety risk, with a focus on timely diagnosis and care coordination to prevent secondary complications that compromise health, function, and quality of life in pediatric neuromuscular disease, spinal cord disorders, and amputation.


Specific reduction of delta-opioid receptor binding in transfected NG108-15 cells.
We have recently identified and sequenced the cDNA for an opioid-binding protein with homologies to cell adhesion molecules (OBCAM) (Schofield, P. R., McFarlard, K. C., Hayflick, J. S., Wilcox, J. N., Cho, T. M., Roy, S., Lee, N. M., Loh, H. H., and Seeburg, P. H. (1989) EMBO J. 8, 489-495). Several lines of evidence using antibodies suggest that OBCAM may play a functional role in NG108-15 neuroblastoma x glioma cells, a useful model system that contains a homogeneous population of delta-opioid receptors. A logical extension of this research is to further test this hypothesis. As part of this study, NG108-15 cells were stably transfected with either sense or antisense sequences of a portion of pROM, the rat cDNA for OBCAM. [3H] Diprenorphine binding was greatly reduced in antisense-transfected cells relative to non-transfected cells. Binding to alpha 2-adrenergic, muscarinic, and insulin receptors was unaffected. These results further support the notion that OBCAM or its analogue is part (or a subunit) of an opioid receptor. Furthermore, our observation of an apparently specific reduction in opioid binding in these transfected cells suggests that they may provide a novel genetic approach for studying regulation of the opioid receptor in this defined cell line.


A negative dielectrophoresis and gravity-driven flow-based high-throughput and high-efficiency cell-sorting system.
We present a negative dielectrophoresis (n-DEP)-based cell separation system for high-throughput and high-efficiency cell separation. To achieve a high throughput, the proposed system comprises macro-sized channel and cantilever-type electrode (CE) arrays (L × W × H = 150 µm × 500 µm × 50 µm) to generate n-DEP force. For high efficiency, double separation modules, which have macro-sized channels and CE arrays in each separation module, are employed. In addition, flow regulators to precisely control the hydrodynamic force are allocated for each outlet. Because the hydrodynamic force and the n-DEP force acting on the target cell are the main determinants of the separation efficiency, we evaluate the theoretical amount of hydrodynamic force and n-DEP force acting on each target cell. Based on theoretical results, separation conditions are experimentally investigated. Finally, to demonstrate the separation performance, we performed the separation of target cells (live K562) from nontarget cells (dead K562) under conditions of low voltage (7Vp-p with 100 kHz) and a flow rate of 15 µL•min⁻¹, 6 µL•min⁻¹, and 8 µL•min⁻¹ in outlets 1, 2, and 3, respectively. The system can separate target cells with 95% separation efficiency in the case of the ratio of 5:1 (live K562:dead K562).


ACTH and prolactin synergistically and selectively regulate CYP17 expression and adrenal androgen production in human foetal adrenal organ cultures.
The essential role of ACTH on the growth and function of the human foetal adrenal (HFA) has long been recognized. In addition, many studies have suggested a role of the pituitary hormone prolactin (PRL) in the regulation of the HFA, but the effects of this hormone on steroidogenesis and gene expression are still unknown. Our objective was to investigate the effect of ACTH and PRL on the steroidogenic capacities of the HFA. In vitro/ex vivo experimental study. We used a hanging drop in vitro organ culture system. First trimester HFA samples were cultured for 14 days in basal conditions or treated with ACTH, PRL, or a combination of the 2 (3 to 11 replicates depending on the experiment). Steroids were measured by liquid chromatography/tandem mass spectrometry or immunoassay, gene expression by RT-qPCR, and protein expression by immunoblot. ACTH significantly increased corticosterone, cortisol, and cortisone production, both by itself and when used together with PRL. PRL stimulation by itself had no effect. Combined stimulation with ACTH + PRL synergistically and selectively increased adrenal androgen (DHEAS and Δ4-androstenedione) production and CYP17A1 expression in the HFA, while treatment with each single hormone had no significant effect on those steroids. These results have important implications for our understanding of the hormonal cues regulating adrenal steroidogenesis in the HFA during the first trimester in physiological and pathological conditions and warrant further studies to characterize the molecular mechanisms of converging ACTH and PRL signalling to regulate CYP17A1 expression.


[Correspondence analysis of association between types of unintentional injuries and influential factors among rural rear pupils].
To explore the association between types of unintentional injuries and influential factors among rural rear pupils. The multistage stratified sampling method was used to select the study participant and thus 594 rural pupils were sampled, 292 rear pupils were confirmed and measured with unintentional injuries and influential factors of rural rear pupils scale. Binary logistic regression analysis indicate that the risk facts related to unintentional injury were left-behind status (OR = 2.68, 95% CI 1.06-6.79), gender (OR = 5.12, 95% C2.68-9.79) and surrounding environment (OR = 3.44, 95% CI 1.37-8.70). Correspondence analysis showed living with father, middle personality and low age were related possibly with traffic accident injury. Living with grandparents, extrovert personality and elder pupils were related possibly with unintentional falls injury. Living with mother, introvert personality and middle-age pupils were related possibly with animmal injury. The personality, ages and guardian types of rural rear pupils are correlated with types of unintentional injuries.


Mechanisms of ketamine and its metabolites as antidepressants.
Treating major depression is a medical need that remains unmet by monoaminergic therapeutic strategies that commonly fail to achieve symptom remission. A breakthrough in the treatment of depression was the discovery that the anesthetic (R,S)-ketamine (ketamine), when administered at sub-anesthetic doses, elicits rapid (sometimes within hours) antidepressant effects in humans that are otherwise resistant to monoaminergic-acting therapies. While this finding was revolutionary and led to the FDA approval of (S)-ketamine (esketamine) for use in adults with treatment-resistant depression and suicidal ideation, the mechanisms underlying how ketamine or esketamine elicit their effects are still under active investigation. An emerging view is that metabolism of ketamine may be a crucial step in its mechanism of action, as several metabolites of ketamine have neuroactive effects of their own and may be leveraged as therapeutics. For example, (2R,6R)-hydroxynorketamine (HNK), is readily observed in humans following ketamine treatment and has shown therapeutic potential in preclinical tests of antidepressant efficacy and synaptic potentiation while being devoid of the negative adverse effects of ketamine, including its dissociative properties and abuse potential. We discuss preclinical and clinical studies pertaining to how ketamine and its metabolites produce antidepressant effects. Specifically, we explore effects on glutamate neurotransmission through N-methyl D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), synaptic structural changes via brain derived neurotrophic factor (BDNF) signaling, interactions with opioid receptors, and the enhancement of serotonin, norepinephrine, and dopamine signaling. Strategic targeting of these mechanisms may result in novel rapid-acting antidepressants with fewer undesirable side effects compared to ketamine.


Laboratory evaluation for Cushing's syndrome in psychiatric patients with cortisol nonsuppression following the overnight dexamethasone suppression test.
Laboratory tests used for the differential diagnosis of Cushing's syndrome have infrequently been employed in investigations of psychiatric patients who demonstrate hypothalamic-pituitary-adrenal (HPA) overactivity, and these laboratory procedures have not previously been applied for the specific purpose of further evaluating the endocrine function of psychiatric patients with serum cortisol nonsuppression following the standard 1-mg overnight Dexamethasone Suppression Test (DST). Low-dose (4 mg/48 hr) and high-dose (16 mg/48 hr) DSTs were administered to 10 psychiatric patients who exhibited cortisol nonsuppression after the overnight DST. Patients all had normal suppression to both the low-dose and high-dose tests. HPA overactivity in these patients was thus not sufficient to meet laboratory criteria for the diagnosis of Cushing's syndrome. Study results suggest that psychiatric patients with abnormal cortisol suppression following the 1-mg overnight DST are likely to have normal responses when assessed by standard laboratory protocols used for the diagnosis of Cushing's syndrome.


Disturbances of selected plasma proteins in hyperdynamic septic shock.
This study was performed on patients (n = 18) suffering from strictly defined hyperdynamic septic shock. Plasma factors (C-reactive protein, acid alpha 1-glycoprotein, fibrinogen, fibrinopeptide A, fibrinogen-fibrin split products, factor XIII, antithrombin III, complement factors C3 and C4, inter-alpha-trypsin-inhibitor and alpha 2-macroglobulin) measured during hyperdynamic septic shock were highly abnormal. The activation and consumption of clotting, fibrinolytic and complement factors due to system-specific proteinases (such as thrombokinase or plasminogen activators) seemed to be intensified by the nonspecific proteolytic activity of granulocytic proteinases probably released by the action of endotoxins. Possible therapeutic measures to maintain the endogeneous defence mechanism against enhanced proteolysis during septic shock are discussed.


Right internal thoracic artery remodeling 18 years after circumflex system grafting.
A 64-year-old man with left main coronary artery disease underwent myocardial revascularization. The left internal thoracic artery (LITA) was sutured to the left anterior descending artery, and the right internal thoracic artery (RITA) was sutured to the obtuse marginal artery. Eighteen years later, angina reoccurred. Catheterization revealed that both the coronary and the left subclavian arteries were occluded and that a patent RITA graft was maintaining the cardiac blood supply. The RITA graft evaluation revealed increased lumen diameters, suggestive of remodeling. The LITA was subsequently disconnected and sutured to the aorta as a free graft in order to restore appropriate myocardial blood flow. This case emphasizes the benefits of using a live graft for left coronary system grafting, which include long-term patency and flow-dependent remodeling.


Intrathoracic gastrojejunostomy for gastric outlet obstruction after Ivor Lewis esophagogastrectomy.
Gastric outlet obstruction after esophagogastrectomy with a drainage procedure is unusual, but when encountered, its management can be formidable. A Rous-en-Y intrathoracic gastrojejunostomy was created in a 74-year-old woman 2 years after Ivor Lewis esophagogastrectomy for benign disease to treat severe gastric outlet obstruction at the native pylorus.