High glucose and angiotensin II increase beta1 integrin and integrin-linked kinase synthesis in cultured mouse podocytes.
Alterations of integrin alpha3beta1 may play a role in the development of diabetic nephropathy. We have investigated the effects of high glucose and angiotensin II on the expression of integrin alpha3 and beta1, and whether these changes are associated with integrin-linked kinase (ILK) in cultured mouse podocytes. Integrin beta1 and ILK mRNA expression and protein production were rapidly up-regulated in a dose-dependent manner by high glucose and angiotensin II stimulation. ILK mRNA levels in the mouse podocytes exposed to 30 mmol/l glucose were 1.66, 1.89, and 1.28 times higher than those in control cells at 6, 24, and 72 h exposure, respectively. ILK mRNA levels in mouse podocytes exposed to 1 nM, 10 nM, and 100 nM angiotensin II for 6 h were 1.38, 1.55, and 1.93 times higher, respectively, than those in control cells. Angiotensin-II-induced integrin beta1 and ILK mRNA expression was significantly inhibited by treatment with losartan (100 muM). In addition, the up-regulation of ILK synthesis induced by these stimuli was related to beta1 integrin synthesis and increased ILK kinase activity. Cell adhesion assay displayed inhibitory effects when podocytes were exposed to high concentrations of angiotensin II. Interestingly, glucose and angiotensin II stimulation induced shrinkage of the cell body and elongation of the podocyte processes, a phenotype similar to that of immature podocytes. In addition, beta1 integrin showed higher levels of staining on both the cell membranes and the cell-cell contact areas. Thus, high glucose and angiotensin II may affect the regulation of the integrin-ILK system in podocytes; this system may therefore play a role in the pathogenesis of diabetic nephropathy and other renal diseases affecting podocytes.


Preventive and improvement effects of exercise training and supplement intake in white adipose tissues on obesity and lifestyle-related diseases.
Recent increases in the number of obese individuals and individuals suffering from lifestyle-related diseases, such as type 2 diabetes, that accompany obesity have become a serious social problem. White adipose tissue (WAT) is more than a mere organ for storage of energy; it is also a highly active metabolic and endocrine organ that secretes physiologically active substances collectively known as adipokines, including tumor necrosis factor-α and adiponectin. Dysregulated expression of adipokines in WAT that is hypertrophied by obesity has been closely associated with the phenomenon of insulin resistance. Therefore, WAT is currently considered to be one of the tissues that promote lifestyle-related diseases. Reduction of excess WAT that results from obesity is seen as an important strategy in preventing and improving lifestyle-related diseases. This review shows that exercise training as well as intake of supplements, such as polyphenols, is one strategy for this, because this regimen can result in reduction of WAT mass, which affects the expression and secretory response of adipokines.


Reconstitution of the glucose transporter from rat skeletal muscle.
As a step in the purification and characterization of the glucose transporter from rat skeletal muscle, we have reconstituted glucose transport activity in liposomes. Plasma membranes were prepared from skeletal muscle which display D-glucose reversible binding of cytochalasin B (10 pmol sites/mg protein; KD = 0.3 microM). Older rats gave a slightly lower specific activity and much lower yield of sites per g muscle than young rats. Glucose transport activity was reconstituted into liposomes by the freeze-thaw procedure using either plasma membranes directly or cholate-extracted membrane proteins; the latter gave a 50% higher specific activity. The reconstituted transport activity was stereospecific, saturable, and inhibited by cytochalasin B, phloretin, and mercuric chloride. The optimum cholate concentration for extraction and reconstitution of transport activity was about 1.5%, and the highest specific activity of reconstituted transport was seen only at low ratios of protein to lipid in the reconstitution. Chromatography on agarose lentil lectin and agarose ethanethiol doubled both the specific activity of reconstituted transport and the fraction of glucose uptake which was stereospecific. In all of these respects the results were similar to our results with the bovine heart transporter (T. J. Wheeler and M. A. Hauck, Biochim. Biophys. Acta 818, 171-182 (1985)). Our findings suggest that further purification procedures developed for the heart transporter may be applicable to the skeletal muscle transporter as well.


Mechanisms for ovariectomy-induced hyperalgesia and its relief by calcitonin: participation of 5-HT1A-like receptor on C-afferent terminals in substantia gelatinosa of the rat spinal cord.
Chronic treatment with calcitonin in osteoporotic patients alleviates the pain associated with this condition by an unknown mechanism. In ovariectomized rats that develop osteoporosis and hyperalgesia, we examined whether a functional change in serotonergic systems in the spinal dorsal horn was involved, using whole-cell recordings from substantia gelatinosa neurons in spinal cord slices and [(3)H]8-hydroxy-2(di-n-propylamino)tetralin ([(3)H]8-OH-DPAT) binding. Hyperalgesia could be attributed to the elimination of presynaptic inhibition by 5-HT of glutamatergic primary C-afferent terminals and an associated decrease in the density of [(3)H]8-OH-DPAT binding sites whose receptors are neither 5-HT(1A)- nor 5-HT(7)-subtype. These changes in serotonergic systems were restored after chronic treatment with calcitonin. Reversal of 5-HT receptor changes by calcitonin treatment may provide an explanation for its analgesic actions in patients.


MH1 domain of SMAD4 binds N-terminal residues of the homeodomain of Hoxc9.
Smad family proteins mediate signaling initiated by bone morphogenetic proteins (BMPs). Upon BMP stimulation, the Smads such as Smad4 can interact directly with Hox proteins and suppress their DNA-binding activity. Although the interaction between the MAD-homology 1 (MH1) domain of Smad4 and Hox was found to regulate the transcription activity of Hox proteins, the molecular mechanism is not well characterized and direct contact residues remain to be elucidated. In the present study, the interaction between the recombinant homeodomain (HD) of Hoxc9 and MH1 domain of Smad4 was investigated with the use of the GST pull-down assay, surface plasmon resonance (SPR) analysis as well as multidimensional nuclear magnetic resonance (NMR) techniques. The Hoxc9-HD was precipitated with the GST-fused Smad4-MH1 but not with GST alone, demonstrating a direct interaction between Hoxc9-HD and Smad4-MH1 in vitro. SPR measurement further confirmed a moderately strong interaction (K(d) approximately 400 nM) between these two domains. Moreover, NMR titration experiments showed that a strong and specific binding occurred between Smad4-MH1 and Hoxc9-HD. NMR triple-resonance experiments and backbone assignments revealed that the N-terminal arm of Hoxc9-HD, spanning the positive-charged DNA-binding segment of Arg190-Arg196, was intimately involved in the interaction with Smad4-MH1. Ala-substitutions of Arg190-Arg196 led to the loss of interaction between Hoxc9-HD and Smad4-MH1 in both GST-pull down assay and SPR analysis; further provided functional evidence for the critical role of this positive-charged region in binding to Smad4-MH1. This suggested that Smad4-MH1 could occupy one of the DNA binding sites of Hoxc9 and consequently inhibits its transcription activity. The above results are in good agreement and yield the first insight into the interaction between the homeodomain of Hox proteins and the conserved MH1 domain of Smad family proteins.


Psychosocial factors associated with HbA1c in adults with insulin pump-treated type 1 diabetes: a systematic review.
To identify currently available studies on the association between psychosocial factors and HbA1c in adults with insulin pump-treated type 1 diabetes, by performing a systematic review of the literature. MEDLINE, Embase, CINAHL and PsycINFO were searched for original studies on the association between psychosocial factors and HbA1c in ≥ 50 adult, non-pregnant, insulin pump users with type 1 diabetes. The search resulted in 1777 unique records, of which eight were eligible for inclusion. All identified studies were observational, with sample sizes ranging from 51 to 214. Seven different psychosocial factors were investigated in the eight studies. Study analysis suggested that HbA1c may be associated with diabetes numeracy and quality of life. There were no indications of associations between HbA1c and fear of hypoglycaemia or self-efficacy. Results regarding associations between HbA1c and coping style, diabetes distress and locus of control were inconsistent. This systematic review summarizes the currently limited information on the association between psychosocial factors and HbA1c during insulin pump therapy. The evidence base of the included studies was weak, and this review highlights the need for more research in these areas, with improved methodological and theoretical frameworks, including exploration of a broader spectrum of psychosocial variables and their potential association with HbA1c and other metabolic outcomes. (PROSPERO International prospective register of systematic reviews registration no: CRD42020145705).


Analysis of chemical and biological features yields mechanistic insights into drug side effects.
Side effects (SEs) are the unintended consequence of therapeutic treatments, but they can also be seen as valuable readouts of drug effects, resulting from the perturbation of biological systems by chemical compounds. Unfortunately, biology and chemistry are often considered separately, leading to incomplete models unable to provide a unified view of SEs. Here, we investigate the molecular bases of over 1,600 SEs by navigating both chemical and biological spaces. We identified characteristic molecular traits for 1,162 SEs, 38% of which can be explained using solely biological arguments, and only 6% are exclusively associated with the chemistry of the compounds, implying that the drug action is somewhat unspecific. Overall, we provide mechanistic insights for most SEs and emphasize the need to blend biology and chemistry to surpass intricate phenomena not captured in the molecular biology view.


Impact of continuity of care on cardiovascular disease risk among newly-diagnosed hypertension patients.
Several previous studies have noted benefits of maintaining continuity of care (COC), including improved patient compliance, decreased health care cost, and decreased incidence of hospitalization. However, the association of COC in hypertension patients with subsequent cardiovascular disease (CVD) risk is yet unclear. Therefore, we aimed to investigate the impact of COC on CVD risk among newly-diagnosed hypertension patients. We conducted a cohort with a study population consisted of 244,187 newly-diagnosed hypertension patients in 2004 from the Korean National Health Insurance Service database. The participants were then divided into approximate quartiles of COC index, and followed from 1 January 2007 until 31 December 2017. Cox proportional hazards models were used to evaluate the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for CVD risk according to quartiles. Compared to patients within the lowest quartile of COC index, those within the highest quartile of COC index had reduced risk for CVD (aHR 0.76, 95% confidence interval; CI 0.73-0.79), CHD (aHR 0.66, 95% CI 0.62-0.69) and stroke (aHR 0.84, 95% CI 0.80-0.88). COC among hypertension patients was associated with improved medication compliance and reduced risk of stroke and CVD. The importance of maintaining COC should be emphasized to reduce the risk of CVD among hypertension patients.


Environmental Risk Factors and Early-Life Exposures in Juvenile Idiopathic Arthritis: A Case-Control Study.
Juvenile idiopathic arthritis (JIA) is a heterogeneous group of disorders characterized by chronic arthritis in children with unknown etiology. Although research evaluating environmental or early-life exposures in JIA is scarce, there are data to suggest that infections, smoking exposure, and lack of breastfeeding play a role. This case-control study investigated the association of selected environmental and early-life risk factors with the development of JIA. JIA cases were identified at a major pediatric rheumatology outpatient clinic. Each case was asked to identify up to 3 healthy playmates of similar age and same sex to serve as controls. Parents/caregivers of cases and controls completed a questionnaire on selected environmental and early-life exposures. Conditional logistic regression adjusted for age and socioeconomic status was used to determine the odds ratio (OR) for developing JIA with 95% confidence intervals (95% CIs) for the playmate-matched design. Included in the study were 225 JIA cases and 138 controls. Compared to playmate-matched controls, preterm delivery (OR 1.8 [95% CI 1.2-2.7]) was associated with JIA. There was no association between JIA and household smoking or maternal prenatal smoking, breastfeeding, hospitalization with infection in the first year of life, daycare attendance before 6 years of age, household pets, or residential area prior to the onset of JIA. There was no association between the previously reported risk factors of smoking, early-life infection, or breastfeeding and development of JIA in this study. The association of preterm delivery with JIA needs to be further studied.


The long-term results of modified maxillomandibular advancement in Asian OSA patients.
Maxillomandibular advancement (MMA) surgery is considered a highly successful treatment for obstructive sleep apnea (OSA). Various modifications to the technique have been described. We aim to study the long-term results in Asian patients who underwent a modified MMA procedure intended to avoid bimaxillary protrusion and which involved four-quadrant bicuspid extractions with posterior maxillary alveolar setback. A review of operative logs from 2000 to 2003 was conducted to identify Asian patients who underwent modified MMA during that period, for treatment of moderate and severe OSA. Sleep indices and psychometric performances were prospectively analyzed. Eight Asian patients were included. The mean length of follow-up was 14.4 years (range: 13.0-16.5). Mean preoperative apnea-hypopnea index (AHI) was 48.9 (range: 19.0 to 84.8). Mean post-operative AHI was 31.6 (range: 6.2 to 79.5). This reduction was statistically significant (p<0.05). Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire (FOSQ) revealed that majority of the patients (75%) did not have excessive daytime somnolence and all patients had high FOSQ totalled scores (mean 17.7, range 11.8 to 20), indicating good functional performance. This series is the longest follow-up of an Asian cohort who underwent modified MMA. With a mean follow-up of 14.4 years, improvement in AHI is still observed but not at a degree as large as prior studies with shorter lengths of follow-up. The purported efficacy of MMA for Caucasian patients may not be reproducible in Asian patients and long-term sustainability of this treatment's efficacy requires rigorous evaluation.


Food provisioning results in functional, but not compositional, convergence of the gut microbiomes of two wild Rhinopithecus species: Evidence of functional redundancy in the gut microbiome.
The consumption of similar diets has led to the convergence of gut microbial compositions and functions across phylogenetically distinct animals. However, given the functional redundancy in gut microbiomes, it remains unclear whether synchrony occurs in their functions only and not in their composition, even within phylogenetically close animals consuming a similar diet. In this study, we collected fresh fecal samples from a Rhinopithecus roxellana population in April 2021 (before food provisioning) and June and December 2021 (after food provisioning) and used high-throughput sequencing methods (full-length 16S rRNA gene sequencing and metagenomes) to investigate changes in the gut microbiome due to food provisioning. Combining the results from our previous studies on a wild Rhinopithecus bieti population, we found that the artificial food provisions (e.g., apples, carrots, and peanuts) affected the gut microbiome, and synchrony occurred only in its functions and antibiotic resistance gene community in both Rhinopithecus species, reflecting its ecological functional redundancy. Given the current findings (e.g., depletion in probiotic microbes, dysbiosis in the gut microbial community, and changes in the antibiotic resistance gene profile), anthropogenic disturbances (e.g., food provisioning) would have potential negative effects on host health. Therefore, human activity in animal conservation should be rethought from the standpoint of gut microbial diversity.


White Light-Emitting Devices Based on Inorganic Perovskite and Organic Materials.
Perovskite-based materials have attracted considerable attention in photoelectric devices. In this paper, we report the one-step fabrication of spin-coated CsPbBr2.5I0.5 perovskite films doped with PAN (polyacrylonitrile) polymer. A red perovskite LED (PeLED) composite film was fabricated which featured a maximum luminance value of 657 cd/m² at 8 V. We fabricated white PeLEDs by combining hole transporting layer material emission, perovskite⁻polymer composite material PAN:CsPbBr2.5I0.5, and pure inorganic perovskite CsPbBr₃ as a luminescent layer. The maximum luminance of the device was 360 cd/m² at 7 V, and the color coordinate was (0.31, 0.36). We obtained an ideal white light-emitting device that paves the way for further development of white PeLEDs.


Yq deletions and AZF locus: molecular analysis in two fetuses with non familial homogeneous Yq rearrangements.
Cytogenetic and molecular analyses were carried out in two fetuses with de novo non mosaic dic (Y)(q11.2) and Yqsat. Molecular deletion of the region to which the AZF locus has been assigned was found in the first case.


The effect of vitamin D supplementation on mortality and intensive care unit admission of COVID-19 patients. A systematic review, meta-analysis and meta-regression.
The aim of this systematic review and meta-analysis was to investigate the effect of vitamin D supplementation on mortality and admission to intensive care unit (ICU) of COVID-19 patients. A systematic search of PubMed, Google Scholar, Embase, Web of Science and medRxiv with terms relative to vitamin D supplementation and COVID-19 was conducted on 26 March 2021. Comprehensive Meta-Analysis software was used for the quantitative assessment of data and random-effects model was applied. To investigate the association between the dose of vitamin D and the outcomes of interest, meta-regression analysis was performed. Two thousand and seventy-eight patients from nine studies with data on mortality were included (583 received vitamin D supplementation, while 1495 did not). Sixty-one (10.46%) individuals in the treated group died, compared to 386 (25.81%) in the non-treated group (odds ratio [OR]: 0.597; 95% CI: 0.318-1.121; p = 0.109). Eight hundred and sixty patients from six studies with data on ICU admission were included (369 received vitamin D supplementation, while 491 did not). Forty-five (12.19%) individuals in the treated group were admitted to ICU, compared to 129 (26.27%) in the non-treated group (OR: 0.326; 95% CI: 0.149-0.712; p = 0.005). No significant linear relationship between vitamin D dose and log OR of mortality or log OR of ICU admission was observed. This meta-analysis indicates a beneficial role of vitamin D supplementation on ICU admission, but not on mortality, of COVID-19 patients. Further research is urgently needed to understand the benefit of vitamin D in COVID-19.


D3CARP: a comprehensive platform with multiple-conformation based docking, ligand similarity search and deep learning approaches for target prediction and virtual screening.
Resource- and time-consuming biological experiments are unavoidable in traditional drug discovery, which have directly driven the evolution of various computational algorithms and tools for drug-target interaction (DTI) prediction. For improving the prediction reliability, a comprehensive platform is highly expected as some previously reported webservers are small in scale, single-method, or even out of service. In this study, we integrated the multiple-conformation based docking, 2D/3D ligand similarity search and deep learning approaches to construct a comprehensive webserver, namely D3CARP, for target prediction and virtual screening. Specifically, 9352 conformations with positive control of 1970 targets were used for molecular docking, and approximately 2 million target-ligand pairs were used for 2D/3D ligand similarity search and deep learning. Besides, the positive compounds were added as references, and related diseases of therapeutic targets were annotated for further disease-based DTI study. The accuracies of the molecular docking and deep learning approaches were 0.44 and 0.89, respectively. And the average accuracy of five ligand similarity searches was 0.94. The strengths of D3CARP encompass the support for multiple computational methods, ensemble docking, utilization of positive controls as references, cross-validation of predicted outcomes, diverse disease types, and broad applicability in drug discovery. The D3CARP is freely accessible at https://www.d3pharma.com/D3CARP/index.php.


Hyperreflective Foci in Age-Related Macular Degeneration are Associated with Disease Severity and Functional Impairment.
To analyze presence of hyperreflective foci (HRF) across different age-related macular degeneration (AMD) severities and examine its correlation with other structural and functional AMD features. Longitudinal, single-center, case-control study. One hundred and fifty-eight participants aged > 50 years old with varying AMD severities (including no AMD). Color fundus imaging was used to assess AMD severity and hyperpigmentation (PGM) presence. Subretinal drusenoid deposits (SDD) and HRF were detected on OCT volumes. The correlations of HRF with additional AMD features were evaluated using linear and logistic mixed-effects models. One study eye per participant underwent dark adaptation (DA) testing to measure rod intercept time (RIT) for structure function associations. Eyes were followed longitudinally and changes in AMD severity and RIT were measured relative to HRF presence. The primary outcome was presence of HRF, which was compared with presence of other AMD features and DA impairment. One hundred and fifty-eight participants (median baseline age of 73.1 [interquartile range (IQR) = 66-79] years) contributing 1277 eye visits were included. Hyperreflective foci (HRF) were detected more frequently in higher AMD severities. Hyperreflective-foci presence was significantly associated with PGM presence (odds ratio 832.9, P < 0.001) and SDD presence (odds ratio 9.42, P = 0.017). Eyes with HRF demonstrated significantly longer DA (median 27.1 [IQR = 16-40] minutes) than those without HRF (13.5 [10-22] minutes) but less than eyes with SDD only (40 [28-40] minutes). Highest RIT values were found in eyes with both HRF and SDD (40.0 [40-40] minutes). Age and HRF explained a similar proportion of RIT variability as age and SDD. Eyes that developed HRF demonstrated baseline RITs closer to eyes with HRF at baseline, compared with eyes that never developed HRF (29.1 [16-40], 38.5 [22-40] versus 13.1 [10-22] minutes; Kruskal-Wallis P < 0.001). The progressively increased presence of HRF in higher AMD severities, and its correlation with previously associated AMD biomarkers, suggests HRF is an important OCT feature adding to the understanding of disease progression. Hyperreflective foci presence was associated with delays in DA, indicating HRF is a marker for visual cycle impairment. Proprietary or commercial disclosure may be found after the references.


Comparative proteomic analysis reveals that caspase-1 and serine protease may be involved in silkworm resistance to Bombyx mori nuclear polyhedrosis virus.
The silkworm Bombyx mori is of great economic value. The B. mori nuclear polyhedrosis virus (BmNPV) is one of the most common and severe pathogens for silkworm. Although certain immune mechanisms exist in silkworms, most silkworms are still susceptible to BmNPV infection. Interestingly, BmNPV infection resistance in some silkworm strains is varied and naturally existing. We have previously established a silkworm strain NB by genetic cross, which is highly resistant to BmNPV invasion. To investigate the molecular mechanism of silkworm resistance to BmNPV infection, we employed proteomic approach and genetic cross to globally identify proteins differentially expressed in parental silkworms NB and 306, a BmNPV-susceptible strain, and their F(1) hybrids. In all, 53 different proteins were found in direct cross group (NB♀, 306♂, F(1) hybrid) and 21 in reciprocal cross group (306♀, NB♂, F(1) hybrid). Gene ontology and KEGG pathway analyses showed that most of these different proteins are located in cytoplasm and are involved in many important metabolisms. Caspase-1 and serine protease expressed only in BmNPV-resistant silkworms, but not in BmNPV-susceptible silkworms, which was further confirmed by Western blot. Taken together, our data suggests that both caspase-1 and serine protease play a critical role in silkworm resistance against BmNPV infection.


Friend or foe: the role of microRNA in chemotherapy resistance.
Chemotherapy has been widely used in treating cancer patients. Despite the tremendous progress in cancer treatment achieved during the last decades, drug resistance still accounts for most of the tumor relapses in chemotherapy-treated patients. Emerging evidence shows that microRNAs play an important role in regulating the drug sensitivity of tumor cells. However, the mechanism of microRNA-mediated drug resistance is not fully understood. Current data suggest that microRNAs can be categorized as oncogenic or tumor-suppressive based on their functions and targets. In tumor cells undergoing drug treatment, microRNAs can function either by decreasing expression of genes associated with multiple drug resistance or by promoting escape from apoptosis and inducing tumor stem cell development. This review aims to provide an updated understanding of the role of microRNAs in regulating chemotherapy resistance and a discussion of potential therapeutic applications.


NuMA1 promotes axon initial segment assembly through inhibition of endocytosis.
Axon initial segments (AISs) initiate action potentials and regulate the trafficking of vesicles between somatodendritic and axonal compartments. However, the mechanisms controlling AIS assembly remain poorly defined. We performed differential proteomics and found nuclear mitotic apparatus protein 1 (NuMA1) is downregulated in AIS-deficient neonatal mouse brains and neurons. NuMA1 is transiently located at the AIS during development where it interacts with the scaffolding protein 4.1B and the dynein regulator lissencephaly 1 (Lis1). Silencing NuMA1 or protein 4.1B by shRNA disrupts AIS assembly, but not maintenance. Silencing Lis1 or overexpressing NuMA1 during AIS assembly increased the density of AIS proteins, including ankyrinG and neurofascin-186 (NF186). NuMA1 inhibits the endocytosis of AIS NF186 by impeding Lis1's interaction with doublecortin, a potent facilitator of NF186 endocytosis. Our results indicate the transient expression and AIS localization of NuMA1 stabilizes the developing AIS by inhibiting endocytosis and removal of AIS proteins.


Translating psychosocial research findings into practice guidelines.
Evidence-based practice guidelines are increasingly used by healthcare professionals to guide patient care and effect positive patient outcomes. These guidelines are usually based on laboratory-based parameters and lack the psychosocial dimensions of patient care. The authors describe the process used by a hospital-based interdisciplinary team to successfully develop evidence-based psychosocial guidelines designed to foster hopefulness in pediatric patients with cancer, their families, and their healthcare providers. From these guidelines, 4 clinical care projects were developed and are described in this article.


Assessment of anti-nucleosome antibody (ANuA) isotypes for the diagnosis and prediction of systemic lupus erythematosus and lupus nephritis activity.
Our study aims to investigate the serum levels of anti-nucleosome antibody (ANuA) isotypes in patients with systemic lupus erythematosus (SLE) and clarify ANuA isotypes that may diagnose and predict SLE. We detected anti-nucleosome antibodies (ANuA) in the serum from 120 patients with SLE, 99 patients suffering from other autoimmune diseases (OAD), and 50 healthy controls by performing IgG-, IgA-, and IgM-specific ELISAs. The serum levels of total anti-nuclear antibodies (ANA IgG), ANuA IgG subclasses (IgG1, IgG2, IgG3, and IgG4), anti-dsDNA antibodies, and the avidities of ANA IgG were also analysed using ELISAs. The levels of three ANuA isotypes (IgG, IgA, and IgM) were significantly higher in patients with SLE than in patients with OAD and healthy controls (p < 0.05). Moreover, the concentrations of ANuA isotypes increased in the active SLE and lupus nephritis (LN) groups and in patients with SLE presenting high-avidity IgG ANA (p < 0.05). Furthermore, ANuA isotype levels decreased significantly with drug therapy, while anti-dsDNA IgG levels decreased with the same trend. Additionally, ANuA isotypes were positively related to the SLEDAI (SLE Disease Activity Index) score, RAI (relative avidity index) of high-avidity IgG ANAs, and serum anti-dsDNA IgG levels. Last, the sensitivity and specificity values for SLE were 83.33 and 96.67% for ANuA IgG, 85.83 and 93.33% for ANuA IgA, and83.33 and 86.67% for ANuA IgM, respectively. The sensitivity and specificity values for LN were 61.67 and 96.67% for ANuA IgG, 49.17 and 96.67% for ANuA IgA, and 52.50 and 96.67% for ANuA IgM, respectively. In conclusion, we evaluated whether ANuA isotypes represent a diagnostic tool to predict SLE activity and define subsets of patients with LN.


Inhibition of growth of Aspergillus flavus and Trichoderma viride by peanut embryos.
Growth of Aspergillus flavus and Trichoderma viride on agar media was inhibited around embryos of green peanut seeds but not around embryos of cured seeds, intact peanut seeds, or testae. Both fungi were able to colonize intact seeds and testae. Substances inhibitory to A. flavus and T. viride were extracted with acetone from cotyledons of freshly harvested peanut seeds. Four compounds inhibitory to A. flavus were detected in crude acetone extracts. Three of the compounds demonstrated properties of phenolics. Results of this study suggest that inhibitory compounds in peanut cotyledons may play a role in protecting the peanut embryo from fungal infection.


Structural brain correlates of fatigue in older adults with and without Parkinson's disease.
Fatigue is one of the most common and disabling nonmotor symptoms seen in Parkinson's disease (PD) and is also commonly seen in healthy older adults. Our understanding of the etiology of fatigue in older adults with or without PD is limited and it remains unclear whether fatigue in PD is specifically related to PD pathology. The objective of this study was thus to determine whether fatigue in PD was associated with structural changes in gray or white matter and explore whether these changes were similar in older adults without PD. Magnetic resonance imaging (T1 weighted) and diffusion tensor imaging were performed in 60 patients with PD (17 females; age = 67.58 ± 5.51; disease duration = 5.67 ± 5.83 years) and 41 age- and sex- matched healthy controls. FSL image processing was used to measure gray matter volume, fractional anisotropy, and leukoariosis differences. Voxel-based morphometry confirmed gray matter loss across the dorsal striatum and insula in the PD patient cohort. PD patients with fatigue had reduced gray matter volume in dorsal striatum relative to PD patients without fatigue (P < 0.05 False Discovery Rate corrected). No significant fatigue-related structural atrophy was found in controls. There were no areas of significant fractional anisotropy differences between high and low fatigue subjects in either the PD or non-PD groups. Control participants with high fatigue, but not PD, showed significantly greater total leukoariosis volumes (p = 0.03). Fatigue in PD is associated with unique structural changes in the caudate and putamen suggesting fatigue in PD is primarily related to PD pathology, particularly in the dorsal striatum, and not simply a consequence of aging.


New insights into the hemodynamics of pulmonary homograft patients under stress echocardiography: The contribution of pressure recovery.
The importance of pulmonary artery pressure recovery (PR) in patients with Ross procedures in whom a homograft substitutes the resected pulmonary valve, is unknown. The aim of the study was to evaluate the occurrence and extent of PR in the pulmonary artery in 65 asymptomatic patients with pulmonary homograft after Ross surgery during rest and exercise. Stress echocardiography was performed in 65 pulmonary homograft patients and 31 controls with native pulmonary valves up to 75 W. Right ventricular systolic pressure (RVSP), transvalvular flow, mean pressure gradient (Pmean ), valve resistance, and RV stroke work were determined in the exercise (max. 75 W) and recovery phases in increments of 25 W each. Pulmonary homografts demonstrated significantly elevated Pmean compared to controls at all stages. When considering pressure recovery (absolute and relative PR at rest 3.8 ± 1.8 mm Hg, 42.6 ± 7.2%, respectively) and transvalvular energy loss (EL; at rest 4.5 ± 4.3 mm Hg) the homograft hemodynamics reached the level of controls. In a subgroup of patients with tricuspid regurgitation, resting RVSP was the same in homograft patients and controls (21.3 ± 6.1 vs. 20.4 ± 6.3, p = .62), despite significant different Pmax values. Ross patients with pulmonary homograft showed systematically increased hemodynamic parameters compared to normal pulmonary valves. These differences were abolished when PR was considered for homograft patients. The equality of RVSP values at rest in both groups shows non-invasive evidence for PR in the pulmonary system after homograft implantation. Therefore, PR appears to be an important measure in calculating the actual hemodynamics in pulmonary homografts.


Regulation of hypoxia inducible factor-1 by nitric oxide in contrast to hypoxia in microvascular endothelium.
Hypoxia activates the transcription factor, hypoxia inducible factor-1 (HIF-1). Besides hypoxia, HIF-1 can be activated under normoxic conditions by nitric oxide. The signal transduction pathways involved in HIF-1alpha stabilization, HIF-1 DNA binding and transactivation by NO and hypoxia in microvascular endothelium remains unknown. We report that protein phosphorylation is involved in HIF-1 activation during hypoxia and NO. The phosphatidylinositol 3-kinase (PI-3K)/Akt pathway has differential effects on HIF-1 activation by hypoxia and NO. Our data indicate that the PI-3K/Akt pathway is insufficient for HIF-1alpha induction by hypoxia. The lipid and protein phosphatase activities of PTEN also appear to be involved in regulation of HIF-1alpha by NO.


Integrated multi-omics reveals the beneficial role of chlorogenic acid in improving the growth performance and immune function of immunologically stressed broilers.
Intensive production can cause immunological stress in commercial broilers. Chlorogenic acid (CGA) regulates the intestinal microbiota, barrier function, and immune function in chickens. As complex interrelations regulate the dynamic interplay between gut microbiota, the host, and diverse health outcomes, the aim of this study was to elucidate the immunoregulatory mechanisms of CGA using multi-omics approaches. A total of 240 one-day-old male broilers were assigned to a 2 × 2 factorial design with 2 CGA levels (0 or 500 mg/kg) either with or without dexamethasone (DEX) injection for a 21-day experimental period. Therefore, there were 4 dietary treatments: control, DEX, CGA, and DEX + CGA, with 6 replicates per treatment. CGA supplementation improved (P < 0.05) growth performance, jejunal morphology, jejunal barrier function, and immune function in DEX-treated broilers. Moreover, in DEX + CGA-treated broilers, the increase in gut microbiome diversity (P < 0.05) was consistent with a change in taxonomic composition, especially in the Clostridiales vadin BB60_group. Additionally, the levels of short-chain fatty acids increased remarkably (P < 0.01) after CGA supplementation. This was consistent with the Kyoto Encyclopedia of Genes and Genomes analysis results that the "pyruvate fermentation to butanoate" pathway was more enriched (P < 0.01) in the DEX + CGA group than in the DEX group. Proteomics revealed that CGA treatment increased the expression of several health-promoting proteins, thymosin beta (TMSB4X) and legumain (LGMN), which were verified by multiple reaction monitoring. Metabolomics revealed that CGA treatment increased the expression of health-promoting metabolites (2,4-dihydroxy benzoic acid and homogentisic acid). Proteomic and metabolic analyses showed that CGA treatment regulated the peroxisome proliferator-activated receptor (PPAR) and mitogen-activated protein kinase (MAPK) pathways. Western blotting results support these findings. Pearson's correlation analyses showed correlations (P < 0.01) between altered immune function, jejunal barrier function, different microbiota, proteins, and metabolites parameters. Overall, our data indicate that CGA treatment increased growth performance and improved the immunological functions of DEX-treated broilers by regulating gut microbiota and the PPAR and MAPK pathways. The results offer novel insights into a CGA-mediated improvement in immune function and intestinal health.


Humoral immune responses against gonadotropin releasing hormone elicited by immunization with phage-peptide constructs obtained via phage display.
Phage display is based on genetic engineering of phage coat proteins resulting in fusion peptides displayed on the surface of phage particles. The technology is widely used for generation of phages with novel characteristics for numerous applications in biomedicine and far beyond. The focus of this study was on development of phage-peptide constructs that stimulate production of antibodies against gonadotropin releasing hormone (GnRH). Phage-peptide constructs that elicit production of neutralizing GnRH antibodies can be used for anti-fertility and anti-cancer applications. Phage-GnRH constructs were generated via selection from a phage display library using several types of GnRH antibodies as selection targets. Such phage constructs were characterized for sequence similarities to GnRH peptide and frequency of their occurrence in the selection rounds. Five of the constructs with suitable characteristics were tested in mice as a single dose 5×10(11) virions (vir) vaccine and were found to be able to stimulate production of GnRH-specific antibodies, but not to suppress testosterone (indirect indicator of GnRH antibody neutralizing properties). Next, one of the constructs was tested at a higher dose of 2×10(12) vir per mouse in combination with a poly(lactide-co-glycolide) (PLGA)-based adjuvant. This resulted in multifold increase in GnRH antibody production and significant reduction of serum testosterone, indicating that antibodies produced in response to the phage-GnRH immunization possess neutralizing properties. To achieve optimal immune responses for desired applications, phage-GnRH constructs can be modified with respect to flanking sequences of GnRH-like peptides displayed on phage. Anticipated therapeutic effects also might be attained using optimized phage doses, a combination of several constructs in a single treatment, or application of adjuvants and advanced phage delivery systems.


Various putative neurotransmitters affect growth hormone (GH) release in rats with anterolateral hypothalamic deafferentation of the medial basal hypothalamus: evidence for mediation by a GH-releasing factor.
Anterolateral deafferentation of the rat medial basal hypothalamus was used to eliminate most of the somatostatinergic innervation of the stalk-median eminence while leaving a functional system producing GH-releasing factor (GHRF) in the partially deafferented hypothalamus. One week after the operation, the rats were anesthetized, the third ventricle was cannulated, and various putative neurotransmitters were infused for 5 min. Plasma GH levels were measured between 10 and 25 min after infusion. When infused into the third ventricle, acetylcholine (50 micrograms), substance P (5 micrograms), dopamine (5 micrograms), and norepinephrine (2.5 micrograms) increased plasma GH levels in the deafferented rats but not in the controls, while 5-hydroxytryptamine (5 micrograms) caused a rise of plasma GH levels in both groups. Histamine (5 micrograms) failed to alter GH in any of the groups. We suggest that acetylcholine, substance P, norepinephrine and dopamine, but not histamine, may increase the secretion of GHRF acting either directly upon the GHRF cells or on neural circuits impinging upon them.


Top tips for PhD thesis examination: nurse clinicians, researchers and novices.
Interestingly, there are very few guidelines in the literature to assist novice nurse PhD examiners. In this paper, we aim to provide information to nurses, researchers or early career academics who have little experience in assessing a university thesis. The article provides background information about recent changes in the university sector; overviews some research on experienced examiners views; presents factors that differentiate between high and low quality PhD theses; and outlines some pointers that may be useful when marking at the doctoral level.


Static and dynamic changes of intrinsic brain local connectivity in internet gaming disorder.
Studies have revealed that intrinsic neural activity varies over time. However, the temporal variability of brain local connectivity in internet gaming disorder (IGD) remains unknown. The purpose of this study was to explore the alterations of static and dynamic intrinsic brain local connectivity in IGD and whether the changes were associated with clinical characteristics of IGD. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed on 36 individuals with IGD (IGDs) and 44 healthy controls (HCs) matched for age, gender and years of education. The static regional homogeneity (sReHo) and dynamic ReHo (dReHo) were calculated and compared between two groups to detect the alterations of intrinsic brain local connectivity in IGD. The Internet Addiction Test (IAT) and the Pittsburgh Sleep Quality Index (PSQI) were used to evaluate the severity of online gaming addiction and sleep quality, respectively. Pearson correlation analysis was used to evaluate the relationship between brain regions with altered sReHo and dReHo and IAT and PSQI scores. Receiver operating characteristic (ROC) curve analysis was used to reveal the potential capacity of the sReHo and dReHo metrics to distinguish IGDs from HCs. Compared with HCs, IGDs showed both increased static and dynamic intrinsic local connectivity in bilateral medial superior frontal gyrus (mSFG), superior frontal gyrus (SFG), and supplementary motor area (SMA). Increased dReHo in the left putamen, pallidum, caudate nucleus and bilateral thalamus were also observed. ROC curve analysis showed that the brain regions with altered sReHo and dReHo could distinguish individuals with IGD from HCs. Moreover, the sReHo values in the left mSFG and SMA as well as dReHo values in the left SMA were positively correlated with IAT scores. The dReHo values in the left caudate nucleus were negatively correlated with PSQI scores. These results showed impaired intrinsic local connectivity in frontostriatothalamic circuitry in individuals with IGD, which may provide new insights into the underlying neuropathological mechanisms of IGD. Besides, dynamic changes of intrinsic local connectivity in caudate nucleus may be a potential neurobiological marker linking IGD and sleep quality.


Primary clear cell adenocarcinoma of the vagina not associated with diethylstilbestrol: A case report.
Primary vaginal cancers are rare and clear cell adenocarcinoma is a malignant tumor that is all the more rare when the woman has not been exposed in utero to synthetic diethylstilboestrol (DES). We report the case of a 60-year-old woman with a history of balanced essential hypertension and partial mastectomy for neoplasia, who presented with a recurrent left inguinal adenopathy. Clinical examination revealed a 3 cm bulging lesion of the anterior vaginal wall in the lower third with indurated left inguinal adenopathy. Biopsy of the nodule showed an invasive clear cell adenocarcinoma. The extension bialn is negative and the multidisciplinary decision is to perform a partial colpectomy with bilateral inguinal curage. The patient is currently undergoing radiochemotherapy. This is a rare case with a poor prognosis. A poor response to adjuvant therapy with a high frequency of distant metastases is reported in the literature. Due to the rarity of this pathology, individual experience based on case reports is the main source of information. The most effective mode of treatment therefore remains unknown and depends on patient-specific factors such as tumor size, surgeon and oncologist team experiences.


The elimination of cross-infection in dental practice--a 5-year follow-up.
A survey in 1983 showed that 16% of general dental practitioners in the Lothian Region wore operating gloves when treating patients; 9% wore them continually and 7% only when performing dento-alveolar surgery. Twelve per cent replied that they would not consider wearing operating gloves and 72% stated that they might consider their use. A similar survey has now been completed 5 years later, involving practitioners in the Lothian and Borders regions. This shows that 163 (97%) of the 168 practitioners who replied now wear operating gloves; 51% restrict their use to the treatment of 'potentially infectious patients' and dento-alveolar surgery; 46% wear them continually. The main objections given to wearing gloves continually were loss of tactile sensation (67%) and cost (13%). The most difficult task to perform wearing gloves was root canal therapy (56%). The majority of practitioners (84%) believed that gloves reduced the dangers of cross-infection. The methods stated to be available for instrument sterilisation in 99.5% of practices were acceptable. This paper proposes that to eliminate cross-infection and protect the dental practitioner, operating gloves should be worn when treating all patients.


Cold hardiness and supercooling along an altitudinal gradient in andean giant rosette species.
Factors affecting supercooling capacity and cold hardiness were investigated in leaves of ten giant rosette species of the genus Espeletia (Compositae). These species grow along a 2,800-4,200 m elevation gradient in the Venezuelan Andes. In this high tropical environment, freezing frequently occurs every night, particularly above 3,300 m, but lasts for only a few hours. Supercooling capacty is linearly related to leaf water potential (Ψ L ) in all species; however supercooling is more responsive to Ψ L changes in Espeletia species from high paramos. The rate of change in the species-specific supercooling point and the rate of change of average annual minimum temperature along the elevation and climatic gradient follow the same trend (approximately -0.6 K per 100 m elevation). At a given elevation, the expanded leaves of the different species tend to supercool 8-10 K below minimum air temperatures. Experimentally-induced freezing was accompanied by the formation of intracellular ice and tissue damage. The relative apoplastic water content (RAWC) of the leaves, which may influence the ice nucleation rate or the facility by which ice propagates, was determined by pressure-volume methods. Species from higher sites tend to exhibit lower RAWC (2%-7%) than species from lower sites (7%-36%). A causal relationship between supercooling capacity and RAWC is suggested. In the high tropical Andes, the temperature oxotherm plateau of Espeletia leaves seems to be sufficiently fow to avoid freezing.


Characterization of E121K mutation of D-amino acid oxidase - Insights into mechanisms leading to amyotrophic lateral sclerosis.
D-amino acid oxidase (DAO) maintains the intracellular d-serine level which modulates the activity of the N-methyl-d-aspartate receptor and its dysfunction has been linked to several neurodegenerative disorders. In targeted next-generation sequencing study by our group, E121K mutation in DAO was associated with amyotrophic lateral sclerosis (ALS) in patients from India. However, variations in molecular mechanisms caused by this mutation which leads to ALS have not been studied. Hence, we carried out comparative biophysical characterization and assay studies of the wildtype- and mutant E121K-DAO. We observed that the purified E121K-DAO was inactive and exhibited a lower affinity for the FAD cofactor and benzoate inhibitor. Structural studies revealed that the E121K mutant has higher beta-sheet content, melting temperature, and oligomeric states compared to the wildtype. Kinetic study of aggregation of the variants using thioflavin-T confirmed that the E121K-DAO was more prone to aggregation. Microscopic visualization showed that the aggregation proceeds through an intermediate step involving the formation of fibrillar structures in the E121K mutant. Our results give insights into the underlying mechanisms leading to ALS pathogenesis.


Localization and characterization of glutathione peroxidase (GPx) in boar accessory sex glands, seminal plasma, and spermatozoa and activity of GPx in boar semen.
Boar ejaculate owes its characteristic large volume mainly to accessory sex gland (ASG) secretions. These are main contributors to the protective functions of seminal plasma, especially against oxidative damage. Numerous antioxidants have been detected in ASG secretions, and, respectively, in seminal plasma. However, as regards one key antioxidant protector -- the Se-dependent enzyme glutathione peroxidase (GPx) -- there is no agreement yet among researchers as to its presence in boar seminal plasma. Nevertheless, the beneficial effect of dietary Se supplementation on male fertility has been widely recognized. The aim of the present study was to investigate the localization and characterization of GPx in boar ASGs, seminal plasma, and spermatozoa, as well as to evaluate GPx activity in boar semen. Immunohistochemical assays demonstrated GPx presence in the epithelial cells, vacuole membranes, and vascular endothelium of boar seminal vesicle, prostate and bulbourethral glands. Western blot analysis demonstrated the presence of a monomer form of GPx with MW 20 kDa in lysates from seminal vesicle, prostate, bulbourethral glands, and spermatozoa, but not in seminal plasma. Surprisingly, peroxidase activity detected in seminal plasma from normal ejaculates was nearly three times as high as in spermatozoa. Our findings confirmed the presence of immunoreactive GPx in the boar reproductive tract, while further investigation is still warranted to uncover the exact protein forms involved and their function.


Diarrhoea in children: an interface between developing and developed countries.
Despite much progress in the understanding of pathogenesis and of management, diarrhoeal illnesses remain one of the most important causes of global childhood mortality and morbidity. Infections account for most illnesses, with pathogens employing ingenious mechanisms to establish disease. In the developed world, an upsurge in immune-mediated gut disorders might have resulted from a disruption of normal bacterial-epithelial cross-talk and impaired maturation of the gut's immune system. Oral rehydration therapies are the mainstay of management of gastroenteritis, and their composition continues to improve. Malnutrition remains the major adverse prognostic indicator for diarrhoea-related mortality, emphasising the importance of nutrition in early management. Drugs are of little use, except for specific indications although new agents that target mechanisms of secretory diarrhoea show promise, as do probiotics. However, preventive strategies on a global scale might ultimately hold the greatest potential to reduce the burden of diarrhoeal disease. These strategies include vaccines and, most importantly, policies to address persisting inequalities between the developed and developing worlds with respect to nutrition, sanitation, and access to safe drinking water.


Computed tomography and neurological soft signs in obsessive-compulsive disorder.
Computed tomography was used to compare the following three groups: obsessive-compulsive disorder (OCD) patients with high scores on a soft neurological sign examination, OCD patients with low soft neurological sign scores, and control subjects. Neuranatomical structures were measured using quantitative volumetric analysis. OCD patients with high soft sign scores had significantly increased ventricular volumes compared with OCD patients with low soft sign scores and control subjects. Caudate and lenticular nucleus volumes did not differ between groups.


The end of ice I.
The appearance of ice I in the smallest possible clusters and the nature of its phase coexistence with liquid water could not thus far be unraveled. The experimental and theoretical infrared spectroscopic and free-energy results of this work show the emergence of the characteristic hydrogen-bonding pattern of ice I in clusters containing only around 90 water molecules. The onset of crystallization is accompanied by an increase of surface oscillator intensity with decreasing surface-to-volume ratio, a spectral indicator of nanoscale crystallinity of water. In the size range from 90 to 150 water molecules, we observe mixtures of largely crystalline and purely amorphous clusters. Our analysis suggests that the liquid-ice I transition in clusters loses its sharp 1st-order character at the end of the crystalline-size regime and occurs over a range of temperatures through heterophasic oscillations in time, a process without analog in bulk water.


Cerebral Hemodynamic Profile in Ischemic and Hemorrhagic Brain Injury Acquired During Pediatric Extracorporeal Membrane Oxygenation.
To describe the cerebral hemodynamic profiles associated with ischemic and hemorrhagic brain injury during neonatal and pediatric extracorporeal membrane oxygenation. A retrospective cohort study. Tertiary PICU. Forty-seven neonatal and pediatric patients (0-15 yr of age) placed on extracorporeal membrane oxygenation from January 2014 to December 2018. Continuous monitoring of mean arterial pressure and cerebral tissue oxygen saturation was conducted through entire extracorporeal membrane oxygenation run. Wavelet analysis was performed to assess changes in cerebral autoregulation and to derive pressure-dependent autoregulation curves based on the mean arterial pressure and cerebral tissue oxygen saturation data. Patients were classified into three brain injury groups: no-injury, ischemic injury, and hemorrhagic injury based on neuroimaging results. No-injury patients (n = 23) had minimal variability in the autoregulation curve over a broad range of blood pressure. Ischemic injury (n = 16) was more common than hemorrhagic injury (n = 8), and the former was associated with increased mortality and morbidity. Ischemic group showed significant abnormalities in cerebral autoregulation in the lower blood pressure range, suggesting pressure-dependent cerebral perfusion. Hemorrhagic group had highest average blood pressure as well as the lowest cerebral tissue oxygenation saturation, suggesting elevated cerebral vascular resistance. Mean heparin dose during extracorporeal membrane oxygenation was lower in both ischemic and hemorrhagic groups compared with the no-injury group. This study outlines distinct differences in underlying cerebral hemodynamics associated with ischemic and hemorrhagic brain injury acquired during extracorporeal membrane oxygenation. Real-time monitoring of cerebral hemodynamics in patients acquiring brain injury during extracorporeal membrane oxygenation can help optimize their management.


Systemic lupus erythematosus: an unusual cause of cardiac tamponade in a young man.
Although pericarditis and pericardial effusion are common cardiac complications of systemic lupus erythematosus (SLE), cardiac tamponade is a very rare initial manifestation of this disease. We describe a case of a young male patient in whom cardiac tamponade secondary to a loculated pericardial effusion was the presenting symptom of SLE.


Endocervical glandular involvement, positive endocervical surgical margin and multicentricity are more often associated with high-grade than low-grade squamous intraepithelial lesion.
The aim of this study was to compare the relative frequencies of endocervical glandular involvement (EGI), multicentricity, positive endocervical surgical margins (ESM) and positive vaginal surgical margins (VSM), and adenocarcinoma in situ of the cervix (AIS) between high-grade and low-grade squamous intraepithelial lesions (HSIL and LSIL, respectively). We identified 238 patients with squamous intraepithelial lesions/cervical intraepithelial neoplasia (CIN) who were treated by loop electrocautery excision (LEEP) or conventional cold-knife conization (CKC). A total of 223 (72 [32.3%] LSIL/CIN I; 85 [38.1%] HSIL/CIN II; 66 [29.6%] HSIL/CIN III; and 151 [67.7%], HSIL/CIN II + III) LEEP/CKC slides were histologically reviewed. The frequencies of EGI, positive ESM, and multicentricity were significantly higher in the HSIL/CIN II + III group than in the LSIL/CIN I group (P = 0.001, 0.001, and 0.025, respectively). Eighteen of the 72 (25%) LSIL/CIN I patients, 44 of the 85 (51.8%) HSIL/CIN II patients, and 60 of the 66 (90.9%) HSIL/CIN III patients (P = 0.001) showed EGI. In four of the 72 (5.6%) LSIL/CIN I patients, 18 of the 85 (21.2%) HSIL/CIN II patients, and 42 of the 66 (63.6%) HSIL/CIN III patients (P = 0.001), ESM was positive. Two of the 72 (2.8%) LSIL/CIN I patients, seven of the 85 (8.2%) HSIL/CIN II patients, and 11 of the 66 (16.7%) HSIL/CIN III patients (P = 0.016) were multicentric. The current study showed that EGI, positive ESM and multicentricity were more often associated with HSIL/CIN II + III than with LSIL/CIN I. Moreover, the frequencies of EGI, multicentricity, and positive ESM increased with increasing severity of the cervical lesion. This result may influence the preference for the type of surgical procedure used for patients with cytological diagnosis of HSIL.


Recent technological advancements in thermometry.
Thermometry is the key factor for achieving successful thermal therapy. Although invasive thermometry with a probe has been used for more than four decades, this method can only detect the local temperature within the probing volume. Noninvasive temperature imaging using a tomographic technique is ideal for monitoring hot-spot formation in the human body. Among various techniques, such as X-ray computed tomography, microwave tomography, echo sonography, and magnetic resonance (MR) imaging, the proton resonance frequency shift method of MR thermometry is the only method currently available for clinical practice because its temperature sensitivity is consistent in most aqueous tissues and can be easily observed using common clinical scanners. New techniques are being proposed to improve the robustness of this method against tissue motion. MR techniques for fat thermometry were also developed based on relaxation times. One of the latest non-MR techniques to attract attention is photoacoustic imaging.


Beneficial effect of botulinum toxin A on secondary ischaemic injury of skin flaps in rats.
Botulinum toxin A (BTX-A) protects against primary ischaemia of skin flaps, but its effect on secondary ischaemia is unknown. We induced secondary arterial or venous ischaemia in skin flaps of 32 Wistar rats, and tested the effectiveness of BTX injected subcutaneously 12hours before the flap was raised. The animals were divided into two groups of 16 (arterial or venous). Eight animals in each group were then treated with saline 1ml (control), and eight with BTX-A 5 IU (treatment). Ischaemia and necrosis were assessed after five days. There was no significant difference in necrosis between the two treatments in either group, but the amount of ischaemia did differ significantly (p=0.031 in the artetial ishcemia and p=0.015 in the venous ischemia group). BTX helped to salvage poor reperfusion in secondary ischaemia of skin flaps.


Gut-Brain Coupling and Multilevel Physiological Response to Biofeedback Relaxation After a Stressful Task Under Virtual Reality Immersion: A Pilot Study.
Human physiological reactions to the environment are coordinated by the interactions between brain and viscera. In particular, the brain, heart, and gastrointestinal tract coordinate with each other to provide physiological equilibrium by involving the central, autonomic, and enteric nervous systems. Recent studies have demonstrated an electrophysiological coupling between the gastrointestinal tract and the brain (gut-brain axis) under resting-state conditions. As the gut-brain axis plays a key role in individual stress regulation, we aimed to examine modulation of gut-brain coupling through the use of an overwhelming and a relaxing module as a first step toward modeling of the underlying mechanisms. This study was performed in 12 participants who, under a virtual reality environment, performed a 9-min cognitive stressful task followed by a 9-min period of relaxation. Brain activity was captured by electroencephalography, autonomic activities by photoplethysmography, and electrodermal and gastric activities by electrogastrography. Results showed that compared with the stressful task, relaxation induced a significant decrease in both tonic and phasic sympathetic activity, with an increase in brain alpha power and a decrease in delta power. The intensity of gut-brain coupling, as assessed by the modulation index of the phase-amplitude coupling between the normogastric slow waves and the brain alpha waves, decreased under the relaxation relative to the stress condition. These results highlight the modulatory effect of biofeedback relaxation on gut-brain coupling and suggest noninvasive multilevel electrophysiology as a promising way to investigate the mechanisms underlying gut-brain coupling in physiological and pathological situations.


Aspirin overcomes Navitoclax-resistance in hepatocellular carcinoma cells through suppression of Mcl-1.
Small-molecule Bcl-2/Bcl-xL inhibitor Navitoclax represents a promising cancer therapeutic since preclinical and clinical studies with Navitoclax have demonstrated strong anticancer activity in several types of cancers. However, because Navitoclax has a low binding affinity to Mcl-1, anticancer activity by Navitoclax is often attenuated by the elevated expression of Mcl-1 in hepatocellular carcinoma (HCC) and other cancers, posing a serious problem for its potential clinical utilities. Therefore, approaches that suppress the expression of Mcl-1 are urgently needed to overcome Navitoclax-resistance in these cancers. Here, we reported that aspirin markedly suppressed Mcl-1 expression, and significantly enhanced Navitoclax-mediated cell viability inhibition and apoptosis induction in HCC cells. We further showed that aspirin robustly enhanced Navitoclax-triggered cytosolic cytochrome c release, activation of initiator caspase-9 and effector caspase-3, and cleavage of PARP. Importantly, the cell death induction by the combination could be rescued by a cell-permeable caspase-9 inhibitor Z-LEHD-FMK, indicative of an indispensable role of mitochondrial apoptosis pathway during the combination effect. Taken together, our study suggests that aspirin can be used to enhance Navitoclax-mediated anticancer activity via suppression of Mcl-1. Since aspirin is one of the most commonly used medicines, our findings therefore have translational impacts on Navitoclax-based therapy for HCC.


Effect of pregnancy on clinical manifestation of bovine trypanosomiasis.
Four groups of non-pregnant, first second and third trimester pregnant Zebu heifers were used to study and compare the clinical manifestations of Trypanosoma vivax infection. All the infected heifers developed clinical trypanosomiasis manifested by massive parasitaemia, fluctuating pyrexia, anaemia, dull hair coat, emaciation, jugular pulse and enlarged superficial lymph nodes. There were group variations in the severity of signs shown. Infected non-pregnant heifers and heifers in the third trimester of pregnancy developed a more severe form of the disease than pregnant heifers in the first and second trimesters of pregnancy.


The Early Evolution of Oral Poliovirus Vaccine Is Shaped by Strong Positive Selection and Tight Transmission Bottlenecks.
The emergence of circulating vaccine-derived polioviruses through evolution of the oral polio vaccine (OPV) poses a significant obstacle to polio eradication. Understanding the early genetic changes that occur as OPV evolves and transmits is important for preventing future outbreaks. Here, we use deep sequencing to define the evolutionary trajectories of type 2 OPV in a vaccine trial. By sequencing 497 longitudinal stool samples from 271 OPV2 recipients and household contacts, we were able to examine the extent of convergent evolution in vaccinated individuals and the amount of viral diversity that is transmitted. In addition to rapid reversion of key attenuating mutations, we identify strong selection at 19 sites across the genome. We find that a tight transmission bottleneck limits the onward transmission of these early adaptive mutations. Our results highlight the distinct evolutionary dynamics of live attenuated virus vaccines and have important implications for the success of next-generation OPV.


Posterior maxillary segmental osteotomy for restoring the mandible with dental implants: a clinical report.
Posterior segmental collapse causes narrowing of interarch space and prevents adequate restoration in the posterior quadrant. Posterior maxillary segmental osteotomy (PMSO) is an alternative option that enables prosthodontic restoration with an implant-supported fixed partial denture. The following clinical report describes prosthodontic rehabilitation with fixed prostheses after a posterior maxillary segmental osteotomy for a patient with a partially edentulous mandible.


Allele-specific in situ analysis of microchimerism by fluorescence resonance energy transfer (FRET) in nonhuman primate tissues.
Rhesus monkeys are relevant models for tolerance induction. Hematopoetic chimerism is believed to be one of these strategies. The purpose of this study was to detect donor class I A locus allele specific mRNA in Rhesus monkey kidney recipient. We report here for the first time the results of frequency resonance energy transfer (FRET) hybridization technology in frozen tissues. Frequency resonance energy transfer hybridization was performed by using two Mamu-A*05 allele specific oligonucleotides: a donor probe labeled with FITC and acceptor probe conjugated to Texas Red. The PCR-SSP microchimerism analysis method produced 0.05% and 0.5% of donor DNA for Mamu-DRB1*1002 and Mamu-DRBw301/3 alleles, respectively. The donor cells were detected in mesenteric and/or inguinal lymph nodes, spleen, and liver, where the signal was the strongest. The results of FRET hybridization demonstrated the identical staining pattern in the recipient frozen tissues to that determined by PCR-SSP. Following FRET hybridization, the sections underwent immunohistochemical analysis, which revealed that donor cells had CD8+ phenotype. We demonstrate here for the first time that FRET in situ hybridization technique can be utilized for microchimerism analysis in frozen tissues. We conclude that using two donor mRNA specific oligonucleotide probes, rather than one, produce higher specificity.


Opposite trends of GAS6 and GAS6-AS expressions in breast cancer tissues.
Growth arrest-specific gene 6 (GAS6) is a growth factor-like cytokine whose function is related with vitamin K. This protein interacts with receptor tyrosine kinase proteins such as Tyro3, Axl, and TAM Receptor family, therefore affecting the tumorigenic processes via different mechanisms. GAS6-antisense 1 (GAS6-AS1) is a long non-coding RNAs (lncRNAs) that is transcribed from a genomic regions nearby GAS6. This lncRNA is also implicated in the pathobiology of cancer. We intended to judge the role of GAS6 and GAS6-AS1 in the pathogenesis of breast cancer through appraisal of their expression levels in breast cancer tissues and their paired neighboring non-cancerous samples. Expression of GAS6 was up-regulated in breast cancer tissues compared with neighboring tissues (Ratio of Mean Expressions = 2.18, P value = 4.98E-02). On the other hand, expression of GAS6-AS1 was down-regulated in breast tumor tissues compared with controls (Ratio of Mean Expressions = 0.37, P value = 4.26E-03). There were substantial correlations between expression levels GAS6 and GAS6-AS1 in non-cancerous tissues (r = 0.74, P value = 1.47e-13) and cancer tissues (r = 0.85, P value = 2.28e-20). Expression of GAS6-AS was associated with progesterone receptor status (P value = 1.36E-02). However, expressions of this gene and the sense transcript were not linked with any other clinical or demographic variable. Taken together, GAS6 and GAS6-AS1 might partake in the development of breast cancer.


Reduced levels of gamma-interferon secretion in response to chlamydial 60 kDa heat shock protein amongst women with pelvic inflammatory disease and a history of repeated Chlamydia trachomatis infections.
Peripheral lymphocytes in uninfected fertile controls, women with various histories of Chlamydia trachomatis infection, pelvic inflammatory disease (PID) and infertility not due to C. trachomatis infection (endometriosis) were cultured overnight with PHA mitogen and the 60 kDa chlamydial heat shock protein. Plasma samples were then assayed for levels of gamma-interferon and IL-10 using a commercial ELISA system. Women with PID and those with a history of multiple C. trachomatis infections showed reduced gamma-interferon production in response to cHSP60, not seen in women infected only once and those with infertility due to other causes (endometriosis). Secretion of IL-10 in response to cHSP60 did not vary significantly across the various patient groups, though all patients showed elevated levels of total IL-10 compared with uninfected controls.


Glycosaminoglycans in human gingival crevicular fluid as indicators of active periodontal disease.
The glycosaminoglycans (GAG) in gingival crevicular fluid (GCF) were investigated by cellulose-acetate electrophoresis of samples from individual sites of defined conditions variously affecting the tissues of the periodontium. The non-sulphated GAG, hyaluronic acid, was present in all samples and was the only major band from sites of chronic gingivitis. An additional sulphated GAG band identified by enzymic digestions as chondroitin-4-sulphate, was detected in GCF from sites of untreated-advanced periodontitis. Initial samples from sites of early periodontitis and juvenile periodontitis yielded a similar additional band which was not detected, however, in samples collected after either surgery to eliminate deep pockets or daily subgingival irrigation with a chlorhexidine solution. Sulphated GAG was also present in fluid from the control situations, i.e. of teeth either undergoing orthodontic movement or showing evidence of trauma from occlusion, and from healing tooth-extraction wounds. Thus the presence of such a component in GCF correlates with those clinical conditions in which degradative changes are occurring in the deeper-periodontal tissues. The electrophoretic profile of GAG in a sample of GCF may be a sensitive laboratory method of indicating active phases of destructive periodontal disease at individual sites.


Wonders & Worries: evaluation of a child centered psychosocial intervention for families who have a parent/primary caregiver with cancer.
Scant evidence exists to guide interventions for children who have a parent with cancer. This study evaluated the outcomes of a community based psychosocial intervention targeted to children dealing with parental or primary caregiver cancer. This curriculum provided an age-appropriate understanding of the illness, facilitated the expression of feelings, identified individual coping skills to help ease feelings related to parent's cancer, and enhanced the family's ability to communicate about the disease. Families whose children participated in the six-week curriculum-based intervention completed a questionnaire that included demographic information, a five-item assessment of changes in parenting abilities, and a nine-item assessment of changes in children's behavioral issues. The prevalence of each reported item was determined through a secondary analyses of cross-sectional data derived from a multi-year sample of these survey results. A sample of 156 families responded to the survey between 2009 and 2014. A majority of families described improvement in all five areas of parenting abilities assessed including communication skills and confidence in parenting. Amelioration of multiple children's issues was reported including improved communication skills (87%), reduced anxiety (84%), increased feeling of security at home (90%), and improved school performance (73%). The results reported here suggest that this child centered psychosocial intervention promoted positive adaptation by actively supporting families and children while a parent/primary caregiver coped with a cancer diagnosis. Future research is planned utilizing a randomized controlled study design to formally evaluate the effectiveness and preventative impact of this manualized six-week curriculum. Copyright © 2016 John Wiley & Sons, Ltd.


Alterations of blood platelet function induced by neutral proteases from human leukocytes.
Washed human platelets are damaged by two neutral proteases from human leukocytes (elastase-like protease, ELP and chymotrypsin-like protease, CLP). The damage is manifested as inhibited aggregation by ristocetin and collagen, and enhanced aggregation by ADP in the presence of fibrinogen. Similarly to alpha-chymotrypsin (alpha-CT), CLP also increases binding of 125I-fibrinogen to platelets and renders platelets aggregable by human fibrinogen. ELP is less effective in this respect possibly due to damage to platelet receptors for fibrinogen. In the plasma medium platelets are not sensitive to leukocytic proteases added at concentrations that provoke some prolongation of the time of plasma clotting by thrombin.


Studying the effect of light intensity on the photosynthetic mechanism of pepper leaf yellowing mutants by proteomics and phosphoproteomics.
The leaf is an important plant organ and is closely related to agricultural yield. Photosynthesis plays a critical role in promoting plant growth and development. Understanding the mechanism of leaf photosynthesis regulation will help improve crop yield. In this study, the pepper yellowing mutant was used as the experimental material, and the photosynthetic changes of pepper leaves (yl1 and 6421) under different light intensities were analyzed by chlorophyll fluorimeter and photosynthesis meter. Changes in proteins and enrichment of phosphopeptides in pepper leaves were determined. The results showed that different light intensities had significant effects on the chlorophyll fluorescence and photosynthetic parameters of pepper leaves. The differentially expressed proteins (DEPs) and differentially expressed phosphorylated proteins (DEPPs) were mainly involved in photosynthesis, photosynthesis-antenna proteins, and carbon fixation in photosynthetic organisms. In yl1 leaves, the phosphorylation levels of photosynthesis and photosynthesis-antenna proteins LHCA2, LHCA3, PsbC, PsbO, and PsbP were lower under low light treatment, but significantly higher under high light intensity compared with wild-type leaves. In addition, many proteins involved in the carbon assimilation pathway, including TKT, Rubisco, and PGK, were phosphorylated, and this modification level was significantly higher in yl1 than in the wild type under high light intensity. These results provide a new perspective for studying the photosynthesis mechanism of pepper under different light intensities.


Trans-saccadic perception.
A basic question in cognition is how visual information obtained in separate glances can produce a stable, continuous percept. Previous explanations have included theories such as integration in a trans-saccadic buffer or storage in visual memory, or even that perception begins anew with each fixation. Converging evidence from primate neurophysiology, human psychophysics and neuroimaging indicate an additional explanation: the intention to make a saccadic eye movement leads to a fundamental alteration in visual processing itself before and after the saccadic eye movement. We outline five principles of 'trans-saccadic perception' that could help to explain how it is possible - despite discrete sensory input and limited memory - that conscious perception across saccades seems smooth and predictable.


Small finger pollicization in the radial club hand.
This article describes pollicization of the small finger. A procedure that should only be used in the rare instance of an inoperable radial club hand. Children with bilateral radial club hands and severe, fixed radial deviation of the hand at the end of the forearm, and stiff elbows that cannot be mobilized either with a tendon transfer, splinting, or triceps release can be considered candidates for this operation. The technique, as described by Dieter Buck-Gramcko for pollicization of the index finger, was modified to be used in this procedure.


Flow cytometry assessment of reactive T-cells distinguishes classic Hodgkin lymphoma from benign lymphadenopathy in children.
Detection of classic Hodgkin lymphoma (cHL) neoplastic cells using flow cytometric immunophenotyping (FCI) remains limited. We hypothesized that characterization of the reactive infiltrates could assist in diagnosing cHL in children. FCI using four-color staining approaches was performed on 156 lymph node specimens with the following histopathologic diagnoses: cHL (25 cases), reactive lymphoid hyperplasia (RLH, 44 cases), and non-Hodgkin lymphoma (87 cases). The overall concordance of FCI data with the histopathologic results of these cases was 81.4%. A reactive expansion of T-cells with increased expression of CD45RO was present in the reactive infiltrate of cHL (CD45RO/CD3, 67.5%) and Epstein-Barr virus (EBV) infected RLH (62.7%) but not in EBV-negative RLH (28.0%). The mean fluorescence intensity (MFI) of CD7 was higher for cHL and differed significantly from EBV-positive RLH (138.5 vs. 63.8). A proposed diagnostic algorithm markedly elevated the overall concordance rate from 81.4% to 97.4%. Immunophenotyping the reactive infiltrate of lymphoid tissue using flow cytometry is a reliable supplement to histopathology for the rapid diagnosis of pediatric cHL.


Evaluation of A Simple DNA Extraction Method and Its Combination with Loop-Mediated Isothermal Amplification Assays for Rapid Plasmodium knowlesi Diagnosis.
The initial and vital stage in the diagnosis of malaria involves extracting DNA. The efficiency of malaria testing is restricted by the multiple steps involved in commercial DNA extraction kits. We attempted to improve an existing loop-mediated isothermal amplification (LAMP) for the detection of Plasmodium knowlesi by using a simple DNA extraction approach, making it a feasible option for mass screening. We utilized a simple nucleic acid extraction method directly from whole blood for the detection of P. knowlesi, taking only 5 min to complete. The extracted DNA was evaluated by two fluorescent-based LAMP and one colorimetric-based LAMP assay. The detection limit for both SYTO-LAMP and SYBR green-LAMP was 0.00001% and 0.0001% parasitemia, respectively. Meanwhile, neutral red-LAMP had a detection limit of 0.01% parasitemia. Combining this simple and inexpensive DNA extraction method, SYTO-LAMP could serve as an alternative molecular diagnosis for the detection of P. knowlesi and other human Plasmodium spp.


Synthesis of carbazole bearing pyridopyrimidine-substituted sulfonamide derivatives and studies their carbonic anhydrase enzyme activity.
The synthesis of carbazole containing pyridopyrimidine-substituted sulfonamide derivatives (3a-i) and their inhibitory effects on human carbonic anhydrase (hCA) I and II were studied. Spectral data and elemental analysis confirmed the structures of the compounds synthesized. The results show that all the synthesized compounds inhibited the CA I and II activities. Among them, 3a was found to be the most active ( K i : 14 µM) for hCA I and 3f ( K i : 126 µM) for hCA II.


Hostility in cancer patients as an underexplored facet of distress.
In the present study, we aimed to assess hostility and to examine its association with formal psychiatric diagnosis, coping, cancer worries, and quality of life in cancer patients. The World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) to make an ICD-10 (International Classification of Disease) psychiatric diagnosis was applied to 516 cancer outpatients. The patients also completed the Brief Symptom Inventory-53 to assess hostility (BSI-HOS), and the Mini-Mental Adjustment to cancer scale (Mini-MAC). A subset of patients completed the Cancer Worries Inventory (CWI), the Openness Scale, and the Quality of Life Index. By analyzing the distribution of the responses 25% of the patients had moderate and 11% high levels of hostility, with about 20% being BSI-HOS "cases." Hostility was higher in patients with a formal ICD-10 psychiatric diagnosis (mainly major depression, other depressive disorders, anxiety disorders) than patients without ICD-10 diagnosis. However, about 25% of ICD-10-non cases also had moderate-to-high hostility levels. Hostility was associated with Mini-MAC hopelessness and anxious preoccupation, poorer quality of life, worries (mainly problems sin interpersonal relationships), and inability to openly discuss these problems within the family. Hostility and its components should be considered as dimensions to be more carefully explored in screening for distress in cancer clinical settings for its implications in negatively impacting on quality of life, coping and relationships with the family, and possibly the health care system.


Serious and Fatal Complications after Neonatal Circumcision.
Neonatal circumcision (NNC) is the most frequently performed surgical procedure worldwide and is generally considered safe in Western societies. Deaths attributed to NNC are seldom reported and are mostly explained by lack of adherence to medical standards. We reviewed our emergency department database for circumcision-related emergency admissions. During 2000-2013, 19 previously healthy neonates were admitted for acute complications after circumcision. Four were admitted for bleeding, with hemophilia identified in two cases and von Willebrand disease in one. Eight boys required emergency surgery, three for severe bleeding. Four boys with amputation of the glans underwent immediate surgical reconstruction. One infant was taken to the operating room to remove an obstructing Plastibell ring. Seven boys were admitted to the intensive care unit with severe bleeding or sepsis, three of whom ultimately progressed to hemorrhagic or septic shock. Two of these children died of their complications. We estimate that the annual incidence of severe complications requiring hospitalization after NNC in the Greater Toronto Area was approximately 0.01%, and the incidence of fatalities over the 14-yr review period was approximately 0.0012%. Our results indicate that the risk of serious complications and death as a result of NNC is greater than generally assumed.


Electrospray ionization-Fourier transform ion cyclotron resonance mass spectrometry at 11.5 tesla: instrument design and initial results.
Initial results obtained using a new electrospray ionization (ESI) Fourier transform ion cyclotron resonance (FTICR) mass spectrometer operated at a magnetic field 11.5 tesla are presented. The new instrument utilized an electrostatic ion guide between the ESI source and FTICR trap that provided up to 5% overall transmission efficiency for light ions and up to 30% efficiency for heavier biomolecules. The higher magnetic field in combination with an enlarged FTICR ion trap made it possible to substantially improve resolving power and operate in a more robust fashion for large biopolymers compared to lower field instruments. Mass resolution up to 10(6) has been achieved for intermediate size biopolymers such as bovine ubiquitin (8.6 kDa) and bovine cytochrome c (12.4 kDa) without the use of frequency drift correction methods. A mass resolution of 370,000 has been demonstrated for isotopically resolved molecular ions of bovine serum albumin (66.5 kDa). Comparative measurements were made with the same spectrometer using a lower field 3.5-tesla magnet allowing the performance gains to be more readily quantified. Further improvements in pumping capacity of the vacuum system and efficiency of ion transmission from the source are expected to lead to further substantial sensitivity gains.


Intrathecal injection of lysine acetylsalicylic acid in the rat: a neurotoxicological study.
Lysine acetylsalicylic acid has been reported to induce analgesic effects in humans after intrathecal (i.t.) injection. Before conducting further studies in humans with this drug, it is important to evaluate potential toxicological effects on the spinal cord in animals. In the present study the effects of chronic intrathecal administration of provocative doses of lysine acetylsalicylic acid (L-ASA) on the rat spinal cord were evaluated using light and electron microscopy and a quantitative morphometric method. We also investigated the effects of single doses of the drug on the spinal cord blood flow (SCBF) using the laser-Doppler flowmetry technique. No histopathological changes or differences in number or density of neuronal cells could be seen after chronic administration of L-ASA as compared to controls. The SCBF decreased immediately after i.t. injection of a large dose (4 mg) of L-ASA and returned to predrug levels within 10 min. At the end of the experiment metabolic acidosis was detected, indicating a systemic effect of acetylsalicylic acid. It is concluded that no neurotoxic effects on the spinal cord were seen after chronic i.t. injection of L-ASA. From a neurotoxicological point of view, our findings do not contraindicate the spinal use of L-ASA in humans.


Carcinogenicity and co-carcinogenicity studies on propoxur in mouse skin.
Propoxur (2-isopropoxyphenyl methylcarbamate) is a widely used broad spectrum carbamate insecticide mainly used to control household pests. Propoxur exposure is reported to inhibit cholinesterase activity in rodents. Apart from other toxic effects, propoxur was found to possess tumorigenic activity in rats after oral administration. Propoxur does not produce tumours in mice or hamsters, or bladder hyperplasia in dogs and monkeys following oral feeding. In this set of investigations the complete carcinogenic, tumour initiating and promoting potential of propoxur was evaluated in male and female Swiss albino mice, since no information was available following dermal exposure of propoxur. The animals were exposed to propoxur through topical painting on the interscapular region at a dose of 100 mg/kg body weight. The results revealed that propoxur has tumour promoting potential on mouse skin following a two-stage initiation-promotion protocol, but it failed to induce the tumour(s) at a significant level, when tested for tumour initiating and complete carcinogenic property.


Biodegradable Zn-Dy binary alloys with high strength, ductility, cytocompatibility, and antibacterial ability for bone-implant applications.
The unique combination of biodegradability, biocompatibility, and functionality of zinc (Zn)-based alloys makes them highly desirable for a wide range of medical applications. However, a long-standing problem associated with this family of biodegradable alloys in the as-cast state is their limited mechanical strength and slow degradation rate. Here we report the development of Zn-xDy (x = 1, 3, and 5 wt.%) alloys with high strength, ductility, cytocompatibility, antibacterial ability, and appropriate degradation rate for biodegradable bone-implant applications. Our results indicate that the mechanical properties of Zn-xDy alloys were effectively improved with increasing Dy addition and hot-rolling due to the second-phase strengthening. The hot-rolled (HR) Zn-3Dy alloy showed the best combined mechanical performance with an ultimate tensile strength of 270.5 MPa, a yield strength of 214.8 MPa, an elongation of 55.1%, and Brinell hardness of 75.9 HB. The corrosion and degradation rates of HR Zn-xDy alloys in Hanks' solution gradually increased with increasing Dy addition due to the intensification of galvanic corrosion. The HR Zn-3Dy alloy showed high antibacterial ability against S. aureus and cytocompatibility toward MC3T3-E1 cells among all the HR alloys. Overall, the HR Zn-3Dy alloy can be considered a promising biodegradable material for bone implants. STATEMENT OF SIGNIFICANCE: This work reports on Zn-xDy (x = 1, 3, and 5%) alloys fabricated by Dy alloying followed by hot-rolling for biodegradable bone-implant applications. Our findings demonstrate that the hot-rolled (HR) Zn-3Dy alloy showed the best combined mechanical performance with an ultimate tensile strength of 270.5 MPa, a yield strength of 214.8 MPa, an elongation of 55.1%, and Brinell hardness of 75.9 HB. The corrosion and degradation rates of HR Zn-xDy alloys in Hanks' solution gradually increased with increasing Dy addition due to the intensification of galvanic corrosion. Furthermore, the HR Zn-3Dy alloy showed greater antibacterial ability against S. aureus and the best cytocompatibility toward MC3T3-E1 cells among all the HR alloys.


Effects of 24-hour blood pressure and heart rate recorded with ambulatory blood pressure monitoring on recovery from acute ischemic stroke.
This study used ambulatory blood pressure (BP) monitoring to generate BP and heart rate (HR) profiles soon after stroke onset and evaluated the association between determined values and 3-month stroke outcomes. We analyzed 24-hour ambulatory BP monitoring records from 104 patients with acute ischemic stroke. Ambulatory BP monitoring was attached at the second and eighth hospitalization days (Days 1 and 7). Both BP and HR were characterized using baseline, mean, maximum, and minimum values and coefficient of variation during 24-hour recording periods. Outcomes at 3 months were assessed as independence according to a modified Rankin Scale score of ≤2 and poor according to the score of ≥5. Sixty-six (63%) patients achieved independence and 12 (11%) had poor outcomes. Mean ambulatory BP monitoring values changed from 150.5±19.5/85.7±11.3 mm Hg on Day 1 to 139.6±19.3/80.0±11.7 mm Hg on Day 7. After multivariate adjustment, mean values of systolic BP (OR, 0.63; 95% CI, 0.45-0.85), diastolic BP (0.61; 0.37-0.98), pulse pressure (0.55; 0.33-0.85), and HR (0.61; 0.37-0.98) recorded on Day 1 as well as mean HR on Day 7 (0.47; 0.23-0.87) were inversely associated with independence and mean values of systolic BP (1.92; 1.15-3.68), diastolic BP (5.28; 1.92-22.85), and HR (4.07; 1.83-11.88) on Day 1 as well as mean HR on Day 7 (4.92; 1.36-36.99) were positively associated with a poor outcome. All of systolic BP, diastolic BP, pulse pressure, and HR on Day 1 and HR on Day 7 assessed using ambulatory BP monitoring were associated with outcomes of patients with stroke at 3 months.


Alzheimer's disease and its related dementias in US Native Americans: A major public health concern.
Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD) are growing public health concerns in aged populations of all ethnic and racial groups. AD and ADRD are caused by multiple factors, such as genetic mutations, modifiable and non-modifiable risk factors, and lifestyle. Studies of postmortem brains have revealed multiple cellular changes implicated in AD and ADRD, including the accumulation of amyloid beta and phosphorylated tau, synaptic damage, inflammatory responses, hormonal imbalance, mitochondrial abnormalities, and neuronal loss. These changes occur in both early-onset familial and late-onset sporadic forms. Two-thirds of women and one-third of men are at life time risk for AD. A small proportion of total AD cases are caused by genetic mutations in amyloid precursor protein, presenilin 1, and presenilin 1 genes, and the APOE4 allele is a risk factor. Tremendous research on AD/ADRD, and other comorbidities such as diabetes, obesity, hypertension, and cancer has been done on almost all ethnic groups, however, very little biomedical research done on US Native Americans. AD/ADRD prevalence is high among all ethnic groups. In addition, US Native Americans have poorer access to healthcare and medical services and are less likely to receive a diagnosis once they begin to exhibit symptoms, which presents difficulties in treating Alzheimer's and other dementias. One in five US Native American people who are 45 years of age or older report having memory issues. Further, the impact of caregivers and other healthcare aspects on US Native Americans is not yet. In the current article, we discuss the history of Native Americans of United States (US) and health disparities, occurrence, and prevalence of AD/ADRD, and shedding light on the culturally sensitive caregiving practices in US Native Americans. This article is the first to discuss biomedical research and healthcare disparities in US Native Americans with a focus on AD and ADRD, we also discuss why US Native Americans are reluctant to participate in biomedical research.


Respiratory depression associated with patient-controlled analgesia: a review of eight cases.
Patient-controlled iv delivery of opioids for postoperative pain management is a popular alternative to the traditional im route of administration. However, occasional patients receiving opioids in this manner develop severe respiratory depression. The purpose of this paper is to determine the incidence of, and factors contributing to, the development of this complication. To do this, the Office of Medical Quality Improvement retrospectively searched for reports of respiratory depression in a database compiled from the charts of approximately 1600 patients who had received PCA at the University of Alberta Hospitals in 1992. Eight cases of serious respiratory depression were detected. Factors associated with the occurrence of respiratory depression included the concurrent use of a background infusion, advanced age, concomitant administration of sedative/hypnotic medications, and pre-existing sleep apnoea syndrome. No cases were attributed to operator error or equipment malfunction. In conclusion, the risk of respiratory depression with patient-controlled opioid administration is similar to that observed when opioids are delivered by the traditional im or spinal routes. The safe and effective use of patient-controlled analgesia depends upon knowledgeable medical and nursing staff, clearly defined nursing policy and procedures, and frequent patient follow-up.


Carcinosarcoma (malignant mixed müllerian (mesodermal) tumor) of the female genital tract: immunohistochemical and ultrastructural analysis of 28 cases.
In an attempt to clarify the histogenesis of carcinosarcoma (malignant mixed müllerian tumor) of the female genital tract, 20 uterine and eight ovarian tumors were studied by light microscopy, transmission electron microscopy, and immunohistochemistry. Cytokeratins (MAK-6 and AE1:AE3) and epithelial membrane antigen were detected in the epithelial component of all tumors and in the stromal component of 15 cases (55%). Vimentin was detected in the stromal component of all cases and was focally positive in the epithelial component of 18 cases (69%). Tumors showing rhabdomyosarcomatous or chondrosarcomatous differentiation were positive for myoglobin and S-100 protein, respectively. At the ultrastructural level epithelial cells were observed in tight clusters (usually surrounded by a basal lamina), in loose aggregates, and singly (sometimes spindle shaped), and were surrounded by cells displaying variable differentiation. The closest examples of "hybrid" epithelial/stromal cells were those with a prominent rough endoplasmic reticulum, cytoplasmic projections, poorly formed intercellular junctions, and an incomplete basal lamina. The observations support the view that carcinosarcomas of the female genital tract could represent examples of biphasic (metaplastic) carcinomas.