Joint association of hyperuricemia and reduced GFR on cardiovascular morbidity: a historical cohort study based on laboratory and claims data from a national insurance provider.
Hyperuricemia is common in patients with chronic kidney disease (CKD). We assessed the relationship of increased serum uric acid levels with cardiovascular risk across levels of kidney function. Historical cohort study. Study data were drawn from administrative records of a national private health insurer (2003-2006). We included all adult beneficiaries with concurrently measured serum creatinine and serum uric acid. Patients with acute kidney failure or undergoing renal replacement therapy at baseline were excluded. Serum uric acid concentration and estimated glomerular filtration rate (eGFR). Cardiovascular diagnoses (myocardial infarction, subacute coronary heart disease, heart failure, cerebrovascular disease, or peripheral arterial disease) ascertained from billing claims. Cox proportional hazard models were used to test the association of predictors with cardiovascular morbidity. Models were adjusted for sociodemographic characteristics, selected comorbid conditions, and laboratory results. In 148,217 eligible patients, mean eGFR was 84 mL/min/1.73 m(2) and the prevalence of CKD stages 3-5 was 6.0%. Hyperuricemia (serum uric acid >7 mg/dL) was found in 15.6% of patients. The 40-month cumulative incidence of cardiovascular events (mean follow-up, 15.3 months) was 8.1%. Cardiovascular risk was associated independently with uric acid level, and this association was stronger in patients with lower eGFRs. Observational design, lack of information for mortality and potential confounders, single creatinine and uric acid assessment. Serum uric acid concentration was an independent correlate of cardiovascular morbidity, and this association was stronger in patients with severely decreased eGFR. This investigation provides a rationale for further study of serum uric acid-lowering interventions on cardiovascular risk in the general population and patients with CKD.


NSP1 defines a novel family of adaptor proteins linking integrin and tyrosine kinase receptors to the c-Jun N-terminal kinase/stress-activated protein kinase signaling pathway.
As part of a program to further understand the mechanism by which extracellular signals are coordinated and cell-specific outcomes are generated, we have cloned a novel class of related adaptor molecules (NSP1, NSP2, and NSP3) and have characterized in more detail one of the members, NSP1. NSP1 has an Shc-related SH2 domain and a putative proline/serine-rich SH3 interaction domain. Treatment of cells with epidermal growth factor or insulin leads to NSP1 phosphorylation and increased association with a hypophosphorylated adaptor protein, p130(Cas). In contrast, cell contact with fibronectin results in Cas phosphorylation and a transient dissociation of NSP1 from p130(Cas). Increased expression of NSP1 in 293 cells induces activation of JNK1, but not of ERK2. Consistent with this observation, NSP1 increases the activity of an AP-1-containing promoter. Thus, we have described a novel family of adaptor proteins, one of which may be involved in the process by which receptor tyrosine kinase and integrin receptors control the c-Jun N-terminal kinase/stress-activated protein kinase pathway.


Exploring breeding opportunities for reduced thermal sensitivity of feed intake in the lactating sow.
The aims of this study were, first, to evaluate the effects of climatic variables on daily feed intake of lactating sows and, second, to establish whether the response of sows to variation in temperature on feed intake during lactation was heritable. A total of 82,614 records for daily feed intake during lactation were available for 848 sows with 3,369 litters farrowing from January 2000 to December 2007. Climatic parameters available from the nearest weather station were maximum 24 h outside temperature, day length changes, and humidity. Although ambient room temperature was modified at the animal level in the farrowing shed, these climatic variables still had a significant effect on feed intake during lactation. Regression coefficients temperature and humidity were 0.01385 ± 0.00300 (temperature) - 0.00031 ± 0.00009 (temperature(2)) and 0.01443 ± 0.00620 (humidity) - 0.00009 ± 0.00004 (humidity(2)). There was an interaction between temperature and humidity, partly due to the climate control in the farrowing shed. At low temperature, feed intake increased considerably with greater humidity, in contrast to a small reduction in feed intake with greater humidity at high temperature. Day length change was modeled with a cosine function. At the start of autumn (September 21), sows ate 0.36 ± 0.056 kg/d less feed than at the start of spring (March 21). Daily feed intake during lactation was described as a function of days in lactation and as a function of both days in lactation and temperature using random regression models. The average heritability and repeatability summarized over the day in lactation at the mean temperature were 0.21 and 0.69, respectively. Genetic variance of temperature response on feed intake was less than 20% of the day effect. The permanent environmental variance was 2-fold (day) and 4-fold (temperature) greater than the corresponding additive genetic variance. Heritabilities of daily feed intake were greater during the first week of lactation compared with the rest of lactation. The genetic correlation between days decreased as time increased down to about 0.2 between the first and last day in lactation. The genetic correlation between feed intake records at the extreme temperatures decreased to about -0.35. It was concluded that random regression models are useful for research and results may be used to develop simpler models that can be implemented in practical breeding programs. An effect of temperature on lactation feed intake was found even in this climate-controlled environment located in a temperate climate zone. Larger effects are expected in more extreme climatic conditions with less temperature-controlled farrowing sheds.


Relative influence of hydrophobicity and net charge in the aggregation of two homologous proteins.
A potentially amyloidogenic protein has to be at least partially unfolded to form amyloid aggregates. However, aggregation of the partially or totally unfolded state of a protein is modulated by at least three other factors: hydrophobicity, propensity to form secondary structure, and net charge of the polypeptide chain. We propose to evaluate the relative importance of net charge, as opposed to the other factors, on protein aggregation and amyloidogenicity. For this aim, we have used two homologous proteins that were previously shown to be able to form amyloid fibrils in vitro, the N-terminal domain of HypF from Escherichia coli (HypF-N) and human muscle acylphosphatase (AcP). The aggregation process from an ensemble of partially unfolded conformations is ca. 1000-fold faster for HypF-N than for AcP. This difference can mainly be attributed to a higher hydrophobicity and a lower net charge for HypF-N than for AcP. By using protein engineering methods, we have decreased the net charge of AcP to a value identical to that of wild-type HypF-N and increased the net charge of HypF-N to a value identical to that of wild-type AcP. Amino acid substitutions were selected to minimize changes in hydrophobicity and secondary structure propensities. We were able to estimate that the difference in net charge between the two wild-type proteins contributes to 20-25% of the difference in their aggregation rates. An understanding of the relative influences of these forces in protein aggregation has implications for elucidating the complexity of the aggregation process, for predicting the effect of natural mutations, and for accurate protein design.


A somatic mutation of RasGRP3 decreases Na+/I- symporter expression in metastases of radioactive iodine-refractory thyroid cancer by stimulating the Akt signaling pathway.
Mutation profiles of advanced radioactive iodine (RAI)-refractory differentiated thyroid cancer have revealed the pathogenic roles of the established oncogenic mutations of BRAF and PI3KCA, but the involvement of other genes is presently unknown. In the present study, we performed whole-exome sequencing on 10 tissue samples of metastases of RAI-refractory differentiated thyroid cancers and identified a recurrent hot-spot mutation (c.1924G>T) in the RasGRP3 gene, which codes for Ras guanine nucleotide-releasing protein 3. This mutation was found to occur at a high frequency (20%) in samples of metastases of RAI-refractory differentiated thyroid cancers compared with other types of thyroid cancer. Overexpression of mutant RasGRP3 significantly promoted cell proliferation, migration, and invasiveness of 8505C and BHT101 cells compared with cells transfected with wild-type RasGRP3 or an empty vector. In addition, mutant RasGRP3 decreased the expression of sodium iodide symporter (NIS) and thyroid-stimulating hormone receptor (TSHR), reduced the iodine uptake ability, and increased Akt phosphorylation in thyroid cancer cells. Finally, we showed that LY294002, an inhibitor of PI3K/Akt signaling, attenuated the effects of mutant RasGRP3 on thyroid cancer cells. Thus, our study revealed that the c.1924G>T hot-spot mutation in RasGRP3 is a more frequent genetic alteration in metastases of RAI-refractory differentiated thyroid cancer. This mutant RasGRP3 activated the Akt pathway, promoted thyroid cancer cell proliferation and invasion, and reduced NIS expression and the iodine uptake ability.


The Clinical SYNTAX score predicts survival better than the SYNTAX score in coronary revascularization.
The Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial showed that the SYNTAX score (SS) is a useful tool for customizing revascularization treatment for patients with multivessel coronary disease. In the past decade, the Clinical SS (CSS) has emerged as a comprehensive tool. This novel tool considers the SS as well as patient clinical parameters such as age, creatinine clearance, and ejection fraction, which were shown to be relevant for patient prognosis. Thus, in the current work we set out to compare the survival predictive values of the SS versus the CSS and their future application in real-world implementation of the revascularization guidelines. This study was a subanalysis of data collected in a prospective national registry in Israel that enrolled consecutive patients with left main and/or 2- to 3-vessel coronary artery disease involving the proximal or mid-left anterior descending artery; the MULTI-vessel Coronary Artery Disease (MULTICAD). The revascularization method was chosen by the physicians taking care of the patients at each hospital and the patients were followed for 5 years. Patients were categorized according to their SS, the CSS, and their revascularization method (primary coronary intervention [PCI] vs coronary artery bypass grafting [CABG]) and patient survival were compared. A total of 585 patients were enrolled in the study and were followed for 5 years. The median CSS was 27, with 288 patients showing a CSS ≥27, with a mean CSS of 47.85 and a mean SS of 29.05. At 3 and 5 years post-treatment, the CSS ≥27 group had a lower survival probability, CSS ≥27 was associated with a lower survival probability among patients who underwent PCI compared with those who underwent CABG. More specifically, the high-CSS CABG group had a 5-year mortality rate of 16.8%, whereas the high-CSS PCI group had a 5-year mortality rate of 32.2%. In a comparison of SS with CSS for the 5-year mortality outcome prediction, CSS was superior to SS with a higher area under the curve. This prospective registry of real-world revascularization strategies in patients with multivessel disease showed that CSS is a better predictive tool of postrevascularization survival than SS. Moreover, it showed that surgical revascularization in patients with CSS ≥27 is associated with better all-cause mortality outcome after CABG as compared with after PCI. This attests to the need for a score that considers clinical parameters in a real-world scenario.


Self-collimating photonic crystal polarization beam splitter.
We present theoretical and experimental results of a polarization splitter device that consists of a photonic crystal (PhC) slab, which exhibits a large reflection coefficient for TE and a high transmission coefficient for TM polarization. The slab is embedded in a PhC tile operating in the self-collimation mode. Embedding the polarization-discriminating slab in a PhC with identical lattice symmetry suppresses the in-plane diffraction losses at the PhC-non-PhC interface. The optimization of the PhC-non-PhC interface is thereby decoupled from the optimization of the polarizing function. Transmissions as high as 35% for TM- and 30% for TE-polarized light are reported.


Epimorphin(-/-) mice have increased intestinal growth, decreased susceptibility to dextran sodium sulfate colitis, and impaired spermatogenesis.
Dynamic and reciprocal epithelial-mesenchymal interactions are critical for the normal morphogenesis and maintenance of epithelia. Epimorphin has been identified as a unique molecule expressed by mesenchymal cells and myofibroblasts and has putative morphogenetic effects in multiple epithelial tissues, including intestine, skin, mammary gland, lung, gallbladder, and liver. To define the in vivo role of epimorphin, we created epimorphin-null mice by targeted inactivation of the epimorphin gene. Male epimorphin-/- mice are sterile due to abnormal testicular development and impaired spermatogenesis. Intestinal growth is increased in epimorphin-/- mice due to augmented crypt cell proliferation and crypt fission during the neonatal (suckling) period, mediated at least in part by changes in bone morphogenetic protein (Bmp) and Wnt/beta-catenin signaling pathways. Colonic mucosal injury and colitis induced by dextran sodium sulfate (DSS) are ameliorated in epimorphin-/- mice, probably due to the increased proliferative capacity of the epimorphin-/- colon. These in vivo findings support the notion that epimorphin is a key stromal regulator of epithelial cell proliferation and growth in the intestine. In addition, our studies demonstrate a novel and critical role for epimorphin in regulating testicular development and growth as well as spermatogenesis.


Thin highly cross-linked polyethylene liners combined with large femoral heads in primary total hip arthroplasty show excellent survival and low wear rates at a mean follow-up of 12.8 years.
Several short- and mid-term studies have shown minimal liner wear of highly cross-linked polyethylene (HXLPE) in total hip arthroplasty (THA), but the safety of using thinner HXLPE liners to maximize femoral head size remains uncertain. The objective of this study was to analyze clinical survival and radiological wear rates of patients with HXLPE liners, a 36 mm femoral head, and a small acetabular component with a minimum of ten years' follow-up. We retrospectively identified 55 patients who underwent primary THA performed at a single centre, using HXLPE liners with 36 mm cobalt-chrome heads in acetabular components with an outer diameter of 52 mm or smaller. Patient demographic details, implant details, death, and all-cause revisions were recorded. Cox regression and Kaplan-Meier survival was used to determine all-cause and liner-specific revision. Of these 55 patients, 22 had a minimum radiological follow-up of seven years and were assessed radiologically for linear and volumetric wear. Overall survival rate for all-cause revision was 94.5% (95% confidence interval (CI) 81.7% to 97.2%) at a mean follow-up of 12.8 years (10.9 to 18.7). Three patients were revised, none for liner wear, fracture, or dissociation. A total of 22 patients were included in the radiological analysis (mean follow-up 9.9 years (7.5 to 13.7)). Mean linear liner wear was 0.085 mm (95% CI -0.086 to 0.257) and the volumetric wear rate was 11.097 mm3/year (95% CI -6.5 to 28.7). Using HXLPE liners with 36 mm heads in 52 mm acetabular components or smaller is safe, with excellent survival and low rates of linear and volumetric wear at medium-term follow-up. Patients did not require revision surgery for liner complications such as fracture, dissociation, or wear. Our results suggest that the advantages of using larger heads outweigh the potential risks of using thin HXLPE liners.Cite this article: Bone Joint J 2023;105-B(1):29-34.


The consequences of regulation of desat1 expression for pheromone emission and detection in Drosophila melanogaster.
Sensory communication depends on the precise matching between the emission and the perception of sex- and species-specific signals; understanding both the coevolutionary process and the genes involved in both production and detection is a major challenge. desat1 determines both aspects of communication-a mutation in desat1 simultaneously alters both sex pheromone emission and perception in Drosophila melanogaster flies. We investigated whether the alteration of pheromonal perception is a consequence of the altered production of pheromones or if the two phenotypes are independently controlled by the same locus. Using several genetic tools, we were able to separately manipulate the two pheromonal phenotypes, implying that desat1 is the sole gene responsible, exerting a pleiotropic effect on both transmission and detection. The levels of the five desat1 trancripts, measured in the head and body of manipulated flies, were related to variation in pheromone production. This suggests that the pleiotropic action of desat1 on pheromonal communication depends on the fine regulation of its transcriptional activity.


[Effects of different mycorrhizal fungi on physiological metabolism of tobacco seedlings].
Tobacco seedlings were inoculated with VA mycorrhizal fungi in natural soil. The results showed that compared with the control, the contents of nitrogen, phosphorus, potassium and chlorophyll, nitrate reductase activity, and protein in leaves were higher, malondialdehyde(MDA) and hydrogen peroxide(H2O2) decreased, while the activities of superoxide dismutase(SOD), catalase(CAT), and peroxidase(POD) increased. Meanwhile, seedlings were inoculated with two strains of ectomycorrhizal fungi respectively, and the above physiological indices trended the same changes. Moreover, the effect of strain Calvatia lilacina was higher than that of VA mycorrhizal fungi.


Communication Theory and Health Communication Practice: The More Things Change, the More They Stay the Same.
This article considers one of the most fundamental concerns of health communication scholars, educators, and professionals--the relationship between communication theory and health communication practice. Assertions about the important role of communication in health care--as both problem and potential solution--have become increasingly common, as have discussions of theoretical advances in communication and health communication. That said, the fundamental challenge of improving provider-patient communication, and health communication outcomes more generally, persists--and, indeed, appears to be resistant to change. Inadequacies in the articulation and translation of communication theory for health care practice represent a substantial part of the problem. Scholars of communication embrace the complexity and nuanced nature of the process. However, when communication concepts are appropriated within health care discourse and practice, the complexity and nuance are often glossed over, favoring instead simpler, information-exchange perspectives. The changing health care and wellness landscape, with its growing range of health information services, sources, and settings, is unlikely to alleviate the consequences of this translation problem; rather, it threatens to exacerbate it. This article examines these issues, provides illustrations of situations that are emblematic of the translational gap, and highlights concepts that may help to enrich the contribution of communication theory in health care, health education, and professional practice.


IGF-1 promotes the growth and metastasis of hepatocellular carcinoma via the inhibition of proteasome-mediated cathepsin B degradation.
To investigate the molecular mechanisms of the high IGF-1 level linking diabetes and cancers, which is a risk factor. We used cell growth, wound healing and transwell assay to evaluate the proliferation and metastasis ability of the hepatocellular carcinoma (HCC) cells. Western blot and reverse transcription polymerase chain reaction were used to assess a previously identified lysosomal protease, cathepsin B (CTSB) expression in the HCC cell lines. C57 BL/6J and KK-Ay diabetic mice are used to detect the growth and metastasis of HCC cells that were depleted with or without CTSB shRNA in vivo. Statistical significance was determined by Student's t-test. IGF-1 promoted the growth and metastasis of the HCC cell lines via its ability to enhance CTSB expression in both a time-dependent and concentration-dependent manner. HCC cells grew much faster in diabetic KK-Ay mice than in C57 BL/6J mice. Additionally, more metastatic nodules were found in the lungs of KK-Ay mice than the lungs of C57 BL/6J mice. CTSB depletion protects against the tumor-promoting actions of IGF-1 in HCC cells, as well tumor growth and metastasis both in vitro and in vivo. IGF-1 did not change the mRNA levels of CTSB but prolonged the half-life of cathepsin B in Hepa 1-6 and H22 cells. Our results showed that IGF-1 promotes the growth and metastasis of the HCC cells most likely by hindering CTSB degradation mediated by the ubiquitin-proteasome system (UPS), but not autophagy. Overexpression of proteasome activator 28, a family of activators of the 20S proteasome, could not only restore IGF-1-inhibited UPS activity but also decrease IGF-1-induced CTSB accumulation. Our study demonstrates that IGF-1 promotes the growth and metastasis of hepatocellular carcinoma by inhibition of proteasome-mediated CTSB degradation.


Eosinophilic meningitis in New Caledonia: The role of Angiostrongylus cantonensis?
Eosinophilic meningitis is a rare form of meningitis with sequelae or death occurring in approximately 2-3% of cases. The most frequent etiological agent is the parasite Angiostrongylus cantonensis. The aim of this study was to characterize New Caledonian cases and to assess the extent to which of A. cantonensis was involved. We performed a retrospective study of all cases of eosinophilic meningitis (EM) admitted to the Territorial Hospital of New Caledonia, from 2004 to 2019. We performed a descriptive and a multivariate analysis to identify association of variables with severe and fatal cases (or cases with sequelae). Angiostrongyliasis was confirmed as being responsible for 17 of the 92 reported EM cases in New Caledonia from 2004 to 2019 with most being young adults and non-walking infants, and with two peaks of incidence one during the dry season and one during the rainy season. Considering the high incidence and regularity of cases, the potential reservoirs should be identified to target prevention campaigns.


Comparing Compliance and Efficacy of Isocaloric Oral Nutritional Supplementation Using 1.5 kcal/mL or 1 kcal/mL Sip Feeds in Mildly to Moderately Malnourished Indonesian Children: A Randomized Controlled Trial.
This study set out to evaluate the compliance to, and efficacy of oral supplementation, using a 1.5 kcal/mL or 1 kcal/mL sip feed, in children with mild to moderate malnutrition. This was a parallel, randomized, controlled open-label trial in children aged 3 to 6 years with a weight for height Z (WHZ) score <-1 and ≥-3, who were randomized to receive a total of 600 kcal/day from either a 1.5 kcal/mL or a 1.0 kcal/mL pediatric sip feed for 28 days. Assessments included daily study product intake, body weight, tolerance and dietary intake from solid food. Of 110 children recruited, 98 (mean±standard deviation of age 49±7 months) completed the study. Both sip feeds were well tolerated, with high compliance (80±24% and 81±22% of prescribed volume in 1.5 kcal/mL and 1.0 kcal/mL groups respectively, p=0.79). Both study groups gained similar weight during the 28 days intervention period (0.42±0.40 kg in 1.5 kcal/mL group vs. 0.49±0.49 kg in 1.0 kcal/mL group, p=0.43). There were no significant differences between the groups in weight gain and in the change in WHZ score over the intervention period. Dietary analysis at the end of the study did not show replacement of solid food by the oral nutritional supplements. In children with mild to moderate malnutrition, both 1.5 kcal/mL and 1 kcal/mL pediatric sip feeds had high compliance and were well tolerated, and were equally effective in promoting weight gain in the 28 days study period.


Postnatal development of mu-opioid receptors in the rat caudate-putamen nucleus parallels asymmetric synapse formation.
The mu-opioid receptor (MOR) in the caudate-putamen nucleus (CPN) appears early during prenatal development, and shows a patch-like distribution throughout the postnatal period and adulthood. In the adult rat CPN, neurons in patch compartments receive glutamatergic excitatory input mainly from the cortex through synapses onto spines, many of which express MORs. Thus, MOR expression in spines may be related to corticostriatal synaptogenesis. We used electron microscopic immunocytochemistry to determine potential age-dependent changes in the distribution pattern of MOR during postnatal synaptogenesis in the rat CPN. Immunogold-silver labeling revealed that the dendritic plasmalemmal density of MOR at postnatal day (P) 0 was significantly lower than, but after P10 was similar to, that of adult. In contrast, such age-dependent changes were not observed in axon terminals. Stereological analysis of immunoperoxidase labeling for MOR showed a good correlation in the developmental numerical densities of synapses with MOR-labeled spines and those of total asymmetric axospinous synapses, linear correlation coefficient r=0.99. Synapses with MOR-labeled dendrites, however, had a low correlation with axodendritic synapses (r=0.61), and synapses with MOR-labeled terminals showed no correlation with axospinous and axodendritic synapses (r=0.19). These results provide ultrastructural evidence that the targeting of MOR on the plasma membrane of dendrites and spines parallels the peak period of synaptogenesis during the third postnatal week in the rat CPN. Thus, the postnatal spatiotemporal expression pattern of MOR appears to match the functional maturation of corticostriatal glutamate transmission.


Family therapy for drug abuse: review and updates 2003-2010.
Just 15 years ago, Liddle and Dakof (Journal of Marital and Family Therapy, 1995; 21, 511) concluded, based on the available evidence, that family therapy represented a "promising, but not definitive" approach for the treatment of drug problems among adolescents and adults. Seven years later, Rowe and Liddle (2003) review described considerable progress in this specialty with encouraging findings on adolescent-focused models based on rigorous methodology, as well as advances with adult-focused family-based treatments. The current review brings the field up to date with highlights from research conducted in the intervening 7 years, cross-cutting issues, recommendations for new research, and practice implications of these findings. Adolescent-focused family-based models that attend to the ecology of the teen and family show the most consistent and strongest findings in recent studies. Adult-focused models based on behavioral and systems theories of change also show strong effects with drug abusers and their families. The overarching conclusion is that family-based models are not only a viable treatment alternative for the treatment of drug abuse, but are now consistently recognized among the most effective approaches for treating both adults and adolescents with drug problems.


Distinct roles for Toll and autophagy pathways in double-stranded RNA toxicity in a Drosophila model of expanded repeat neurodegenerative diseases.
Dominantly inherited expanded repeat neurodegenerative diseases are caused by the expansion of variable copy number tandem repeat sequences in otherwise unrelated genes. Some repeats encode polyglutamine that is thought to be toxic; however, other repeats do not encode polyglutamine indicating either multiple pathogenic pathways or an alternative common toxic agent. As these diseases share numerous clinical features and expanded repeat RNA is a common intermediary, RNA-based pathogenesis has been proposed, based on its toxicity in animal models. In Drosophila, double-stranded (rCAG.rCUG∼100) RNA toxicity is Dicer dependent and generates single-stranded (rCAG)7, an entity also detected in affected Huntington's Disease (HD) brains. We demonstrate that Drosophila rCAG.rCUG∼100 RNA toxicity perturbs several pathways including innate immunity, consistent with the observation in HD that immune activation precedes neuronal toxicity. Our results show that Drosophila rCAG.rCUG∼100 RNA toxicity is dependent upon Toll signaling and sensitive to autophagy, further implicating innate immune activation. In exhibiting molecular and cellular hallmarks of HD, double-stranded RNA-mediated activation of innate immunity is, therefore, a candidate pathway for this group of human genetic diseases.


Anchoring CoFe2O4 Nanoparticles on N-Doped Carbon Nanofibers for High-Performance Oxygen Evolution Reaction.
The exploration of earth-abundant and high-efficiency electrocatalysts for the oxygen evolution reaction (OER) is of great significant for sustainable energy conversion and storage applications. Although spinel-type binary transition metal oxides (AB2O4, A, B = metal) represent a class of promising candidates for water oxidation catalysis, their intrinsically inferior electrical conductivity exert remarkably negative impacts on their electrochemical performances. Herein, we demonstrates a feasible electrospinning approach to concurrently synthesize CoFe2O4 nanoparticles homogeneously embedded in 1D N-doped carbon nanofibers (denoted as CoFe2O4@N-CNFs). By integrating the catalytically active CoFe2O4 nanoparticles with the N-doped carbon nanofibers, the as-synthesized CoFe2O4@N-CNF nanohybrid manifests superior OER performance with a low overpotential, a large current density, a small Tafel slope, and long-term durability in alkaline solution, outperforming the single component counterparts (pure CoFe2O4 and N-doped carbon nanofibers) and the commercial RuO2 catalyst. Impressively, the overpotential of CoFe2O4@N-CNFs at the current density of 30.0 mA cm-2 negatively shifts 186 mV as compared with the commercial RuO2 catalyst and the current density of the CoFe2O4@N-CNFs at 1.8 V is almost 3.4 times of that on RuO2 benchmark. The present work would open a new avenue for the exploration of cost-effective and efficient OER electrocatalysts to substitute noble metals for various renewable energy conversion/storage applications.


Comparison of adjustment methods for stratified two-sample tests in the context of ROC analysis.
We compare several nonparametric and parametric weighting methods for the adjustment of the effect of strata. In particular, we focus on the adjustment methods in the context of receiver-operating characteristic (ROC) analysis. Nonparametrically, rank-based van Elteren's test and inverse-variance (IV) weighting using the area under the ROC curve (AUC) are examined. Parametrically, the stratified t-test and IV AUC weighted method are applied based on a binormal monotone transformation model. Stratum-specific, pooled, and adjusted estimates are obtained. The pooled and adjusted AUCs are estimated. We illustrate and compare these weighting methods on a multi-center diagnostic trial and through extensive Monte-Carlo simulations.


Health literacy and cultural responsiveness of primary health care systems and services in Australia: reflections from service providers, stakeholders, and people from refugee backgrounds.
Primary health care [PHC] services with general practitioners (GPs) as the first point of access to health care services for people from refugee backgrounds in Australia can play a crucial role in building health literacy and promoting access to culturally appropriate services. To achieve equitable access and engagement, services and systems must be responsive to diverse health literacy and cultural needs. This study aims to explore how primary health services respond as a system and organisation to the health literacy and cultural needs of people from refugee backgrounds in Australia. This exploratory qualitative study involved 52 semi-structured interviews among 19 Africans from refugee backgrounds, 14 service providers, including GPs and nurses, and 19 other stakeholders, such as service managers/directors. Participants resided in New South Wales, Victoria, and Queensland. Interviews were audio-recorded, transcribed, and coded into QSR NVivo 12. Data analysis was guided by reflexive thematic analysis. Three interrelated themes were identified from the data relating to the health literacy and cultural responsiveness of PHC systems and services. The first theme, 'variable and ad hoc organisational response to health literacy and culturally responsive care,' demonstrated that some organisations did not systematically address the inherent complexity of navigating the health system nor the capacity of services and providers to respond to the cultural needs of people from refugee backgrounds. The second theme, 'individual provider responsibility,' captured the individual providers' interpersonal and relational efforts in supporting the health literacy and cultural needs of people from refugee backgrounds based on their motivation and adaptation. The third theme, 'refugee patient responsibility,' encapsulated people from refugee backgrounds' adaptations to and learning of the health system to navigate and access services. Health literacy and culturally responsive practices need to be systematised by PHC organisations to be implemented and sustained over time. There is a need for diversity in the organisational leadership and health care workforce, organisational commitment, health literacy and culturally responsive care policies, provider training, and auditing practice as essential components of the change process. Engaging with refugee communities would allow services to focus on people from refugee backgrounds' needs by design.


DNA adducts: Formation, biological effects, and new biospecimens for mass spectrometric measurements in humans.
Hazardous chemicals in the environment and diet or their electrophilic metabolites can form adducts with genomic DNA, which can lead to mutations and the initiation of cancer. In addition, reactive intermediates can be generated in the body through oxidative stress and damage the genome. The identification and measurement of DNA adducts are required for understanding exposure and the causal role of a genotoxic chemical in cancer risk. Over the past three decades, 32 P-postlabeling, immunoassays, gas chromatography/mass spectrometry, and liquid chromatography/mass spectrometry (LC/MS) methods have been established to assess exposures to chemicals through measurements of DNA adducts. It is now possible to measure some DNA adducts in human biopsy samples, by LC/MS, with as little as several milligrams of tissue. In this review article, we highlight the formation and biological effects of DNA adducts, and highlight our advances in human biomonitoring by mass spectrometric analysis of formalin-fixed paraffin-embedded tissues, untapped biospecimens for carcinogen DNA adduct biomarker research.


A common pharmacophore for cytotoxic natural products that stabilize microtubules.
Taxol (paclitaxel), a complex diterpene obtained from the Pacific yew, Taxus brevifolia, is arguably the most important new drug in cancer chemotherapy. The mechanism of cytotoxic action for paclitaxel-i.e., the stabilization of microtubules leading to mitotic arrest-is now shared by four recently identified natural products, eleutherobin, epothilones A and B, and discodermolide. Their ability to competitively inhibit [3H]paclitaxel binding to microtubules strongly suggests the existence of a common binding site. Recently, we have developed nonaromatic analogues of paclitaxel that maintain high cytotoxicity and tubulin binding (e.g., nonataxel). We now propose a common pharmacophore that unites paclitaxel, nonataxel, the epothilones, eleutherobin, and discodermolide, and rationalizes the extensive structure-activity relationship data pertinent to these compounds. Insights from the common pharmacophore have enabled the development of a hybrid construct with demonstrated cytotoxic and tubulin-binding activity.


Impairment of the mitochondrial respiratory chain activity in diethylnitrosamine-induced rat hepatomas: possible involvement of oxygen free radicals.
Alterations in the energy metabolism of cancer cells have been reported for many years. However, the deleterious mechanisms involved in these deficiencies have not yet been clearly proved. The main goal of this study was to decipher the harmful mechanisms responsible for the respiratory chain deficiencies in the course of diethylnitrosamine (DENA)-induced rat hepatocarcinogenesis, where mitochondrial DNA abnormalities had been previously reported. The respiratory activity of freshly isolated hepatoma mitochondria, assessed by oxygen consumption experiments and enzymatic assays, presented a severe complex I deficiency 19 months after DENA treatment, and later on, in addition, a defective complex III activity. Since respiratory complex subunits are encoded by both nuclear and mitochondrial genes, we checked whether the respiratory chain defects were due to impaired synthesis processes. The specific immunodetection of complex I failed to show any alterations in the steady-state levels of both nuclear and mitochondrial encoded subunits in the hepatomas. Moreover, in vitro protein synthesis experiments carried out on freshly isolated hepatoma mitochondria did not bring to light any modifications in the synthesis of the mitochondrial subunits of the respiratory complexes, whatever the degree of tumor progression. Finally, Southern blot analysis of mitochondrial DNA did not show any major mitochondrial DNA rearrangements in DENA-induced hepatomas. Because the synthetic processes of respiratory complexes did not seem to be implicated in the respiratory chain impairment, these deficiencies could be partly ascribed to a direct toxic impact of highly reactive molecules on these complexes, thus impairing their function. The mitochondrial respiratory chain is an important generator of noxious, reactive oxygen free radicals such as superoxide and H2O2, which are normally catabolized by powerful antioxidant scavengers. Nineteen months after DENA treatment, a general collapse of the antioxidant enzymatic system was demonstrated in the hepatomas, as recurrently observed in cancer cells. This oxidant versus antioxidant imbalance was characterized by the establishment of oxidative stress in the course of hepatocarcinogenesis, as partly shown by the important decrease of glutamine synthetase activity, an enzyme whose function is highly sensitive to oxidant reactions. This disequilibrium would result in a net increase of the steady-state concentration of superoxide generated between respiratory complexes I and III in the mitochondria. Once generated, superoxide would likely inactivate complexes I and III via oxidant reactions on their superoxide-sensitive [4Fe, 4S] clusters. The role of mitochondrial respiratory chain impairment in chemical carcinogenesis and/or the persistence of the cancerous state is further discussed.


Comment on "An association between the kinship and fertility of human couples".
Helgason et al. (Reports, 8 February 2008, p. 813) reported a positive association between kinship and fertility in the Icelandic population. We point out that the data further suggest that fertility initially increases with kinship and then decays. This is supported by another large study on the Danish population suggesting a superposition of effects of inbreeding and outbreeding depression on human fertility.


Virtual prenatal visits associated with high measures of patient experience and satisfaction among average-risk patients: a prospective cohort study.
Virtual visits have the potential to decrease barriers to prenatal care stemming from transportation, work, and childcare concerns. However, data regarding patient experience and satisfaction with virtual visits remain limited in obstetrics. To address this gap, we explore average-risk pregnant women's experiences with virtual visits and compare satisfaction with virtual vs. in-person visits as a secondary aim. In this IRB-approved, prospective cohort study, we surveyed pregnant women after their first virtual visit between October 7, 2019 and March 20, 2020. Using heterogeneous purposive sampling, we identified a subset of respondents with diverse experiences and opinions for interviews. For comparison, Consumer Assessment of Healthcare Providers and Systems (CAHPS) satisfaction data were collected after in-person visits during the study timeframe from a control cohort with the same prenatal providers. Logistic regression controlling for age, previous pregnancies, and prior live births compared satisfaction data between virtual and in-person visits. Other quantitative survey data were analyzed through descriptive statistics. Free text survey responses and interview data were analyzed using content analysis. Ninety five percent (n = 165/174) of surveys and 90% (n = 18/20) of interviews were completed. Most participants were Caucasian, married, and of middle to high income. 69% (114/165) agreed that their virtual appointment was as good as in-person; only 13% (21/165) disagreed. Almost all (148/165, 90%) would make another virtual appointment. Qualitative data highlighted ease of access, comparable provider-patient communication, confidence in care quality, and positive remote monitoring experiences. Recognizing these advantages but also inherent limitations, interviews emphasized interspersing telemedicine with in-person prenatal encounters. CAHPS responses after in-person visits were available for 60 patients. Logistic regression revealed no significant difference in three measures of satisfaction (p = 0.16, 0.09, 0.13) between virtual and in-person visits. In an average-risk population, virtual prenatal visits provide a patient-centered alternative to traditional in-person encounters with high measures of patient experience and no significant difference in satisfaction. Obstetric providers should explore telemedicine to improve access - and, during the ongoing pandemic, to minimize exposures - using patients' experiences for guidance. More research is needed regarding virtual visits' medical quality, integration into prenatal schedules, and provision of equitable care for diverse populations.


Prototypes of intrafamily homicide and serious assault among insanity acquittees.
Public concern with societal violence is intensified when persons who have been found not guilty by reason of insanity (NGRI) of having committed a homicide or serious assault are returned to the community. Successful management of such acquittees in the community requires a sophisticated understanding of the person and the illness within the larger context of the violent incident, the family, the community, and the culture. In this article, we present an analysis of psychotic violence within a family context. A qualitative study of 64 subjects who were found NGRI of killing or seriously injuring a family member resulted in four prototypes of intrafamilial homicide/assault: Till Death Us Do Part; Overwhelming Burden, Elimination of the Limit Setter; and Family-Focused Delusional Killing. The prototypes are presented as a model for developing management strategies both for future risk assessment and for successful transition of the insanity acquittee into the community.


Substitutions in conserved dodecapeptide motifs that uncouple the DNA binding and DNA cleavage activities of PI-SceI endonuclease.
The PI-SceI endonuclease from yeast belongs to a protein family whose members contain two conserved dodecapeptide motifs within their primary sequences. The function of two acidic residues within these motifs, Asp218 and Asp326, was examined by substituting alanine, asparagine, and glutamic acid residues at these positions. All of the purified mutant proteins bind to the PI-SceI recognition site with the same affinity and specificity as the wild-type enzyme. By contrast, substituting alanine or asparagine amino acids at the two positions completely eliminates strand cleavage of substrate DNA, whereas substitution with glutamic acid markedly reduces the cleavage activity. Experiments using nicked substrates demonstrate that the wild-type enzyme shows no strand preference during cleavage. These results are consistent with a model in which both acidic residues are part of a single catalytic center that cleaves both DNA strands. Furthermore, substrate binding by wild-type PI-SceI stimulates hydroxyl radical or hydroxide ion attack at the cleavage site while binding by the alanine-substituted proteins either stimulates this attack significantly less or protects the DNA at this position. These finding are discussed in terms of possible reaction mechanisms for PI-SceI-mediated endonucleolytic cleavage.


Pure Laparoscopic Donor Hepatectomy: Right Posterior Section Graft.
The use of laparoscopic liver resection (LLR) is widespread owing to its several advantages, especially smaller incision (Kaneko et al., Ann Gastroenterol Surg 1:33-43, 1; Ciria et al., Surg Endosc 34:349-360, 2). However, both posterior sectionectomy and donor hepatectomy are extremely difficult procedures to perform in LLR (Hasegawa et al., Ann Gastroenterol Surg 2:376-382, 3; Soubrane and Kwon, J Hepatobiliary Pancreat Sci 24:E1-E5, 4; Takahara et al., Transplantation 101:1628-1636, 5; Lee et al., Clin Transplant 33:e13683, 6; Hong et al., Surg Endosc 33:3741-3748, 7; Rhu et al., J Hepatobiliary Pancreat Sci 27:16-25, 8). Moreover, the right posterior section graft procurement is also difficult even in open laparotomy procedure (Sugawara et al., Transplantation 73:111-114, 9; Hwang et al., Liver Transpl 10:1150-1155, 10; Hori, Kirino, and Uemoto, Hepatol Res 45:1076-1082, 11; Kusakabe et al., Liver Transpl 26:299-303, 12). The pure laparoscopic donor posterior sectionectomy has not been reported yet. Therefore, we aimed to introduce a novel procedure through a video clip. The donor was placed in the semi-left lateral decubitus position with the reverse Trendelenburg position using a bean bag device. The right liver was mobilized, and the right hepatic vein was exposed. To adopt the liver hanging maneuver, a tape was inserted between the middle and right hepatic veins along the inferior vena cava. The posterior Glissonean pedicle was encircled and controlled, and the liver parenchyma was completely transected using the liver hanging maneuver. The vessels to the posterior section were respectively isolated. The posterior branches of the hepatic duct, hepatic artery, and portal vein were cut. The right hepatic vein was divided, and the graft liver was retrieved via a suprapubic incision. This study was approved by institutional ethics board (No. MH2019-119), and informed consent was taken from the patient. The overall surgical time was 503 min, and the blood loss was 400 mL. No complications were observed, and the donor was discharged from the hospital on postoperative day 11. This is the first report of pure laparoscopic donor hepatectomy of the posterior section graft. This procedure is more difficult than other laparoscopic donor hepatectomies because it involves parenchymal transection in the right intersectional plane and dissection of the posterior branches of hilar vessels.


Assembling Biocompatible Polymers on Gold Nanoparticles: Toward a Rational Design of Particle Shape by Molecular Dynamics.
Gold nanoparticles (AuNPs) have received great attention in a number of fields ranging from the energy sector to biomedical applications. As far as the latter is concerned, due to rapid renal clearance and a short lifetime in blood, AuNPs are often encapsulated in a poly(lactic-co-glycolic acid) (PLGA) matrix owing to its biocompatibility and biodegradability. A better understanding of the PLGA polymers on the AuNP surface is crucial to improve and optimize the above encapsulation process. In this study, we combine a number of computational approaches to explore the adsorption mechanisms of PLGA oligomers on a Au crystalline NP and to rationalize the PLGA coating process toward a more efficient design of the NP shape. Atomistic simulations supported by a recently developed unsupervised machine learning scheme show the temporal evolution and behavior of PLGA clusterization by tuning the oligomer concentration in aqueous solutions. Then, a detailed surface coverage analysis coupled with free energy landscape calculations sheds light on the anisotropic nature of PLGA adsorption onto the AuNP. Our results prove that the NP shape and topology may address and privilege specific sites of adsorption, such as the Au {1 1 1} crystal planes in selected NP samples. The modeling-based investigation suggested in this article offers a solid platform to guide the design of coated NPs.


Evolutionary and developmental dynamics of the dentition in Muroidea and Dipodoidea (Rodentia, Mammalia).
When it comes to mouse evo-devo, the fourth premolar-first molar (P4-M1) dental complex becomes a source of longstanding controversies among paleontologists and biologists. Muroidea possess only molar teeth but with additional mesial cusps on their M1. Developmental studies tend to demonstrate that the formation of such mesial cusps could result from the integration of a P4 germ into M1 during odontogenesis. Conversely, most Dipodoidea conserve their fourth upper premolars and those that lost these teeth can also bear additional mesial cusps on their first upper molars. The aim of this study is to assess this developmental model in both Muroidea and Dipodoidea by documenting the morphological evolution of the P4-M1 complex across 50 Ma. Fourteen extinct and extant species, including abnormal and mutant specimens were investigated. We found that, even if their dental evolutionary pathways strongly differ, Dipodoidea and Muroidea retain common developmental characteristics because some of them can present similar dental morphological trends. It also appears that the acquisition of a mesial cusp on M1 is independent from the loss of P4 in both superfamilies. Actually, the progressive decrease of the inhibitory effect of P4, consequent to its regression, could allow the M1 to lengthen and mesial cusps to grow in Muroidea. Apart from these developmental explanations, patternings of the mesial part of first molars are also deeply constrained by morpho-functional requirements. As there is no obvious evidence of such mechanisms in Dipodoidea given their more variable dental morphologies, further developmental investigations are needed.


A new technique for surgical treatment of vaginal agenesis using combined abdominal-perineal approach.
Optimum therapeutic approach in vaginal agenesis has always been an area of extensive controversies. Although surgical management gained priority due to the evolution of techniques, there is currently no consensus in the literature regarding the best type of surgical approach. The most commonly preferred surgical procedure among gynecologists is McIndoe operation which involves the creation of a space between bladder and rectum, insertion of a mold covered with split-thickness skin graft into that neovaginal space, and use of postoperative vaginal dilation to avoid stenosis. However, many modifications have been introduced in time in an attempt to increase the success rates. In this paper, we describe two cases with vaginal agenesis with functioning uterus who were subjected to surgery by combined abdominal-perineal approach. The surgical technique also included the use of a specially designed vaginal mold made up of polymethyl methacrylate and use of Hyalobarrier gel which is an adhesion-preventing agent.


Vitamin D Deficiency During Development Permanently Alters Liver Cell Composition and Function.
Vitamin D, a fat-soluble vitamin, plays a critical role in calcium homeostasis, the immune system, and normal development. Many epidemiological cohort studies globally have found high prevalence rates of vitamin D deficiency and insufficiency, recognized as an important health issue that needs to be solved. In particular, reproductive age and pregnant women low in vitamin D status may confer risks of diseases like obesity on their offspring. While observational studies have suggested associations between prenatal vitamin D deficiency and metabolic phenotypes in offspring, not yet determined is whether prenatal vitamin D deficiency permanently alters the development of the liver, a major metabolic organ. We tested the histopathology and the transcriptomic profiles of livers from male C57BL/6J mice exposed to prenatal vitamin D deficiency through a maternal dietary intervention model. We found that prenatal vitamin D deficiency increases the prevalence of histopathological changes in the liver, and alters its gene expression profile. Cell subtype proportion analysis showed that the liver of prenatal vitamin D deficiency alters non-parenchymal cells of the liver, specifically macrophages, a subset of endothelial cells, and dendritic cells. Our results indicate the long-term memory of prenatal vitamin D deficiency exposure in the adult liver, a potential contributor to offspring health risks.


A Noncausal Relation Between Casual Sex in Adolescence and Early Adult Depression and Suicidal Ideation: A Longitudinal Discordant Twin Study.
Research on relations between casual sex and mental health is inconclusive; while some studies indicate casual sex may lead to more negative mental health (e.g., depression), other studies report no such relationship. Using a genetically informed approach, this study examined whether earlier casual sex (i.e., ever engaging in casual sex and number of casual sex partners) in adolescence has a causal influence on later mental health in young adulthood (i.e., depressive symptoms and suicidal ideation), as well as the reverse relationship (adolescent negative mental health on young adult casual sex) by exploiting the quasi-experimental nature of discordant-twin models. Multilevel models that measured within-twin and between-twin pair effects of adolescent casual sex were estimated, using 714 twins (357 twin pairs) from the sibling subsample of the National Longitudinal Study of Adolescent Health (Add Health). Results indicated that there was no causal relationship between casual sex in adolescence and higher levels of depressive symptoms or suicidal ideation in young adulthood, and these effects did not differ by gender. There were also no causal relations between adolescent depressive symptoms or suicidal ideation and casual sexual experience in young adulthood. Implications for ways to increase scientific rigor by using different methods (e.g., genetically informed analyses) are discussed.


Peripheral Blood and Salivary Biomarkers of Blood-Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts.
Within the neurovascular unit (NVU), the blood-brain barrier (BBB) operates as a key cerebrovascular interface, dynamically insulating the brain parenchyma from peripheral blood and compartments. Increased BBB permeability is clinically relevant for at least two reasons: it actively participates to the etiology of central nervous system (CNS) diseases, and it enables the diagnosis of neurological disorders based on the detection of CNS molecules in peripheral body fluids. In pathological conditions, a suite of glial, neuronal, and pericyte biomarkers can exit the brain reaching the peripheral blood and, after a process of filtration, may also appear in saliva or urine according to varying temporal trajectories. Here, we specifically examine the evidence in favor of or against the use of protein biomarkers of NVU damage and BBB permeability in traumatic head injury, including sport (sub)concussive impacts, seizure disorders, and neurodegenerative processes such as Alzheimer's disease. We further extend this analysis by focusing on the correlates of human extreme physiology applied to the NVU and its biomarkers. To this end, we report NVU changes after prolonged exercise, freediving, and gravitational stress, focusing on the presence of peripheral biomarkers in these conditions. The development of a biomarker toolkit will enable minimally invasive routines for the assessment of brain health in a broad spectrum of clinical, emergency, and sport settings.


Health and disease in a traditional-living tribe in southern Africa.
An isolated traditional-living tribe has been identified in Southern Africa. The lifestyle, eating habits and socio-economic conditions have been studied intensively and are being correlated with the pattern of health and disease of the people. Physical examination, urinalyses, biochemical studies and X-ray investigations show a remarkable absence of the diseases normally associated with a Western lifestyle and yet no evidence of malnutrition was found. Those findings are compared with the results of investigations on urbanized black people. The aim of the study is to determine the long-term effects of inevitable westernization on this tribe.


Structure and expression of the mouse beta-hexosaminidase genes, Hexa and Hexb.
Two genes, HEXA and HEXB, encode the alpha- and beta-subunits, respectively, of human beta-hexosaminidase. In the mouse, the corresponding genes are termed Hexa and Hexb. The subunits dimerize to yield three isozymes, beta-hexosaminidase A (alpha beta), B (beta beta), and S (alpha alpha), that have the capacity to degrade a variety of substrates containing beta-linked N-acetylglucosamine and N-acetylgalactosamine residues. Mutations in the HEXA or HEXB gene resulting in a beta-hexosaminidase deficiency cause Tay-Sachs or Sandhoff disease, respectively. As a prelude to the creation of mouse models of these lysosomal storage diseases, we have characterized the molecular biology of the mouse beta-hexosaminidase system. Protein sequences derived from the cloned Hexa and Hexb cDNAs were 55% identical to each other and were also very similar to the cognate human sequences: 84% sequence identity with human HEXA and 75% with HEXB. The mouse hexosaminidase subunits, when expressed in HeLa cells from the cDNAs, displayed specificity toward synthetic substrates similar to the human subunits. The Hexa and Hexb genes were 25 and 22 kb in length, respectively. Each gene was divided into 14 exons, with the positions of introns precisely matching those of the corresponding human genes. The 5' flanking regions of the mouse genes demonstrated promoter activity as ascertained by their ability to drive chloramphenicol acetyltransferase gene expression in transfected NIH 3T3 cells. The sequences of these regulatory regions were G+C-rich in the 200 bp upstream of the respective initiator ATGs. Several putative promoter elements were present, including Sp1, AP2, CAAT, and TATA motifs.(ABSTRACT TRUNCATED AT 250 WORDS)


Randomized clinical trial to evaluate the efficacy of a 5-day ceftiofur hydrochloride intramammary treatment on nonsevere gram-negative clinical mastitis.
The objective of this study was to evaluate the efficacy of intramammary treatment with ceftiofur hydrochloride of nonsevere, clinical coliform mastitis. One hundred four cases on 5 farms met the enrollment criteria for the study. Escherichia coli was the most common coliform species identified in milk samples from cows with mild to moderate clinical mastitis, followed by Klebsiella spp. and Enterobacter spp. At enrollment, a milk sample from the affected quarter was taken and used for on-farm culture or submitted to the laboratory. For cows in the treatment group, treatment was initiated with ceftiofur hydrochloride via intramammary infusion at 24-h intervals for 5 d according to label standards. Cows in the control group did not receive treatment. Culture results were available on the day after enrollment and only cows with coliform mastitis continued in the treatment and untreated control groups. Bacteriological cure was defined based on 2 posttreatment milk samples. Molecular typing was used for final definition of bacteriological cure. Treatment of nonsevere clinical gram-negative mastitis with ceftiofur hydrochloride resulted in a significant increase in bacteriological cure compared with nontreated controls in animals infected with E. coli or Klebsiella spp. Treated animals clinically improved significantly more compared with control cows. No significant differences were observed between treated and control animals in milk production or linear score before or after clinical mastitis. Treated animals left the study less frequently compared with control animals.


Care of patients with pulmonary arterial hypertension during the coronavirus (COVID-19) pandemic.
The COVID-19 pandemic presents many unique challenges when caring for patients with pulmonary hypertension. The COVID-19 pandemic has altered routine standard of care practice and the acute management particularly for those patients with pulmonary arterial hypertension, where pulmonary arterial hypertension-specific treatments are used. It is important to balance the ongoing care and evaluation of pulmonary arterial hypertension patients with "exposure risk" to COVID-19 for patients coming to clinic or the hospital. If there is a morbidity and mortality benefit from starting pulmonary arterial hypertension therapies, for example in a patient with high-likelihood of pulmonary arterial hypertension, then it remains important to complete the thorough evaluation. However, the COVID-19 outbreak may also represent a unique time when pulmonary hypertension experts have to weigh the risks and benefits of the diagnostic work-up including potential exposure to COVID-19 versus initiating targeted pulmonary arterial hypertension therapy in a select high-risk, high likelihood World Symposium Pulmonary Hypertension Group 1 pulmonary arterial hypertension patients. This document will highlight some of the issues facing providers, patients, and the pulmonary arterial hypertension community in real-time as the COVID-19 pandemic is evolving and is intended to share expected common clinical scenarios and best clinical practices to help the community at-large.


Changes in skeletal muscle gene expression consequent to altered weight bearing.
Skeletal muscle is a dynamic organ that adapts to alterations in weight bearing. This brief review examines changes in muscle gene expression resulting from the removal of weight bearing by hindlimb suspension and from increased weight bearing due to eccentric exercise. Acute (less than or equal to 2 days) non-weight bearing of adult rat soleus muscle alters only the translational control of muscle gene expression, while chronic (greater than or equal to 7 days) removal of weight bearing appears to influence pretranslational, translational, and posttranslational mechanisms of control. Acute and chronic eccentric exercise are associated with alterations of translational and posttranslational control, while chronic eccentric training also alters the pretranslational control of muscle gene expression. Thus alterations in weight bearing influence multiple sites of gene regulation.


Long Q-T syndrome: a preventable form of sudden death.
The long Q-T syndrome, with or without congenital deafness, is characterized by syncopal attacks and prolongation of Q-T interval on the electrocardiogram. Untreated cases with syncope are usually fatal, but if diagnosed and treated appropriately with beta adrenergic blockers or surgical left stellate ganglionectomy, prognosis is markedly improved. This report describes an 11-year follow-up of a child with the long Q-T syndrome, in whom frequent syncopal attacks were successfully treated with propranolol.


Accuracy of Parkinson's disease diagnosis in 610 general practice patients in the West of Scotland.
UK-based community studies have found high rates of misdiagnosis in Parkinson's disease (PD). Searches of prescription databases and case records identified 610 patients taking antiparkinson therapy for a PD diagnosis in 92 West of Scotland General Practices. Patients with no documented progression of parkinsonism and/or no increase in antiparkinson medication for 3 years were assessed by two movement disorder specialists. FP-CIT SPECT scanning was performed in clinically uncertain cases. Those considered unlikely to have PD had antiparkinson drugs tapered then stopped, with a minimum of 6 months follow-up. Age, sex and disease duration matched controls were also assessed. 64 of 89 (71.9%) patients meeting selection criteria were assessed, of whom 36 (56.3%) were appropriate for therapy withdrawal. Thirty three of those 36 patients (91.7%) and 3 of 64 (4.7%) controls stopped antiparkinson therapy without deterioration giving an overall total of 36 of 610 (5.9%). The revised diagnoses in this group were mainly essential tremor (ET) (n = 14) and vascular parkinsonism (VP) (n = 10). Patients managed in Primary Care were significantly more likely to complete therapy withdrawal than those attending a specialist clinic (15.3% vs. 2.6%, P < 0.0001). The total annual cost of antiparkinson medication for these 36 patients was 13,400 pounds; the mean duration of diagnosis was 6.8 years (SD 5.6). At least 1 in every 20 patients taking medication for PD is misdiagnosed. Nearly all of these patients can be identified by simple screening of prescription databases and case records in Primary Care, followed by clinical review, which allows withdrawal of unnecessary medication.


Maximizing Resource Efficiency in Wireless Networks through Virtualization and Opportunistic Channel Allocation.
Wireless cellular networks have become increasingly important in providing data access to cellular users via a grid of cells. Many applications are considered to read data from smart meters for potable water, gas, or electricity. This paper proposes a novel algorithm to assign paired channels for intelligent metering through wireless connectivity, which is particularly relevant due to the commercial advantages that a virtual operator currently provides. The algorithm considers the behavior of secondary spectrum channels assigned to smart metering in a cellular network. It explores spectrum reuse in a virtual mobile operator to optimize dynamic channel assignment. The proposed algorithm exploits the white holes in the cognitive radio spectrum and considers the coexistence of different uplink channels, resulting in improved efficiency and reliability for smart metering. The work also defines the average user transmission throughput and total smart meter cell throughput as metrics to measure performance, providing insights into the effects of the chosen values on the overall performance of the proposed algorithm.


Ectopic pancreas of the gastric antrum contiguous to a gastrointestinal stromal tumor manifesting as upper gastrointestinal bleeding: report of a case.
A 54-year-old woman was referred to us for investigation of recurrent episodes of melena. Gastroduodenal endoscopic examination revealed a hemorrhagic, polypoid tumor, about 3 cm in diameter, in the posterior wall of the gastric antrum, near the greater curvature. The lesion had a smooth surface with ulceration, and was fixed to the sublying planes. The source of the bleeding was the mucosa overlying the tumor. We performed a distal subtotal gastrectomy with Roux-en-Y anastomosis. Histopathological examination of the resected specimen revealed an ectopic pancreas and a gastrointestinal stromal tumor contiguous to the ectopic pancreatic tissue in the gastric antrum. The patient was discharged after an uneventful postoperative course and has not experienced any recurrence of symptoms since.


Should troponin and creatinine kinase be routinely measured after vascular surgery?
The current guidelines for the evaluation and prediction of adverse cardiovascular events (CVEs) following vascular surgery in high-risk patients recommends serial electrocardiograms (ECGs) but not biomarkers such as cTn-I and CK-MB. The objective of this study was to determine whether biomarkers should be routinely measured in high-risk patients undergoing vascular surgery. A multicenter, prospective study with investigators blinded to core laboratory results was conducted. cTn-I and CK-MB were obtained on the day of surgery, as well as 24 hours, 72 hours and 120 hours after surgery, 24 hours prior to planned hospital discharge and at the onset of symptoms of a suspected CVE. The CVE was adjudicated by an endpoint committee using ECG, biomarker and symptoms data and was defined as cardiac death or myocardial infarction (MI) occurring up to 30 days after surgery. A total of 784 patients, with a mean age of 70.1 (SD +/- 9.8), underwent vascular surgery. Of the 83 patients with a CVE, cTn-I was positive in 42 and CK-MB was positive in 29 on or before the day of the CVE. The number of patients not classified as having a CVE but positive for elevation of cTn-I or CK-MB was 64 and 20, respectively. cTn-I was more sensitive than CK-MB (50.6% versus 34.9%) for predicting a CVE. The optimum time for measuring cTn-I after surgery with the highest positive predictive value was 24 hours. In conclusion, these data support routine serial measurement of cTn-I after vascular surgery.


Low-level environmental lead exposure and children's intellectual function: an international pooled analysis.
Lead is a confirmed neurotoxin, but questions remain about lead-associated intellectual deficits at blood lead levels < 10 microg/dL and whether lower exposures are, for a given change in exposure, associated with greater deficits. The objective of this study was to examine the association of intelligence test scores and blood lead concentration, especially for children who had maximal measured blood lead levels < 10 microg/dL. We examined data collected from 1,333 children who participated in seven international population-based longitudinal cohort studies, followed from birth or infancy until 5-10 years of age. The full-scale IQ score was the primary outcome measure. The geometric mean blood lead concentration of the children peaked at 17.8 microg/dL and declined to 9.4 microg/dL by 5-7 years of age; 244 (18%) children had a maximal blood lead concentration < 10 microg/dL, and 103 (8%) had a maximal blood lead concentration < 7.5 microg/dL. After adjustment for covariates, we found an inverse relationship between blood lead concentration and IQ score. Using a log-linear model, we found a 6.9 IQ point decrement [95% confidence interval (CI), 4.2-9.4] associated with an increase in concurrent blood lead levels from 2.4 to 30 microg/dL. The estimated IQ point decrements associated with an increase in blood lead from 2.4 to 10 microg/dL, 10 to 20 microg/dL, and 20 to 30 microg/dL were 3.9 (95% CI, 2.4-5.3), 1.9 (95% CI, 1.2-2.6), and 1.1 (95% CI, 0.7-1.5), respectively. For a given increase in blood lead, the lead-associated intellectual decrement for children with a maximal blood lead level < 7.5 microg/dL was significantly greater than that observed for those with a maximal blood lead level > or = 7.5 microg/dL (p = 0.015). We conclude that environmental lead exposure in children who have maximal blood lead levels < 7.5 microg/dL is associated with intellectual deficits.


Paradoxes of Cellular SUMOylation Regulation: A Role of Biomolecular Condensates?
Protein SUMOylation is a major post-translational modification essential for maintaining cellular homeostasis. SUMOylation has long been associated with stress responses as a diverse array of cellular stress signals are known to trigger rapid alternations in global protein SUMOylation. In addition, while there are large families of ubiquitination enzymes, all small ubiquitin-like modifiers (SUMOs) are conjugated by a set of enzymatic machinery comprising one heterodimeric SUMO-activating enzyme, a single SUMO-conjugating enzyme, and a small number of SUMO protein ligases and SUMO-specific proteases. How a few SUMOylation enzymes specifically modify thousands of functional targets in response to diverse cellular stresses remains an enigma. Here we review recent progress toward understanding the mechanisms of SUMO regulation, particularly the potential roles of liquid-liquid phase separation/biomolecular condensates in regulating cellular SUMOylation during cellular stresses. In addition, we discuss the role of protein SUMOylation in pathogenesis and the development of novel therapeutics targeting SUMOylation. SIGNIFICANCE STATEMENT: Protein SUMOylation is one of the most prevalent post-translational modifications and plays a vital role in maintaining cellular homeostasis in response to stresses. Protein SUMOylation has been implicated in human pathogenesis, such as cancer, cardiovascular diseases, neurodegeneration, and infection. After more than a quarter century of extensive research, intriguing enigmas remain regarding the mechanism of cellular SUMOylation regulation and the therapeutic potential of targeting SUMOylation.


DNA damage in cultured skin microvascular endothelial cells exposed to gamma rays and treated by the combination pentoxifylline and alpha-tocopherol.
This in vitro study aims at evaluating the effect of the combination of pentoxifylline (PTX) and trolox (Tx), the water-soluble analogue of alpha-tocopherol, on the oxidative state and DNA damage in dermal microvascular endothelial cells exposed to doses up to 10 Gy of ionizing radiation. Confluent primary cultures of dermal endothelial cells were gamma irradiated at 3 and 10 Gy, and 0.5 mM of both drugs, PTX and Tx, was added either before (15 min) or after (30 min or 24 h) irradiation. Reactive oxygen species (ROS), measured by the dichlorodihydrofluorescein diacetate assay, and DNA damage, assessed by the comet and micronucleus assays, were measured at different times after exposure (0 - 21 days). The PTX/Tx treatment decreased the early and delayed peak of ROS production by a factor of 2.8 in 10 Gy-irradiated cells immediately after irradiation and the basal level by a factor of 2 in non-irradiated control cells. Moreover, the level of DNA strand breaks, as measured by the comet assay, was shown to be reduced by half immediately after irradiation when the PTX/Tx treatment was added 15 min before irradiation. However, unexpectedly, it was decreased to a similar extent when the drugs were added 30 min after radiation exposure. This reduction was accompanied by a 2.2- and 3.6-fold higher yield in the micronuclei (MN) frequency observed on days 10 and 14 post-irradiation, respectively. These results suggest that oxidative stress and DNA damage induced in dermal microvascular endothelial cells by radiation can be modulated by early PTX/Tx treatment. These drugs acted not only as radical scavengers, but they were also responsible for the increased MN frequency in 10 Gy-irradiated cells. Thus, these drugs may cause a possible interference with DNA repair processes.


Urinary Ultrasound and Other Imaging for Ureteropelvic Junction Type Hydronephrosis (UPJHN).
Ultrasound is the main imaging study used to diagnose ureteropelvic junction (UPJ) obstruction. On ultrasound, abnormal dilatation of the pelvicalyceal system of varying degrees is seen, whereas the ureter is normal in caliber. A properly performed study provides essential information regarding laterality, renal size, thickness, and architecture of the renal cortex and degree of dilatation of the pelvicalyceal system. Doppler ultrasound may identify a crossing vessel, when present. This imaging method also has been used differentiating obstructive from non-obstructive hydronephrosis by renal arterial resistive index measurements. Abdominal radiographs may show soft tissue fullness, bulging of the flank, and displacement of bowel loops from the affected side. The voiding/micturating cystourethrogram helps exclude other causes of upper tract dilatation, including vesicoureteral reflux, urethral valves, and ureteroceles. Computerized Tomography angiography with multiplanar reformation and three-dimensional images may be used to depict suspected crossing vessels as a cause of UPJ obstruction in older children and adults. Magnetic Resonance Urography has progressed significantly in recent years due to the development of both hardware and software that are used to generate high-resolution images. This imaging technique currently allows for the detailed assessment of urinary tract anatomy, while also providing information regarding renal function, including differential renal function, and the presence or absence of obstructive uropathy.


Nursing clinical developments units--A strategy to promote the relationship between practice and academia.
Bridging the theory-practice gap has historically been acknowledged as a priority for the nursing profession. Enhancing nurses' attitudes regarding the relevance of theory to practice has been considered as crucial in order that the relationship between theory and practice becomes strong and complimentary. A review of the literature suggests that strategies such as joint clinical and academic positions have not had a significant impact in this respect. Nursing Clinical Development Units (NCDUs) were introduced in the United Kingdom as an initiative to promote the recognition and utilisation of research findings as an inherent component of nursing practice. However, there is limited literature addressing the impact of NCDUs on relationships between academia and the clinical field. The aim of this paper is to present the findings of a qualitative evaluation conducted with participants (n=14) of an NCDU program in Victoria, Australia. The findings suggest that this initiative can significantly enhance relationships with, and attitudes towards, academia.


Activation of ectopic olfactory receptor 544 induces GLP-1 secretion and regulates gut inflammation.
Olfactory receptors are ectopically expressed in extra-nasal tissues. The gut is constantly exposed to high levels of odorants where ectopic olfactory receptors may play critical roles. Activation of ectopic olfactory receptor 544 (Olfr544) by azelaic acid (AzA), an Olfr544 ligand, reduces adiposity in mice fed a high-fat diet (HFD) by regulating fuel preference to fats. Herein, we investigated the novel function of Olfr544 in the gut. In GLUTag cells, AzA induces the cAMP-PKA-CREB signaling axis and increases the secretion of GLP-1, an enteroendocrine hormone with anti-obesity effects. In mice fed a HFD and orally administered AzA, GLP-1 plasma levels were elevated in mice. The induction of GLP-1 secretion was negated in cells with Olfr544 gene knockdown and in Olfr544-deficient mice. Gut microbiome analysis revealed that AzA increased the levels of Bacteroides acidifaciens and microbiota associated with antioxidant pathways. In fecal metabolomics analysis, the levels of succinate and trehalose, metabolites correlated with a lean phenotype, were elevated by AzA. The function of Olfr544 in gut inflammation, a key feature in obesity, was further investigated. In RNA sequencing analysis, AzA suppressed LPS-induced activation of inflammatory pathways and reduced TNF-α and IL-6 expression, thereby improving intestinal permeability. The effects of AzA on the gut metabolome, microbiome, and colon inflammation were abrogated in Olfr544-KO mice. These results collectively demonstrated that activation of Olfr544 by AzA in the gut exerts multiple effects by regulating GLP-1 secretion, gut microbiome and metabolites, and colonic inflammation in anti-obesogenic phenotypes and, thus, may be applied for obesity therapeutics.


Methamphetamine causes acute hyperthermia-dependent liver damage.
Methamphetamine-induced neurotoxicity has been correlated with damage to the liver but this damage has not been extensively characterized. Moreover, the mechanism by which the drug contributes to liver damage is unknown. This study characterizes the hepatocellular toxicity of methamphetamine and examines if hyperthermia contributes to this liver damage. Livers from methamphetamine-treated rats were examined using electron microscopy and hematoxylin and eosin staining. Methamphetamine increased glycogen stores, mitochondrial aggregation, microvesicular lipid, and hydropic change. These changes were diffuse throughout the hepatic lobule, as evidenced by a lack of hematoxylin and eosin staining. To confirm if these changes were indicative of damage, serum aspartate and alanine aminotransferase were measured. The functional significance of methamphetamine-induced liver damage was also examined by measuring plasma ammonia. To examine the contribution of hyperthermia to this damage, methamphetamine-treated rats were cooled during and after drug treatment by cooling their external environment. Serum aspartate and alanine aminotransferase, as well as plasma ammonia were increased concurrently with these morphologic changes and were prevented when methamphetamine-induced hyperthermia was blocked. These findings support that methamphetamine produces changes in hepatocellular morphology and damage persisting for at least 24 h after drug exposure. At this same time point, methamphetamine treatment significantly increases plasma ammonia concentrations, consistent with impaired ammonia metabolism and functional liver damage. Methamphetamine-induced hyperthermia contributes significantly to the persistent liver damage and increases in peripheral ammonia produced by the drug.


Phagocytosis of Cryptococcus neoformans by rat alveolar macrophages.
A radiolabeling method was developed to investigate the interaction in vitro between Cryptococcus neoformans and Lewis rat alveolar macrophages (AM phi). AM phi were harvested by lung lavage, monolayers of adherent cells were established in wells of microtiter plates and [51Cr]-labeled yeast cells were added to the monolayers. After removal of extracellular yeasts, the adherent radioactivity associated with the AM phi was directly proportional both to the number of yeasts added and to the number of yeasts per AM phi as determined by microscopic examination of Giemsa-stained monolayers. Phagocytosis (attachment and/or ingestion) of radiolabeled C. neoformans by AM phi was a sensitive, quantitative and reproducible assay for the evaluation of the AM phi-C. neoformans interaction. AM phi were able to phagocytose encapsulated strains of C. neoformans. The extent of phagocytosis was inversely related to the capsule size. Normal rat serum (NRS) was an excellent source of opsonins for the ingestion. Inactivation of serum complement or depletion of C3 by affinity chromatography removed most of the opsonic activity of NRS. Specific antibodies against C. neoformans did not increase phagocytosis.


Barttin activates ClC-K channel function by modulating gating.
Barttin is an accessory subunit that modifies protein stability, subcellular distribution, and voltage-dependent gating of ClC-K chloride channels expressed in renal and inner ear epithelia. ClC-K channels are double-barreled channels with two identical protopores that may be opened by individual or common gating processes. Using heterologous expression in mammalian cells and patch-clamp recordings, we studied the effects of barttin on gating of rat ClC-K1 and human ClC-Ka. In the absence of barttin, rClC-K1 channels displayed two gating processes with distinct kinetics and voltage dependence. A fast gating process, activated by membrane hyperpolarization, opens and closes individual rClC-K1 protopores. In addition, slow common gating steps, stimulated by membrane depolarization, act on both protopores together. Coexpression of barttin results in voltage-independent open probabilities of the common gate, causing increased channel activity at physiologic potentials. In contrast to rClC-K1, human ClC-Ka is functional only when coexpressed with barttin. Single-channel recordings of hClC-Ka/barttin show double-barreled channels with fast protopore gating without apparent cooperative gating steps. These findings demonstrate that barttin stimulates chloride flux through ClC-K channels by modifying cooperative gating of the double-barreled channels and highlight a physiologic role for gating of epithelial ClC chloride channels.


Alterations to embryonic serotonin change aggression and fearfulness.
Prenatal stress can alter the serotonin (5-HT) system in the developing and adult brain and lead to mood and behavioral disorders in children and adults. The chicken provides a unique animal model to study the effects of embryonic stressors on childhood and adolescent behavior. Manipulations to the egg can be made in the absence of confounding maternal effects from treatment. Eggs were injected with 50 μL of excess 5-HT (10 μg/egg), 8-OH-DPAT (a 5-HT1A receptor agonist; 16 μg/egg), or saline on day 0 prior to the 21 days incubation. Injections were performed at 0.5 cm below the shell. Behavior was analyzed at 9 weeks of age and again at the onset of sexual maturity (18 weeks). Hens treated with excess embryonic 5-HT exhibited significantly less aggressive behaviors at 9 weeks of age compared to both 5-HT1A agonist treated and saline hens (P < 0.05), and at 18 weeks of age compared to saline control birds only (P < 0.05). Excess embryonic 5-HT also increased fearfulness response (P < 0.05) as tested by duration of tonic immobility. Increased degree of fluctuating asymmetry at 18 weeks in 5-HT-treated birds (P < 0.05) suggests that excess 5-HT in early embryonic stages may create a developmental instability, causing phenotypic variations. These results showed that modification of the serotonergic system during early embryonic development alters its functions in mediating aggressive and fearful or anxious behaviors. Prenatal modification of the serotonergic system has long lived implications on both physiology and behavior, especially aggressive and fearful behaviors.


Impact of Beads and Drops on a Repellent Solid Surface: A Unified Description.
We investigate freely expanding sheets formed by ultrasoft gel beads, and liquid and viscoelastic drops, produced by the impact of the bead or drop on a silicon wafer covered with a thin layer of liquid nitrogen that suppresses viscous dissipation thanks to an inverse Leidenfrost effect. Our experiments show a unified behavior for the impact dynamics that holds for solids, liquids, and viscoelastic fluids and that we rationalize by properly taking into account elastocapillary effects. In this framework, the classical impact dynamics of solids and liquids, as far as viscous dissipation is negligible, appears as the asymptotic limits of a universal theoretical description. A novel material-dependent characteristic velocity that includes both capillary and bulk elasticity emerges from this unified description of the physics of impact.


Oral mucosal pellicle. Adsorption and transpeptidation of salivary components to buccal epithelial cells.
The present investigation was carried out to examine the mechanism(s) whereby salivary molecules interact with human buccal epithelial cells. By utilizing antiserum against human parotid saliva, selected salivary components were detected by electrophoretic-transfer analysis of 1.5% SDS extracts of epithelial cells. Incubation of the cells and their aqueous cell-free extracts with 125I-labelled parotid saliva resulted in the formation of an iodinated high-molecular-mass complex which was not present in 125I-labelled saline alone. Formation of this complex was time-dependent and was inhibited by treating the buccal epithelial cells or their cell-free extracts with EGTA, iodoacetamide, N-ethylmaleimide or by heating at 100 degrees C for 15 min. The epithelial cells also promoted incorporation of [14C]putrescine into high-molecular-mass complexes whose formation was inhibited by iodoacetamide, unlabelled putrescine and EGTA. Cell extracts mediated cross-linking of monodansylcadaverine into alpha-casein, and this interaction was inhibited by iodoacetamide. Significant amounts of radioactivity were recovered with the epithelial-cell envelopes after exhaustive extraction of 125I-saliva- or [14C]putrescine-treated epithelial cells with 4% (w/v) SDS/10% (v/v) beta-mercaptoethanol. The incorporation of radioactivity into epithelial-cell envelopes was inhibited by pretreatment of the cells with putrescine, EGTA, iodoacetamide, or heating at 100 degrees C for 15 min. These data suggest that: (1) oral mucosal pellicle is formed by the selective adsorption of saliva to the epithelial-cell plasma membrane and its associated cytoskeleton; and (2) the adsorbed salivary components may be cross-linked to each other or the epithelial cytoskeleton by epithelial transglutaminases.


Novel total antioxidant capacity index for dietary polyphenols and vitamins C and E, using their cupric ion reducing capability in the presence of neocuproine: CUPRAC method.
The chemical diversity of antioxidants makes it difficult to separate and quantify antioxidants from the vegetable matrix. Therefore, it is desirable to establish a method that can measure the total antioxidant activity level directly from vegetable extracts. The current literature clearly states that there is no "total antioxidant" as a nutritional index available for food labeling because of the lack of standard quantitation methods. Thus, this work reports the development of a simple, widely applicable antioxidant capacity index for dietary polyphenols and vitamins C and E, utilizing the copper(II)-neocuproine [Cu(II)-Nc] reagent as the chromogenic oxidizing agent. Because the copper(II) (or cupric) ion reducing ability of polyphenols is measured, the method is named by our research group "cupric reducing antioxidant capacity" abbreviated as the CUPRAC method. This method should be advantageous over the ferric reducing antioxidant power (FRAP) method because the redox chemistry of copper(II)-as opposed to that of ferric ion-involves faster kinetics. The method comprises mixing of the antioxidant solution (directly or after acid hydrolysis) with a copper(II) chloride solution, a neocuproine alcoholic solution, and an ammonium acetate aqueous buffer at pH 7 and subsequent measurement of the developed absorbance at 450 nm after 30 min. Because the color development is fast for compounds such as ascorbic acid, gallic acid, and quercetin but slow for naringin and naringenin, the latter compounds were assayed after incubation at 50 degrees C on a water bath for 20 min [after Cu(II)-Nc reagent addition] so as to force the oxidation reaction to reach completion. The flavonoid glycosides were hydrolyzed to their corresponding aglycons by refluxing in 1.2 M HCl-containing 50% MeOH so as to exert maximal reducing power toward Cu(II)-Nc. Certain compounds also needed incubation after acid hydrolysis to fully exhibit their reducing capability. The CUPRAC antioxidant capacities of synthetic mixtures of antioxidants were experimentally measured as Trolox equivalents and compared to those theoretically found by making use of the principle of additivity of absorbances assuming no chemical interaction between the mixture constituents. Because ascorbic acid is not resistant to elevated temperature incubation, it should be assayed initially by measuring the absorbance (at 450 nm) difference of original and ascorbate oxidase-added mixture solutions at the end of 1 min of Cu(II)-Nc reagent addition. Thus, the total CUPRAC antioxidant capacity of a mixture containing various antioxidants should be that finally measured after a suitable combination of hydrolysis and incubation procedures, added to the initially measured capacity due to ascorbate. The antioxidant polyphenolic compounds tested demonstrate that the highest capacities in the CUPRAC method were observed for epicatechin gallate, epigallocatechin gallate, quercetin, fisetin, epigallocatechin, catechin, and caffeic acid in this order, in accordance with theoretical expectations, because the number and position of the hydroxyl groups as well as the degree of conjugation of the whole molecule are important. The antioxidant potency of flavonoids is nearly proportional to the total number of -OH groups and is positively affected by the presence of an o-dihydroxy moiety in the B-ring. beta-Carotene, which did not react with the CUPRAC reagent in alcoholic aqueous medium, could be assayed in dichloromethane solvent. Linear calibration curves for ascorbic acid and flavonoids were redrawn in synthetic solutions containing a mixture of antioxidants, and also in real matrices such as grape and orange juices, green tea, and blackberry tea, showing an initial nonzero absorbance with the CUPRAC reagent. The parallellism of the linear calibration curves of pure compounds in a given complex matrix effectively demonstrated that there were no interferent chemical interactions among the solution constituents and that the antioxidant capacities of the tested antioxidants were additive. The CUPRAC reagent is reasonably selective, stable, easily accessible, and sensitive toward thiol-type oxidants, unlike the FRAP method. The reaction is carried out at nearly physiological pH as opposed to the unrealistic acidic pH of FRAP.


Estradiol Replacement as a Potential Enhancer of Working Memory and Neuroplasticity in Hypogonadal Trans Women.
The cognitive effects of cross-sex hormone therapy (CSHT) are not well understood. In cisgender individuals, sex hormone therapy can impact neurotransmitter levels and structural anatomy. Similarly, in gender-diverse persons, CSHT has been associated with neural adaptations, such as growth in brain structures resembling those observed in cisgender individuals of the same sex. Hormone-related changes in learning and memory, as seen in menopause, are associated with physiological hypogonadism or a decline in hormones, such as estradiol. The present study examined the effect of estradiol administration in humans on glutamate concentration in brain regions involved in semantic and working memory (i.e., the dorsolateral prefrontal cortex [DLPFC], the posterior hippocampus, and the pregenual anterior cingulate cortex) and its relationship with memory. Eighteen trans women (male biological sex assigned at birth) ceased CSHT for 30 days for a washout phase (t1) upon study enrollment to reach a hypogonadal state. Working and semantic memory, cognition, hormonal assays, and brain imaging were assessed. Participants resumed CSHT for 60 days for a replacement phase (t2), after which the same evaluations from t1 were repeated. Estradiol increased among trans women after 60 days of resumed CSHT with significant improvements in semantic memory compared to the hypogonadal phase. Working memory recall was significantly and positively correlated to glutamate in the DLPFC during the reinstatement phase, although the relationship was not moderated by levels of estradiol. These results may have clinical implications for the therapeutic effects of estradiol replacement, serving as a protective factor against cognitive decline and impairment for trans women post-gonadectomy.


Higher Order Polynomial Transformer for Fine-Grained Freezing of Gait Detection.
Freezing of Gait (FoG) is a common symptom of Parkinson's disease (PD), manifesting as a brief, episodic absence, or marked reduction in walking, despite a patient's intention to move. Clinical assessment of FoG events from manual observations by experts is both time-consuming and highly subjective. Therefore, machine learning-based FoG identification methods would be desirable. In this article, we address this task as a fine-grained human action recognition problem based on vision inputs. A novel deep learning architecture, namely, higher order polynomial transformer (HP-Transformer), is proposed to incorporate pose and appearance feature sequences to formulate fine-grained FoG patterns. In particular, a higher order self-attention mechanism is proposed based on higher order polynomials. To this end, linear, bilinear, and trilinear transformers are formulated in pursuit of discriminative fine-grained representations. These representations are treated as multiple streams and further fused by a cross-order fusion strategy for FoG detection. Comprehensive experiments on a large in-house dataset collected during clinical assessments demonstrate the effectiveness of the proposed method, and an area under the receiver operating characteristic (ROC) curve (AUC) of 0.92 is achieved for detecting FoG.