Predictors of ASDAS-CRP inactive disease in axial spondyloarthritis during treatment with TNF-inhibitors: Data from the EuroSpA collaboration.
In patients with axial spondyloarthritis (axSpA) initiating their first tumor necrosis factor alpha-inhibitor (TNFi), we aimed to identify common baseline predictors of Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP) inactive disease (primary objective) and clinically important improvement (CII) at 6 months, and drug retention at 12-months across 15 European registries. Baseline demographic and clinical characteristics were collected. Outcomes were investigated per registry and in pooled data using logistic regression analyses on multiply imputed data. The consistency of baseline predictors in individual registries justified pooling the data. In the pooled dataset (n = 21,196), the 6-month rates for ASDAS inactive disease and ASDAS CII were 26% and 51%, and the 12-month drug retention rate 65% in patients with available data (n = 9,845, n = 6,948 and n = 21,196, respectively). Nine common baseline predictors of ASDAS inactive disease, ASDAS CII and 12-month drug retention were identified, and the odds ratios (95%-confidence interval) for ASDAS inactive disease were: age, per year: 0.97 (0.97-0.98), men vs. women: 1.88 (1.60-2.22), current vs. non-smoking: 0.76 (0.63-0.91), HLA-B27 positive vs. negative: 1.51 (1.20-1.91), TNF start year 2015-2018 vs. 2009-2014: 1.24 (1.06-1.45), CRP>10 vs. ≤10 mg/l: 1.49 (1.25-1.77), one unit increase in health assessment questionnaire (HAQ): 0.77 (0.58-1.03), one-millimeter (mm) increase in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) fatigue and spinal pain: 0.99 (0.99-1.00) and 0.99 (0.99-1.99), respectively CONCLUSION: Common baseline predictors of treatment response and adherence to TNFi could be identified across data from 15 European registries, indicating that they may be universal across different axSpA populations.


Pathogenesis of osteopenia/osteoporosis induced by highly active anti-retroviral therapy for AIDS.
The advent of highly active anti-retroviral therapy (HAART) has dramatically decreased the rate of AIDS-related mortality and significantly extended the life span of patients with AIDS. A variety of metabolic side effects are associated with these therapies, one of which is metabolic bone disease. A higher prevalence of osteopenia and osteoporosis in HIV-infected patients receiving anti-retroviral therapy than in patients not on therapy has now been reported in several studies. Several factors have been demonstrated to influence HIV-associated decreases in bone mineral density (BMD), including administration of nucleoside reverse transcriptase inhibitors (NRTIs). In this article, discussion will focus on the molecular pathogenesis and treatment of HAART-associated osteopenia and osteoporosis.


Three-dimensional ultrasonography of choroidal melanoma: extrascleral extension.
To describe the results of three-dimensional ultrasonography used to evaluate extrascleral extension of a choroidal melanoma. Case report. The three-dimensional ultrasound system uses a 10-MHz B-mode transducer combined with a motorized rotating holder. The system acquires 180 sequential images that are stored and processed to create a three-dimensional block of the region of interest. Unique coronal and oblique perspectives were obtained from interactive manipulation of the three-dimensional reconstruction. Examination of the three-dimensional image allowed us to detect the transscleral uveal-orbital connection. Extrascleral melanomatous extension was confirmed on histopathologic examination. Three-dimensional ultrasonography is a promising imaging technique for evaluating melanomatous extrascleral extension.


Bilateral medial medullary infarction: a systematic review.
Bilateral infarction of the medial medulla (MMI) is rare. Limited information is available on clinical characteristics, etiology, and prognosis. High-resolution neuroimaging has a major role in elucidating the underlying stroke mechanism. The aim of this systematic review was to analyze the clinical presentations, stroke mechanisms, and outcomes in patients with bilateral MMI. We performed a systematic review of the literature from 1992-2011 that reported on clinical presentations, stroke mechanism, and/or outcomes in patients with magnetic resonance imaging-proven bilateral MMI. Medline, EMBASE, and Web of Science Scholars Portal were searched without language restriction. Two reviewers independently assessed identified studies to determine eligibility, validity, and quality. The primary outcome was inpatient mortality; a secondary outcome was case fatality at 12 months. We identified 138 articles from Medline, EMBASE, and Scholars Portal including the MeSH terms "brainstem infarction," "medulla," and "bilateral." Twenty-nine articles met our inclusion criteria, including a total of 38 cases with bilateral MMI, and included in our study. These 38 patients had a mean age of 62.2 years and were predominately male (74.2%). The most common clinical presentations were motor weakness in 78.4%, dysarthria in 48.6%, and hypoglossal palsy in 40.5%. The most common vascular pathology was vertebral artery atherosclerosis, in 38.5%. The clinical outcome was poor (mortality, 23.8%; dependency, 61.9%). Bilateral medial medullary infarction is a rare stroke syndrome. Clinical presentations were mostly rostral medullary lesions. Large-artery atherosclerosis and branch disease were the most common stroke mechanisms. The clinical outcome was usually poor.


CD4+CD25+FoxP3+ regulatory T cells in autoimmune diseases.
Maintenance of immune tolerance in the periphery can be envisioned as a balance between autoreactive lymphocytes and regulatory mechanisms that counteract them. The naturally occurring CD4(+)CD25(+) regulatory T cells (T(REGs)) have a major role in modulating the activity of self-reactive cells. The identification of Forkhead box P3 transcription factor (FoxP3) as the critical determinant of T(REG) development and function has provided new opportunities and generated expanded interest in studying the balance between autoimmunity and regulatory mechanisms in human autoimmune diseases. The identification of both human and mouse diseases resulting from the lack of FoxP3 expression, and consequently the absence of T(REGs), has rapidly expanded knowledge of T(REG) development and function during the past 5 years. Although it is still unclear how these regulatory cells function, they can inhibit the activation of potentially pathogenic T cells in vitro. Using in vitro functional assays and phenotypic analysis, T(REGs) isolated from patients with a variety of autoimmune diseases have been shown to exhibit reduced regulatory function as compared with those isolated from healthy controls. This Review will focus on the current state of knowledge on human T(REGs) and their association with specific autoimmune diseases.


Ligula intestinalis (L.) (Cestoda: Pseudophyllidea): polarization of cyprinid leucocytes as an indicator of host- and parasite-derived chemoattractants.
Freshly isolated pronephric leucocytes from roach, Rutilus rutilus and gudgeon, Gobio gobio were exposed to extracts of plerocercoids of Ligula intestinalis from these two cyprinid fish. Addition of the extracts or an increase in incubation temperature from 10 to 20 degrees C induced polarization of neutrophils and L1 granulocytes. Cells were transformed from their typical spherical shape to elongate forms possessing a ruffled leading edge. Extracts obtained from gudgeon-Ligula stimulated polarization of both roach and gudgeon leucocytes at 10 and 20 degrees C. In contrast, extracts from roach-Ligula, whilst having little effect at 10 degrees C, suppressed temperature-induced polarization of leucocytes at 20 degrees C. Addition of serum to all the essays enhanced polarization and abolished the roach-Ligula-induced suppression. It is suggested that leucocyte chemoattractants are present in Ligula from roach and gudgeon and only parasites from the former host contain an inhibitor of polarization. In addition, host-derived factors possibly complement, may be involved in leucocyte chemoattraction.


Metastatic squamous cell carcinoma of the paranasal sinuses from a primary squamous cell carcinoma of the urinary bladder.
Metastatic tumours of the paranasal sinuses from primary lesions of the urogenital tract are rare, with about 50 cases so far being reported in the literature. The most frequent primary lesions is a renal carcinoma. We have experienced a case of paranasal sinus malignancy. There were no symptoms of urinary tract carcinoma preceding those in the paranasal sinuses. This case was later revealed at autopsy to be a metastasis from a diverticulum of the urinary bladder.


Comparison of reversibility of rat forestomach lesions induced by genotoxic and non-genotoxic carcinogens.
Reversibility of forestomach lesions induced by genotoxic and non-genotoxic carcinogens was compared histopathologically. Groups of 30 to 33 male F344 rats were given dietary 0.1% 8-nitroquinoline, dietary 0.4-0.2% 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, an intragastric dose of 20 mg/kg body weight N-methyl-N'-nitro-N-nitrosoguanidine once a week, or 20 ppm N-methylnitrosourethane in the drinking water as a genotoxic carcinogen, or 2% butylated hydroxyanisole, 2% caffeic acid, 2% sesamol or 2% 4-methoxyphenol in the diet as a non-genotoxic carcinogen for 24 weeks. Ten or 11 rats in each group were killed at week 24. Half of the remainder were maintained on basal diet alone for an additional 24 weeks and the other half were given the same chemical for 48 weeks, and then killed. Forestomach lesions induced by genotoxic carcinogens did not regress after removal of carcinogens. In contrast, simple or papillary hyperplasia (SPH), but not basal cell hyperplasia (BCH), induced by non-genotoxic carcinogens clearly regressed after cessation of insult. SPH labeling indices in the non-genotoxic carcinogen-treated cases decreased after removal of the carcinogenic stimulus whereas BCH values were low irrespective of treatment. Atypical hyperplasia (AH), observed at high incidences in rats treated with genotoxic carcinogens, was also evident in animals receiving non-genotoxic agents, even after their withdrawal, albeit at low incidences. AH labeling indices remained high even without continued insult. These results indicate that even with non-genotoxic carcinogens, heritable alterations at the DNA level could occur during strong cell proliferation and result in AH development. This putative preneoplastic lesion might then progress to produce carcinomas.


Structure of a neutral polymer isolated from the lipopolysaccharide of the reference strain for Serratia marcescens serogroup O18.
A neutral polymer (the putative O antigen) has been isolated from the lipopolysaccharide of the reference strain for Serratia marcescens serogroup 018. From the results of spectroscopic and degradative studies, the repeating unit of the polymer was identified as a linear tetrasaccharide having the structure shown. ----2)-alpha-L-Rhap-(1----2)-alpha-L-Rhap-(1----6)-alpha-D- GlcpNAc-(1----


Prostaglandin-induced eosinopenia in splenectomized rats.
PGE1, PGE2, and PGF2alpha over a dose range of 1 to 50 microgram/kg decreased the number of circulating eosinophils in splenectomized rats. Pretreatment with a beta-blocking agent, propranolol, did not alter this effect, but adrenalectomy eliminated it. Anterior hypothalamic destruction also abolished eosinopenia induced by PGE1 and PGF2alpha but not that induced by PGE2.


A Novel Fluorescent GFP Chromophore Analog-Based Dye for Quantitative PCR.
This is the first report describing the possibility of using a green fluorescent protein chromophore synthetic analog, P-HOBDI-BF2, as a fluorescent dye for a linear hydrolysis probe used in qPCR. The study was carried out on a system for detection of the plant pathogenic fungus Fusarium avenaceum using a plasmid containing translation elongation factor 1α fragment as a template. To estimate fluorogenic properties of P-HOBDI-BF2, 6-FAM- and BDP-FL-labeled probes were used. It was demonstrated that a synthetic dye based on the P-HOBDI-BF2 chromophore can be used for labeling hydrolysis probes for qPCR, but fluorescence increase levels for P-HOBDI-BF2-labeled probes were slightly lower than those for 6-FAM-labeled ones. At the same time, the sensitivity of P-HOBDI-BF2-based assays remained high, and this fact together with acceptable fluorescence levels suggests that this dye can be considered as an efficient alternative for reporters traditionally used for fluorescence detection in the FAM channel.


N95 masks worn to protect against COVID-19 prevented tuberculosis exposure in healthcare workers.
Since the start of the COVID-19 pandemic, the healthcare workers in our institution have been equipped with N95 masks when performing aerosol-generating procedures, as these are associated with an increased risk of infection. We present a case in which using an N95 mask prevented tuberculosis (TB) exposure among healthcare workers administering prehospital care in rapid response vehicles. Even after the resolution of the COVID-19 pandemic in the future, wearing N95 masks among healthcare workers is recommended to protect against pathogens, including TB, when performing aerosol-producing procedures or prehospital activities for patients suspected of having respiratory diseases.


Determinants of gefitinib pharmacokinetics in healthy Chinese male subjects: A pharmacogenomic study of cytochrome p450 enzymes and transporters.
Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, exhibited a wide interindividual variability in pharmacokinetics. In the present study, we aimed to evaluate the impact of single-nucleotide polymorphisms in the metabolizing enzymes and transporters on gefitinib disposition in healthy Chinese subjects. Fourteen single-nucleotide polymorphisms, including polymorphisms of ATP-binding cassette (ABC) transporters and cytochrome P450 enzymes, were genotyped by Sanger sequencing, and the concentration of gefitinib was measured by ultrafast liquid chromatography-tandem mass spectrometry. The association between the pharmacokinetic parameters (peak plasma concentration [Cmax ], time to reach Cmax , plasma half-life, area under the concentration-time curve from 0 to 168 hours [AUC(0-168h) ], AUC(0-∞) and plasma clearance [CL/F]) and genotypes was evaluated using unpaired t test or Mann-Whitney U test. A stepwise multiple linear regression analysis was applied to assess the relationships between multiple factors and gefitinib pharmacokinetics. Thirty-nine healthy Chinese male subjects were enrolled in the pharmacokinetic study. Subjects carrying an ABCG2 A allele (c.421CA + c.421AA genotypes) exhibited 33 and 37% increases in the mean gefitinib AUC(0-168h) and AUC(0-∞) values (P < .05), respectively, compared to that of subjects carrying wild-type ABCG2 (c.421CC). Additionally, the mean CL/F of the c.421A allele carriers was 32% less than that of the c.421CC carriers (P < .05). No associations were found between polymorphisms in other metabolic enzymes or ABC transporters and gefitinib pharmacokinetics. Our results suggested that a single-nucleotide polymorphism in ABCG2 (c.421C>A) significantly affected the pharmacokinetics of gefitinib. Further studies are required to evaluate the effects of single-nucleotide polymorphism on the pharmacokinetics, pharmacodynamics and toxicity of gefitinib.


The Impact of Gender on Use of Pelvic Lymphadenectomy at the Time of Radical Cystectomy.
Although women are less likely to be diagnosed with bladder cancer than men, they experience a disproportionally high rate of cancer specific mortality. Underuse of evidence-based processes of care may contribute to this mortality difference. We explored variation in the use of pelvic lymphadenectomy at the time of radical cystectomy between men and women, and determined if this was impacted by surgeon or hospital volume. We identified all patients with bladder cancer who underwent radical cystectomy from 1996 to 2009 in the New York, Maryland and Florida State Inpatient Databases. The effect of gender on the use of pelvic lymphadenectomy was analyzed using multivariate logistic regression models. Approximately 25% of our cohort was female. Compared to men, women were less likely to be treated with pelvic lymphadenectomy (54% vs 60%, p <0.001), and tended to be treated by lower volume surgeons and at lower volume hospitals. Women had 21% lower odds (95% CI 5-35) of undergoing pelvic lymphadenectomy compared to men when adjusting for patient characteristics, even when treated by high volume surgeons and at high volume hospitals. At radical cystectomy women were less likely to undergo pelvic lymphadenectomy even when treated by high volume providers. Since pelvic lymphadenectomy is an evidence-based process of care that is associated with improved survival in patients with bladder cancer, lower use of pelvic lymphadenectomy may contribute to the lower bladder cancer survival rate observed in women. Our findings identify an opportunity to improve quality of care in women with bladder cancer.


Embryonic development and secretory differentiation in the pars tuberalis of the mouse hypophysis.
The pars tuberalis (PT) of the mouse, like that of other mammals, consists mainly of glandular cells rich in glycogen and peculiar to this lobe. In the mouse, the glandular cells are characterized by large, dense secretory vesicles (up to 300 nm in diameter), the abundance of which indicates a marked secretory activity. The PT develops from a distinct antero-ventral area of Rathke's pouch. The border between the anlagen of the PT and the pars distalis is formed by Atwell's recessus which represents the access for the vessels afferent to the pars distalis. The pedicle of Rathke's pouch is incorporated into the PT anlage, thus contributing to its formation. The entire PT anlage is characterized by glycogen accumulation from the commencement of its formation and persisting in the adult tuberal lobe. Secretory differentiation of the glandular cells of the PT occurs at day 12 of gestation, preceding that of all other adenohypophysial cell types. The secretory features of these cells (development of ergastoplasm and Golgi apparatus, abundance of dense secretory vesicles) appear at an early stage of the enbryonic life (14 days) comparable to those of mature cells. These results confirm earlier observations in the foetal rat where hypophysial secretion also begins in the PT. The existence of peculiar glandular cells speaks in favour of a specific but still unknown function of the PT during foetal and adult life.


Misery loves company: Predictors of treatment response to a loneliness intervention.
The last 10 years have seen a surge of interest in loneliness and interventions to reduce it. However, there is little evidence regarding differential treatment effectiveness and predictors of treatment outcome. This paper aimed to investigate possible predictors of treatment response. We analysed data from two clinical trials of an evidence-based loneliness intervention: Groups 4 Health (G4H). Study 1 had 163 observations across two timepoints, n = 94; Study 2 had 297 observations across four timepoints; n = 84. Theorised predictors-symptom severity at baseline, program engagement, and demographic characteristics-were assessed for their effect on the primary outcome: loneliness. Across both trials, participants with more severe baseline loneliness or social anxiety, or who attended more sessions, experienced greater improvement in loneliness. In Study 2, those with diagnosed mental illness or more severe baseline depression also tended to have better outcomes. There was no evidence that age, gender, or ethnicity predicted program efficacy. Overall, those with greater need-reflected in either severity of loneliness or psychological distress-tended to show greater improvement over time. This was due, in part, to greater engagement with the program among those who were lonelier. We discuss how loneliness interventions can be deployed most effectively to combat this profound public health challenge.


Co-combustion, life-cycle circularity, and artificial intelligence-based multi-objective optimization of two plastics and textile dyeing sludge.
Given the globally abundant availability of waste plastics and the negative environmental impacts of textile dyeing sludge (TDS), their co-combustion can effectively enhance the circular economies, energy recovery, and environmental pollution control. The (co-)combustion performances, gas emissions, and ashes of TDS and two plastics of polypropylene (PP) and polyethylene (PE) were quantified and characterized. The increased blend ratio of PP and PE improved the ignition, burnout, and comprehensive combustion indices. The two plastics interacted with TDS significantly in the range of 200-600 ℃. TDS pre-ignited the combustion of the plastics which in turn promoted the combustion of TDS. The co-combustions released more CO2 but less CH4, C-H, and CO as CO2 was less persistent than the others in the atmosphere. The Ca-based minerals in the plastics enhanced S-fixation and reduced SO2 emission. The activation energy of the co-combustion fell from 126.78 to 111.85 kJ/mol and 133.71-79.91 kJ/mol when the PE and PP additions rose from 10% to 50%, respectively. The co-combustion reaction mechanism was best described by the model of f(α) = (1-α)n. The reaction order was reduced with the additions of the plastics. The co-combustion operation interactions were optimized via an artificial neural network so as to jointly meet the multiple objectives of maximum energy production and minimum emissions.


Delayed diagnosis of congenital hypopituitarism associated with low socio-economic status and/or migration.
The clinical presentation of combined pituitary hormone deficiency (CPHD) is variable. Some patients present with hypoglycemia during the neonatal period or during the first few years of life. Others present later in childhood with growth failure. We report on 7 patients with very late diagnosed severe hypopituitarism with pituitary stalk interruption syndrome. Five out of the 7 patients had recently migrated to Belgium and the 2 other patients were from low socio-economic status families. All of them presented to our clinic for short stature and some also complained of lack of pubertal development. Four out of the 7 patients reached final height which was within their target height, despite very delayed treatment.Conclusion: We illustrate the overall good outcome of these children with delayed diagnosed severe hypopituitarism. Adverse life conditions and social deprivation are thought to be the cause of their late diagnosis. In the current global socio-politic context, pediatricians in high-income countries should stay aware that migration and poor socio-economic status can be associated with specific clinical presentations.What is Known:• The clinical presentation of combined pituitary hormone deficiency (CPHD) is variable. Some patients present with hypoglycemia during the neonatal period or during the first few years of life. Others present later in childhood with growth failure.• A few case reports are published with very late diagnosis of congenital hypopituitarism.What is New:• We report on the largest series of delayed diagnosis of congenital hypopituitarism and illustrate the survival of these children with overall good prognosis.• Migration and social deprivation are thought to be the main cause of this late diagnosis.


Understanding the metabolic and health effects of low-calorie sweeteners: methodological considerations and implications for future research.
Consumption of foods, beverages, and packets containing low-calorie sweeteners (LCS) has increased markedly across gender, age, race/ethnicity, weight status, and socio-economic subgroups. However, well-controlled intervention studies rigorously evaluating the health effects of LCS in humans are limited. One of the key questions is whether LCS are indeed a beneficial strategy for weight management and prevention of obesity. The current review discusses several methodological considerations in the design and interpretation of these studies. Specifically, we focus on the selection of study participants, inclusion of an appropriate control, importance of considering habitual LCS exposure, selection of specific LCS, dose and route of LCS administration, choice of study outcomes, and the context and generalizability of the study findings. These critical considerations will guide the design of future studies and thus assist in understanding the health effects of LCS.


Importance of checking prehospital neurological findings to reveal incidence of spinal cord concussion.
To clarify the incidence and characteristics of spinal cord concussion in an urban city in Japan. The current retrospective study was conducted by reviewing the medical records of patients with spinal cord injuries admitted between January 2007 and December 2010. The subjects were divided into two groups: a spinal cord concussion group and a spinal cord injury group. There were 36 patients with spinal cord injuries admitted during this period. Among them, there were 8 patients with spinal cord concussions. No significant differences were apparent between the two groups with regard to sex, mechanism of injury, Glasgow Coma Scale, incidence of shock, inhospital Frankel classification, level of spinal cord injury, frequency of vertebral dislocation/fracture, surgery and the survival rate. However, the mean age in the spinal cord concussion group was lower than that in the spinal cord injury group. The systolic blood pressure, the heart rate and the diameter of minimum spinal canal in the concussion group were all higher than those in the spinal cord injury group. Half of the subjects in the spinal cord concussion group demonstrated immediate neurological improvement between prehospital and inhospital findings, however none of the subjects in the spinal cord injury group demonstrated such improvement. This difference was statistically significant. Spinal cord concussion is not rare in urban Japan. Checking neurological findings at the scene leads to the revelation of the true high incidence of spinal cord concussion among spinal cord injuries.


Challenging Mycobacterium tuberculosis dormancy mechanisms and their immunodiagnostic potential.
Mycobacterium tuberculosis is the etiologic agent of tuberculosis, one of the world's greatest cause of morbidity and mortality due to infectious disease. Many evolutionary mechanisms have contributed to its high level of adaptation as a host pathogen. Prior to become dormant, a group of about 50 genes related to metabolic changes are transcribed by the DosR regulon, one of the most complex and important systems of host-pathogen interaction. This genetic mechanism allows the mycobacteria to persist during long time periods, establishing the so-called latent infection. Even in the presence of a competent immune response, the host cannot eliminate the pathogen, only managing to keep it surrounded by an unfavorable microenvironment for its growth. However, conditions such as immunosuppression may reestablish optimal conditions for bacterial growth, culminating in the onset of active disease. The interactions between the pathogen and its host are still not completely elucidated. Nonetheless, many studies are being carried out in order to clarify this complex relationship, thus creating new possibilities for patient approach and laboratory screening.


LOWER POSTERIOR CINGULATE CORTEX GLUTATHIONE LEVELS IN OBSESSIVE-COMPULSIVE DISORDER.
Several lines of evidence support the hypothesis that lower cerebral levels of glutathione (GSH), associated with increased oxidative stress, may contribute to obsessive-compulsive disorder (OCD). However, no studies to date have investigated brain GSH levels in individuals with OCD. Twenty-nine individuals with OCD and 25 age-, sex-, and race-matched comparison individuals without OCD underwent single voxel 2D J-resolved proton magnetic resonance spectroscopy (MRS) to examine GSH levels in the posterior cingulate cortex (PCC). MRS data were analyzed using LCModel and a simulated basis set. Group metabolite differences referenced to total creatine (Cr), as well as relationships between metabolite ratios and symptom severity as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), were analyzed using linear regression with adjustment for age, sex, and race. One OCD participant failed to produce usable PCC MRS data. We found significantly lower PCC GSH/Cr in OCD participants compared with non-OCD participants (β = -0.027 [95% CI: -0.049 to -5.9 × 10-3]; P = 0.014). PCC GSH/Cr was not significantly associated with total Y-BOCS score in the OCD group (β = 5.7 × 10-4 [95% CI: -4.8 × 10-3 to 5.9 × 10-3]; P = 0.83). Lower PCC GSH/Cr may be indicative of increased oxidative stress secondary to hypermetabolism in this brain region in OCD. Future MRS studies are warranted to investigate GSH levels in other brain regions that comprise the cortico-striato-thalamo-cortical circuit thought to be abnormal in OCD.


Carbonized wood impregnated with bimetallic nanoparticles as a monolithic continuous-flow microreactor for the reduction of 4-nitrophenol.
Porous monolithic microreactors show great promise in catalytic applications, but are usually based on non-renewable materials. Herein, we demonstrate a Ni/Au nanoparticle-decorated carbonized wood (Ni/Au-CW) monolithic membrane microreactor for the efficient reduction of 4-nitrophenol. The hierarchical porous wood structure supports uniformly distributed heterobimetallic Ni/Au nanoparticles. As a consequence of these two factors, both mass diffusion and electron transfer are enhanced, resulting in a superior reduction efficiency of 99.5% as the liquor flows through the optimised Ni/Au-CW membrane. The reaction mechanism was investigated by electron paramagnetic resonance spectroscopy and density functional theory calculations. The proposed attraction-repulsion mechanism facilitated by the bimetallic nanoparticles has been ascribed to the different electronegativities of Ni and Au. The Ni/Au-CW membrane exhibits excellent catalytic performance and could be applicable to other catalytic transformations.


Selective distribution pattern of gamma-hydroxybutyrate receptors in the rat forebrain and midbrain as revealed by quantitative autoradiography.
Using quantitative autoradiography to study the precise distribution of gamma-hydroxybutyrate high-affinity binding sites, the present results showed the heterogeneous localization of these sites in cortical and hippocampal layers and also in some diencephalic and mesencephalic nuclei. In frontal, parietal and temporal cortex, GHB binding sites are generally distributed in three distinct layers. The olfactory system, the amygdala, septum, basal ganglia and substantia nigra also exhibited significant amounts of GHB receptors. In thalamus, the radioactivity was heterogeneously distributed, the highest amounts being in the lateral posterior nucleus. Hypothalamus, cerebellum, colliculi and pons-medulla were apparently devoid of binding sites. This more accurate mapping of GHB high-affinity receptors in rat brain is due to some technical improvements and the use of [3H]GHB of higher specific activity.


Occluso-cranial correlates of attrition in a preliterate population. A cross-sectional study.
Evaluation of dental casts of 202 living Lengua Indians from Paraguay finds progressive reduction in overjet with age, but no Class III or indication of altered relationship of mandible to cranial base.


Correction: Chromosomal-Level Assembly of the Asian Seabass Genome Using Long Sequence Reads and Multi-layered Scaffolding.
[This corrects the article DOI: 10.1371/journal.pgen.1005954.].


Partial characterization and amino acid composition of a high molecular weight peptide with salmon calcitonin immunoreactivity in a crustacean: Nephrops norvegicus.
Anti-salmon calcitonin antibodies were used to follow the purification of a high molecular weight peptide present both in the haemolymph and in the hepatopancreas of the Norway lobster Nephrops norvegicus. An apparent molecular weight of 22 kDa has been measured in electrophoresis on SDS gels and amino acid composition compared to salmon calcitonin. The amount determined by the immunoreactivity assay corresponds to about 1/40 and 1/140 of that which is based on direct protein measurement for the hepatopancreas and the haemolymph respectively. The total amount of this peptide could be estimated as 3.5 mg/g fresh weight for the hepatopancreas and 140 ug/ml for the haemolymph. The function of this peptide is still unknown.


Stimulatory effects of chitinase on growth and immune defense of orange-spotted grouper (Epinephelus coioides).
Chitinase, belonging to either family 18 or family 19 of the glycosylhydrolases, hydrolyze chitin into oligosaccharides. In the present study, the cDNA fragment encoding orange-spotted grouper (Epinephelus coioides) chitinase1 was subcloned into pPIC3.5K vector and expressed in Pichia pastoris GS115. The results showed that a band with the size of about 53 kDa could be detected by SDS-PAGE and Western blot. The recombinant protein of grouper chitinase1 (rgChi1) was added into the fish diet containing shrimp shell chitin for feeding experiment lasting 8 weeks. The weight of orange-spotted grouper, fed with diets containing rgChi1 at 0, 5, 10 and 20 μg/g was calculated on the 2nd, 4th, 6th and 8th weeks, and difference in growth rates was first observed in the 6th week of the feeding period and it kept until the end of the feeding experiment. At the end of 8 weeks feeding trial, the percent weight gain (PWG), growth rate (GR) and specific growth rate (SGR) of fish fed with 10 and 20 μg rgChi1/g feed were significantly higher compared to the control group. The neuropeptide Y (NPY), growth-hormone-releasing hormone (GHRH), growth-hormone (GH), interleukin-1beta (IL-1β), cyclooxygenase-2 (COX-2), superoxide dismutase (SOD) (Cu/Zn) and SOD (Mn) mRNA expression of fish fed with diet containing 10 μg/g or/and 20 μg/g rgChi1 were obviously higher than the control group. The lysozyme (LZM) and total SOD activity of fish fed with diet containing rgChi1 at 10 and 20 μg/g were significantly higher than that of the control. The aspartate aminotransferase (AST)/glutamic oxalacetic transaminases (GOT) activity in 20 μg/g group decreased compared to the control group. These results indicated that the grouper chitinase1 was successfully produced using the P. pastoris expression system and the recombinant protein had obvious effects on growth and immune defense. The mRNA expression and protein secretion of grouper chitinase1 and chitinase2 were significantly stimulated in spleen in response to bacterial lipopolysaccharide (LPS) challenge, strongly suggesting the existence of an innate pathway for local defense against chitin-containing organisms. Moreover, the pathogen such as Escherichia coli and Staphylococcus aureus could be inhibited by the recombinant protein of grouper chitinase1 to a certain extent.


Determination of in vitro stability of routine haematinics tests using EFLM standards and the CRESS checklist.
Laboratories should be aware of the stability of the analytes they are testing in order to avoid incorrect reporting and patient management. Stability studies are difficult to interpret and reproduce, with little guidance on how to determine appropriate clinical cut off values. Here we describe a standardised approach to determining stability for routine haematinics tests using published EFLM guidelines. The haematinics panel at UHNM contains vitamin B12, folate, ferritin, iron and transferrin. Blood tubes included were serum separator tubes, gel-free serum and lithium-heparin plasma. Conditions tested were room temperature, 2-8°C and -20°C. For each condition and tube, three samples were analysed in duplicate at 0, 24, 48, 72, 96 and 120 h using the Siemens Atellica platform. The percentage difference was calculated for each respective blood tube and storage condition, in addition to individual analyte maximum permissible instability scores. The majority of analytes for all blood tubes were stable for 5 days or more when stored at 4-8°C and -20°C. Ferritin (excluding gel-free), iron and transferrin further showed stability >5 days when stored at room temperature. However, vitamin B12 and folate demonstrated poor stability data for all tube types tested. Here we describe a stability study for the haematinics panel on the Siemens Atellica platform using the standardised EFLM Checklist for Reporting Stability Studies (CRESS). The checklist was used in order to promote a standardised and transferable scientific approach to what has previously been lacking in the literature when performing stability experiments.


Application of FISH 7q in MDS patients without monosomy 7 or 7q deletion by conventional G-banding cytogenetics: does -7/7q- detection by FISH have prognostic value?
Chromosomal abnormalities are detected in 40-60% of patients with de novo myelodysplastic syndromes (MDS). This study used the FISH technique in 773 patients with de novo MDS without evidence of monosomy 7 (-7) or 7q deletion (7q-) by conventional G-banding cytogenetics (CC) to analyze their prognostic impact by FISH alone. FISH detected -7/7q- in 5.2% of patients. Presence of -7/7q- was associated with shorter overall survival than absence of such aberrations. Our results suggest that FISH 7q could be beneficial in patients with intermediate WHO morphologic risk stratification and no evidence of -7/7q- by CC.


Multiple antibodies targeting tumor-specific mutations redirect immune cells to inhibit tumor growth and increase survival in experimental animal models.
T cell therapy for cancer involves genetic introduction of a target-binding feature into autologous T cells, ex vivo expansion and single large bolus administration back to the patient. These reprogrammed T cells can be highly effective in killing cells, but tumor heterogeneity results in regrowth of cells that do not sufficiently express the single antigen being targeted. We describe a cell-based therapy that simultaneously targets multiple tumor-specific antigens. High-affinity polyclonal rabbit antibodies were generated against nine different surface-related tumor-specific mutations on B16F10 cells. Unsorted splenic effector cells from syngeneic mice were incubated with a cocktail of the nine anti-B16F10 antibodies. These 'armed' effector cells were used to treat mice previously inoculated with B16F10 melanoma cells. The cocktail of nine antibodies resulted in dense homogeneous binding to histological sections of B16F10 cells. Five treatments with the armed effector cells and PD1 inhibition inhibited tumor growth and improved survival. Shortening the interval of the five treatments from every three days to every day increased survival. Arming effector cells with the four antibodies showing best binding to B16F10 cells even further increased survival. This study demonstrates that ex vivo arming a mixed population of immune effector cells with antibodies targeting multiple tumor-specific mutated proteins in conjunction with PD1 inhibition delayed tumor growth and prolonged survival in mice inoculated with an aggressive melanoma. A remarkably low total antibody dose of less than 5 µg was sufficient to accomplish tumor inhibition. Scaling up to clinical level may be feasible.


Alirocumab: A Review in Hypercholesterolemia.
Alirocumab (Praluent(®)) is a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered via subcutaneous injection every 2 weeks. Across ten phase III studies from the ODYSSEY clinical trial program in patients with heterozygous familial hypercholesterolemia (heFH) or nonfamilial hypercholesterolemia (nonFH), including some with mixed dyslipidemia, subcutaneous alirocumab 75 or 150 mg every 2 weeks was significantly more effective with regard to reducing low-density lipoprotein-cholesterol (LDL-C) over 24 weeks than comparator agents (i.e. matching placebo, once-daily oral ezetimibe, or modified oral statin therapy), including when administered as monotherapy or in combination with statin therapy, and when administered with non-statin lipid-lowering therapy (LLT) in patients with statin intolerance. Alirocumab provided sustained LDL-C-lowering efficacy over 52-78 weeks' treatment in longer-term trials, and was associated with significantly favorable effects on several other lipid parameters, including non-high-density lipoprotein-cholesterol (non-HDL-C) and lipoprotein (a) [Lp(a)]. Alirocumab was generally well tolerated in phase III trials, with no apparent increase in muscle-related adverse events compared with placebo. Thus, alirocumab is a valuable emerging option for use in patients with hypercholesterolemia, particularly patients with statin intolerance or inadequately-controlled LDL-C despite statin therapy; however, more data are needed to establish its potential cardiovascular benefits.


The 1.8 Å cholix toxin crystal structure in complex with NAD+ and evidence for a new kinetic model.
Certain Vibrio cholerae strains produce cholix, a potent protein toxin that has diphthamide-specific ADP-ribosyltransferase activity against eukaryotic elongation factor 2. Here we present a 1.8 Å crystal structure of cholix in complex with its natural substrate, nicotinamide adenine dinucleotide (NAD(+)). We also substituted hallmark catalytic residues by site-directed mutagenesis and analyzed both NAD(+) binding and ADP-ribosyltransferase activity using a fluorescence-based assay. These data are the basis for a new kinetic model of cholix toxin activity. Further, the new structural data serve as a reference for continuing inhibitor development for this toxin class.


Treatment Pattern and Outcomes in Newly Diagnosed Multiple Myeloma Patients Who Did Not Receive Autologous Stem Cell Transplantation: A Real-World Observational Study : Treatment pattern and outcomes in patients with multiple myeloma.
The objective of this study was to describe the treatment patterns among patients with newly diagnosed multiple myeloma (MM) who had not received autologous stem cell transplantation (ASCT). It further compares the safety and clinical outcomes across different frontline regimens as well as explores whether treatment duration predicts outcomes. Patients with MM (> 45 years) who had not received ASCT were retrospectively identified from the US SEER-Medicare (Jan 2007-Dec 2016) and Optum (Jan 2007-Sep 2018) databases. Cox proportional hazard models were used to compare overall survival (OS) among bortezomib + lenalidomide + dexamethasone regimen (VRd), lenalidomide + dexamethasone regimen (Rd), cyclophosphamide + bortezomib + dexamethasone regimen (CyBorD), bortezomib + dexamethasone regimen (Vd), and other bortezomib-containing therapies based on propensity score matching. To address immortal time bias, time-fixed and time-dependent Cox models were employed to estimate the association of longer frontline treatment exposure with outcomes. Mean (standard deviation; SD) age was 71 (9.8) years; and 49.51% were women. Bortezomib and lenalidomide-based combinations were the most common treatment modalities. After matching, the HR (95% CI) of OS by frontline therapies comparing VRd with Vd was 0.76 (0.66, 0.86), CyBorD was 0.87 (0.75, 1.05), for other bortezomib-based therapies was 0.56 (0.49, 0.64), Rd was 0.83 (0.73, 0.95), and for other therapies was 0.70 (0.61, 0.80). Longer frontline treatment duration was associated with better OS for overall frontline [HR (95% CI) 0.86 (0.82, 0.90)]; Vd [0.81 (0.74, 0.89)]; CyBorD [0.79 (0.64, 0.98)] and Rd [0.86 (0.78, 0.95)]. Results demonstrated that the frontline therapies prescribed to most patients who did not receive ASCT for MM in the United States were consistent with the NCCN guideline recommendations. Longer frontline treatment duration was associated with improved OS.


Triterpenoid saponins from the roots of two Gypsophila species.
Two triterpenoid saponins with two known ones have been isolated from the roots of Gypsophila arrostii var. nebulosa, and two new ones from the roots of Gypsophila bicolor. Their structures were established by extensive NMR and mass spectroscopic techniques as 3-O-β-d-galactopyranosyl-(1→2)-[β-d-xylopyranosyl-(1→3)]-β-d-glucuronopyranosylquillaic acid 28-O-β-d-xylopyranosyl-(1→4)-[β-d-glucopyranosyl-(1→3)]-α-l-rhamnopyranosyl-(1→2)-[β-d-glucopyranosyl-(1→4)]-β-d-fucopyranosyl ester (1), 3-O-β-d-galactopyranosyl-(1→2)-[β-d-xylopyranosyl-(1→3)]-β-d-glucuronopyranosylgypsogenin 28-O-β-d-xylopyranosyl-(1→4)-[β-d-glucopyranosyl-(1→3)]-α-l-rhamnopyranosyl-(1→2)-[β-d-glucopyranosyl-(1→4)]-β-d-fucopyranosyl ester (2), 3-O-β-d-galactopyranosyl-(1→2)-[β-d-xylopyranosyl-(1→3)]-β-d-glucuronopyranosylgypsogenin 28-O-β-d-xylopyranosyl-(1→3)-β-d-xylopyranosyl-(1→4)-α-l-rhamnopyranosyl-(1→2)-[(4-O-acetyl)-β-d-quinovopyranosyl-(1→4)]-β-d-fucopyranosyl ester (3), gypsogenic acid 28-O-β-d-glucopyranosyl-(1→3)-{6-O-[3-hydroxy-3-methylglutaryl]-β-d-glucopyranosyl-(1→6)}-β-d-galactopyranosyl ester (4). Three compounds were evaluated against one human colon cancer cell line SW480 and one rat cardiomyoblast cell line H9c2.


Use of an Enrichment Broth Improves Detection of Extended-Spectrum-Beta-Lactamase-Producing Enterobacteriaceae in Clinical Stool Samples.
This study evaluated the impact of preenrichment on the detection of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) in clinical stool samples. ESBL-E were detected in 41 of 343 patients (12.0%). As 31.7% of the ESBL-E carriers were identified by preenrichment, only this additional diagnostic step significantly improved the detection of ESBL-E.


A meta-analysis to identify novel diagnostic and therapeutic targets for Dupuytren's disease.
The aim of this study was to determine novel candidate genes for Dupuytren's disease by performing a meta-analysis. We identified 261 genes (111 up-regulated and 150 down-regulated) that were consistently expressed differentially in Dupuytren's disease across the studies. We performed functional enrichment on total sets of the identified 261 genes and confirmed that most of the genes were closely related to common processes of diseases in general. From the integrated studies of the gene-correlation network and the protein-protein interaction network, we identified three functional modules in the gene co-expression network and four hub gene clusters in the protein-protein interaction network that shared the same genes and represented similar biological functions, implying that the seven groups identified in the systematic analysis of these two networks might be involved in the pathogenesis of Dupuytren's disease. This work demonstrates potential in developing experimental and clinical strategies for understanding and treating Dupuytren's disease.


Acquired erythropoietin responsiveness of interleukin-2-dependent T lymphocytes retrovirally transduced with genes encoding chimeric erythropoietin/interleukin-2 receptors.
Adoptive immunotherapy with tumor-infiltrating lymphocytes (TILs) causes regression of some human tumors. However, the sustained proliferation and antitumor activity of TILs requires the coadministration of potentially toxic amounts of interleukin-2 (IL-2). In an effort to overcome the requirement by T cells for IL-2, we have introduced alternative growth factor receptors that use the relatively nontoxic cytokine erythropoietin (Epo) as a ligand. In our model system, the coexpression of chimeric receptors consisting of the extracellular portion of the Epo receptor (EpoR) and the intracellular portions of the IL-2 receptor subunits, beta and gamma, conferred Epo responsiveness on a T-cell line. By contrast, cells expressing the wild-type EpoR did not proliferate in response to Epo. This suggested that Epo binding caused the activation of an IL-2 signal pathway mediated by the chimeric receptors. This approach can be used to minimize toxicity and potentially improve cancer immunotherapy with TILs.


Sex- and Age-Specific Trends in Cardiovascular Health in Korea, 2007-2018.
We illustrated sex- and age-specific temporal trends in cardiovascular health among Korean adults. From the Korean National Health and Nutrition Examination Survey 2007-2018, we included 61,408 participants aged 20 years or older. The ideal levels of 6 components of cardiovascular health metrics were defined as never-smoking, ≥75 min/week of vigorous or ≥150 min/week of moderate-to-vigorous physical activity, body mass index (BMI) <23 kg/m², total cholesterol <200 mg/dL, blood pressure (BP) <120/80 mmHg, and fasting glucose <100 mg/dL. Temporal trends in the number of ideal cardiovascular health components and distribution of each component were assessed by sex and age. The average number of ideal cardiovascular health components decreased from 3.37 in 2007-2009 to 2.86 in 2016-2018. Never smoking increased from 56.0% to 59.2%, largely contributed by young men. Ideal physical activity halved (41.4-21.3%); such decline was more pronounced in women and with older age. Ideal BMI decreased from 44.3% to 42.2%, more apparently in young and elderly men. In contrast, ideal BMI increased in middle-aged and elderly women. Ideal cholesterol decreased from 65.5% to 50.3%, profoundly in young adults and relatively greater in men. Ideal BP declined from 55.1% to 46.9%, more evidently in men. However, ideal BP discernibly increased in middle-aged women. Ideal glucose decreased from 74.6% to 66.0%, comparatively greater and earlier in men. The proportion of Korean adults with ideal cardiovascular health decreased between 2007 and 2018, but the course of responsible factors differed across sex and age groups.


Ball-and-socket ankle joint.
The ball-and-socket ankle joint is a malformation of the ankle in which the articular surface of the talus is hemispherical in both the anteroposterior and lateral projections and has a congruent, concave tibial articular surface. Fourteen patients with this condition were identified retrospectively. Thirteen patients were thought to have the congenital type of ball-and-socket ankle joint which in many was associated with tarsal coalition, short limb, and ray fusion and deletion anomalies. One case of the acquired type, demonstrating less geometric rounding of the talar margins, was seen in a patient with myelomeningocele, probably resulting from sensory and motor deficits. Although the exact etiology of the congenital type is unknown, its association with other malformations suggests that the ball-and-socket ankle joint results from an overall maldevelopment of the ankle and foot.


Study of the metabolism of pyrazinamide using a high-performance liquid chromatographic analysis of urine samples.
A reversed-phase high-performance liquid chromatographic method was developed for the simultaneous determination of pyrazinamide and its metabolites in urine. Study of the metabolism of pyrazinamide by this method demonstrated that 5-hydroxypyrazinamide excretion was compatible with pyrazinoic acid excretion and allopurinol decreased in vivo conversion of pyrazinamide to 5-hydroxypyrazinamide and blocked that of pyrazinoic acid to 5-hydroxypyrazinoic acid.


Enzyme linked immunosorbent assay (ELISA) for the determination of protein-A.
A competitive ELISA for the determination of protein-A concentration in culture supernatants is described. The sensitivity of the assay is 50 ng/ml and it may be used to determine concentrations of protein-A up to 1000 ng/ml. The assay is specific, rapid and suitable for routine screening of protein-A producing microorganisms.


Alterations in ingestive behavior following experimental portacaval anastomosis in rats.
Following surgical construction of an end-to-side portacaval shunt (PCS), male rats exhibited exaggerated consumption of glucose, saccharin, saline, and ethanol solutions relative to sham-operated rats in 24-hr preference tests with water present. Spontaneous daily water intake was also increased, but daily food intake and body weight were decreased by PCS. The overconsumption of glucose, saccharin, and saline exhibited by rats with portacaval shunts was reduced, or eliminated, by providing a corn supplement to their diet, consistent with the view that the disturbance of amino acid balance may have contributed to this ingestive abnormality. In a series of short drinking tests, rats with portacaval shunts consumed more of both 10% glucose and 10% fructose (given in separate tests) than sham-operated rats and glucose intake was greater than fructose intake for both of these groups. However, neither surgical nor saccharide condition affected the duration of the first bout or the initial inter-bout interval, indicating that the relative satiating properties of these two monosaccharides were probably not altered by portacaval shunting.


Macrophage Dectin-1 mediates Ang II renal injury through neutrophil migration and TGF-β1 secretion.
Macrophage activation has been shown to play an essential role in renal fibrosis and dysfunction in hypertensive chronic kidney disease. Dectin-1 is a pattern recognition receptor that is also involved in chronic noninfectious diseases through immune activation. However, the role of Dectin-1 in Ang II-induced renal failure is still unknown. In this study, we found that Dectin-1 expression on CD68 + macrophages was significantly elevated in the kidney after Ang II infusion. We assessed the effect of Dectin-1 on hypertensive renal injury using Dectin-1-deficient mice infused by Angiotensin II (Ang II) at 1000 ng/kg/min for 4 weeks. Ang II-induced renal dysfunction, interstitial fibrosis, and immune activation were significantly attenuated in Dectin-1-deficient mice. A Dectin-1 neutralizing antibody and Syk inhibitor (R406) were used to examine the effect and mechanism of Dectin-1/Syk signaling axle on cytokine secretion and renal fibrosis in culturing cells. Blocking Dectin-1 or inhibiting Syk significantly reduced the expression and secretion of chemokines in RAW264.7 macrophages. The in vitro data showed that the increase in TGF-β1 in macrophages enhanced the binding of P65 and its target promotor via the Ang II-induced Dectin-1/Syk pathway. Secreted TGF-β1 caused renal fibrosis in kidney cells through Smad3 activation. Thus, macrophage Dectin-1 may be involved in the activation of neutrophil migration and TGF-β1 secretion, thereby promoting kidney fibrosis and dysfunction.


C-reactive protein and dietary nutrients in urban Asian Indian adolescents and young adults.
The relationship between C-reactive protein (CRP), a surrogate marker of cardiovascular risk, and dietary nutrients is not known. We investigated the relationship between serum CRP levels and dietary nutrients in young Asian Indians residing in a major metropolitan city in north India. Dietary nutrient intake values (24-h dietary recall and monthly consumption data) and serum CRP levels were studied in 359 healthy adolescents and young adults (312 male and 47 female) (mean age, 18.0 +/- 2.3 y; range, 14-25 y), after carefully excluding those with history of infections and smoking. Bivariate and multivariate logistic regression analysis was performed with CRP [raised (>3.0 mg/L)/normal] as the outcome variable and various dietary nutrients and anthropometric variables as covariates. Mean CRP level was 1.3 +/- 2.3 mg/L (range, 0.02-17.5 mg/L). Raised CRP levels (>3 mg/L) were noted in 9% study subjects (8.6% males and 12.8% females). After adjustment for other covariates, saturated fat emerged as the single most important nutrient contributing to increase in serum CRP levels. The odds of having a raised CRP level in subjects consuming more than 10% energy as saturated dietary fat were twice as compared to subjects having a normal saturated fat intake [Adjusted odds ratio (OR) (95% CI) = 2.0 (0.94-4.1)]. For every one percent decrease in energy intake by saturated fat, CRP level was calculated to decrease by 0.14 mg/L. For decreasing CRP levels to <1.0 mg/L (low risk for cardiovascular disease), Asian Indian adolescents and young adults should ensure saturated fat intake <7% of caloric intake. We suggest that daily saturated fat intake should be limited to <7% of caloric intake in urban adolescents and young adult Asian Indians to decrease their future cardiovascular risk.


Intractable seizures in a 4-month-old girl.
A 4-month-old, 7-kg girl with a 3-day history of mild diarrhea was brought into a rural emergency department (ED) by private vehicle. The patient's parents reported that the child was in her usual state of health until the past several days, when she began having multiple loose stools. After an extensive interview, the family said she was born full term without any complications. She had never been hospitalized and was up to date on all of her immunizations. Family also stated emphatically that there was no alteration in her formula concentration and intake before her presentation. Approximately 30 minutes before her arrival, her parents noticed "shaking of the extremities" consistent with seizure activity. Concurrently, they noted she had irregular respirations and was not acting at her baseline.


Visible light functioning photocatalyst based on Al2O3 doped Mn3O4 nanomaterial for the degradation of organic toxin.
Al2O3 doped Mn3O4 nanomaterial was synthesized by low-temperature stirring method and applied as a catalyst for the degradation of organic pollutants under solar light for prospective environmental applications. The morphological and physiochemical structure of the synthesized solar photocatalyst was investigated by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), energy-dispersive spectroscopy (EDS), Fourier transform infrared spectroscopy (FT-IR), and X-ray photoelectron spectroscopy (XPS). FESEM showed a mixture of nanowires and aggregated nanoparticles. This Al2O3 doped Mn3O4 nanomaterial exhibited high solar photocatalytic degradation in a short time when applied to brilliant cresyl blue (BCB). Thus, the synthesized nanoparticles can be used as an efficient solar photocatalyst for the degradation of BCB.


Avoiding revascularization with lifestyle changes: The Multicenter Lifestyle Demonstration Project.
The Multicenter Lifestyle Demonstration Project was designed to determine if comprehensive lifestyle changes can be a direct alternative to revascularization for selected patients without increasing cardiac events. A total of 333 patients completed this demonstration project (194 in the experimental group and 139 in the control group). We found that experimental group patients were able to avoid revascularization for at least 3 years by making comprehensive lifestyle changes at substantially lower cost without increasing cardiac morbidity and mortality. These patients reported reductions in angina comparable with what can be achieved with revascularization.


The Evolution of Educational Technology in Veterinary Anatomy Education.
"All learning is in the learner, not the teacher." Plato was right. The adage has passed the test of time and is still true in an era where technology accompanies us in not only professional but also recreational life every day, everywhere. On the other hand, the learner has evolved and so have the sources being used to satisfy curiosity and learning. It therefore appears intuitive to embrace these technological advances to bring knowledge to our pupils with the aim to facilitate learning and improve performance. It must be clear that these technologies are not intended to replace but rather consolidate knowledge partly acquired during more conventional teaching of anatomy. Veterinary medicine is no outlier. Educating students to the complexity of anatomy in multiple species requires that three-dimensional concepts be taught and understood accurately if appropriate treatment is to be set in place thereafter. Veterinary anatomy education has up to recently walked diligently in the footsteps of John Hunter's medical teaching using specimens, textbooks, and drawings. The discipline has yet to embrace fully the benefits of advancement being made in technology for the benefit of its learners. Three-dimensional representation of anatomy is undeniably a logical and correct way to teach whether it is through the demonstration of cadaveric specimen or alternate reality using smartphones, tablets, headsets or other digital media. Here we review some key aspects of the evolution of educational technology in veterinary anatomy.


Evidence for two different types of P2 receptors stimulating insulin secretion from pancreatic B cell.
Adenine nucleotides have been shown to stimulate insulin secretion by acting on P2 receptors of the P2Y type. Since there have been some discrepancies in the insulin response of different analogues of ATP and ADP, we investigated whether two different types of P2 receptors exist on pancreatic B cells. The effects of alpha,beta-methylene ATP, which is more specific for the P2X subtype, were studied in vitro in pancreatic islets and isolated perfused pancreas from rats, in comparison with the potent P2Y receptor agonist ADPbetaS. In isolated islets, incubated with a slightly stimulating glucose concentration (8.3 mM), alpha,beta-me ATP (200 microM) and ADPbetaS (50 microM) similarly stimulated insulin secretion; by contrast, under a non stimulating glucose concentration (3 mM), alpha,beta-me ATP was still effective whereas ADPbetaS was not. In the same way, in islets perifused with 3 mM glucose, alpha,beta-me ATP but not ADPbetaS induced a partial but significant reduction in the peak 86Rb efflux induced by the ATP-dependent potassium channel opener diazoxide. In the isolated pancreas, perfused with a non stimulating glucose concentration (4.2 mM), ADPbetaS and alpha,beta-me ATP (5-50 microM), administered for 10 min, induced an immediate, transient and concentration-dependent increase in the insulin secretion; their relative potency was not significantly different. In contrast, with a slightly stimulating glucose concentration (8.3 mM), ADPbetaS was previously shown to be 100 fold more potent than alpha,beta-me ATP. Furthermore, at 4.2 mM glucose a second administration of alpha,beta-me ATP was ineffective. In the same way, ADPbetaS was also able to desensitize its own insulin response. At 3 mM glucose, alpha,beta-me ATP as well as ADPbetaS (50 microM) induced a transient stimulation of insulin secretion and down regulated the action of each other. These results give evidence that pancreatic B cells, in addition to P2Y receptors, which potentiate glucose-induced insulin secretion, are provided with P2X receptors, which transiently stimulate insulin release at low non-stimulating glucose concentration and slightly affect the potassium conductance of the membrane.


New spirostanol glycosides from Solanum nigrum and S. jasminoides.
A new characteristic steroidal glycoside possessing a hydroxyl group at C-23, inunigroside A (1), was isolated from the withered berries of Solanum nigrum L. On the basis of spectroscopic analysis, the structure of 1 was characterized as (5α,22S,23S,25R)-3β,23-dihydroxyspirostane 3-O-β-lycotetraoside. Next, a major steroidal sapogenol, (22R, 25S)-3β,15α-dihydroxy-spirost-5-ene (3), was obtained from the acid hydrolysate of the methanolic extract of the aerial parts of Solanum jasminoides L. A new bisdesmoside, 3-O-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl (22R,25S)-3β,15α-dihydroxyspirost-5-ene 15-O-α-L-rhamnopyranoside (4), named jasminoside A, was isolated from the methanolic extract of S. jasminoides.


PTEN-induced kinase 1 (PINK1) and Parkin: Unlocking a mitochondrial quality control pathway linked to Parkinson's disease.
Dissection of the function of two Parkinson's disease-linked genes encoding the protein kinase, PTEN-induced kinase 1 (PINK1) and ubiquitin E3 ligase, Parkin, has illuminated a highly conserved mitochondrial quality control pathway found in nearly every cell type including neurons. Mitochondrial damage-induced activation of PINK1 stimulates phosphorylation-dependent activation of Parkin and ubiquitin-dependent elimination of mitochondria by autophagy (mitophagy). Structural, cell biological and neuronal studies are unravelling the key steps of PINK1/Parkin-dependent mitophagy and uncovering new insights into how the pathway is regulated. The emerging role for aberrant immune activation as a driver of dopaminergic neuron degeneration after loss of PINK1 and Parkin poses new exciting questions on cell-autonomous and noncell-autonomous mechanisms of PINK1/Parkin signalling in vivo.


Allo-immunization during pregnancy. Clinical results from 1983 to 1989 in a Scandinavian university hospital.
From 1983 to 1989, 147,068 pregnancies were analyzed for allo-immunization against erythrocyte antigens. Approximately half of the cases were due to immunization against factor D and the others were due to allo-immunization against other antigens (K, c, E, etc.). In 61 cases exchange transfusion of the newborn was needed and in 115 cases diagnostic amniocentesis was done during pregnancy. Intrauterine transfusions were performed in 10 cases. Fetal and neonatal mortality was 4% in these moderate to severe cases, all due to immunization against D. Immunization against D was due to failure to give immunoglobulin anti-D in about 2/3 of the cases. Systematic prophylactic treatment with anti-D during pregnancy would probably not be cost-effective in this population.


A general synthetic method toward uridylylated picornavirus VPg proteins.
Small proteins called viral protein genome-linked (VPg), attached to the 5'-end of the viral RNA genome are found as common structure in the large family of picornaviruses. The replication of these viruses is primed by this VPg protein linked to a single uridylyl residue. We report a general procedure to obtain such nucleoproteins employing a pre-uridylylated tyrosine building block in an on-line solid phase-based approach.


Enzyme-amplified protein microarray and a fluidic renewable surface fluorescence immunoassay for botulinum neurotoxin detection using high-affinity recombinant antibodies.
Two immunoassay platforms were developed for either the sensitive or rapid detection of botulinum neurotoxin A (BoNT/A), using high-affinity recombinant monoclonal antibodies against the receptor binding domain of the heavy chain of BoNT/A. These antibodies also bind the same epitopes of the receptor binding domain present on a nontoxic recombinant heavy chain fragment used for assay development and testing in the current study. An enzyme-linked immunosorbent assay (ELISA) microarray using tyramide amplification for localized labeling was developed for the specific and sensitive detection of BoNT. This assay has the sensitivity to detect BoNT in buffer and blood plasma samples down to 14fM (1.4 pg mL(-1)). Three capture antibodies and one antibody combination were compared in the development of this assay. Using a selected pair from the same set of recombinant monoclonal antibodies, a renewable surface microcolumn sensor was developed for the rapid detection of BoNT/A in an automated fluidic system. The ELISA microarray assay, because of its sensitivity, offers a screening test with detection limits comparable to the mouse bioassay, with results available in hours instead of days. The renewable surface assay is less sensitive but much faster, providing results in less than 10 min.


Psychological correlates of fasting and vigorous exercise as compensatory strategies in undergraduate women.
Vigorous exercise and fasting are commonly used compensatory behaviors. However, it is unknown how non-clinical individuals who engage in one or both of these compensatory behaviors differ from one another. This research compared women who engaged in both fasting and vigorous exercise as compensatory strategies (n=76) with women who engaged in either fasting (n=56) or excessive exercise (n=82) and women who employed no compensatory strategies (n=113) on body image/eating and psychological symptomatology. Participants completed questionnaires assessing body dissatisfaction, restrained eating, thin-ideal internalization, depression, self-esteem, and general psychological distress. Women who utilize any compensatory strategies report significantly greater body dissatisfaction and restrained eating than women who use no compensatory strategies at all. Moreover, fasting as a compensatory behavior is associated with more significant psychological and behavioral symptoms than vigorous exercise as a compensatory behavior. Implications of these findings for clinical intervention and research are discussed.


Do environmental regulation and urbanization help decouple economic growth from water consumption at national and subnational scales in China?
Moving to economic growth without water consumption growth is essential to sustainability of both water and economy. This work is aimed to estimate the decoupling state between economic growth and water consumption and then to investigate the effects of urbanization and environmental regulation on water consumption at national and subnational scales using panel data of 30 provinces in China from 2004 to 2019. The decoupling results show that (i) there are only two types between China's water consumption and economic growth: weak decoupling (80%) and strong decoupling (20%); (ii) the weak decoupling has transitioned to strong decoupling after 2013; and that (iii) the decoupling degree of the water-poor region is weaker than that of the water-rich region. The results of causal relationships estimation show that an average 1% increase in urbanization level and environmental regulation leads to 0.3359% and 0.0104% drop in water consumption, respectively, which indicates that urbanization and environmental regulation have inhibited water consumption at the national scale. At the subnational sale, the effects of environmental regulation and urbanization on water consumption are heterogeneous. An average 1% increase in environmental regulation led to only a 0.0161% drop in water consumption in the water-poor region, whereas an average 1% increase in urbanization level led to only a 0.9838% drop in water consumption in the water-rich region. This means that the inhibition of environmental regulation on water use appears in the water-poor region, while the inhibition of urbanization is more prominent in the water-rich region.


Etiologic factors in head and neck wound infections.
The use of antibiotic prophylaxis does not prevent all postoperative wound infections. The records of 245 patients undergoing major head and neck surgery were reviewed to determine the cause of wound infection which developed in 17 patients. Patients with Stage IV tumors had an increased infection rate as compared to lesser stages (p less than .01). Reconstruction with a myocutaneous flap was associated with an increased infection rate when compared to primary closure or split-thickness skin graft reconstruction (p less than .001). Probable errors in surgical technique were identified in 10 of 17 infected patients. Neither weight loss, diabetes mellitus, prior radiation therapy, nor prior tracheotomy were found to increase the risk of wound infection (p greater than .05). This study lends insight into factors that may potentiate the development of wound infection despite antibiotic prophylaxis. A strategy to minimize postoperative infection is offered.


Incremental utility of real-time three-dimensional echocardiography in the diagnosis and preoperative assessment of cleft mitral valve in adults.
Cleft mitral valve is a rare congenital anomaly that may present in isolation or accompany other cardiac malformations. Our illustrative case series highlights the advantages of three-dimensional over conventional two-dimensional echocardiography in the diagnosis and morphologic assessment cleft mitral valve in adults.


Fusaric acid-producing strains of Fusarium oxysporum alter 2,4-diacetylphloroglucinol biosynthetic gene expression in Pseudomonas fluorescens CHA0 in vitro and in the rhizosphere of wheat.
The phytotoxic pathogenicity factor fusaric acid (FA) represses the production of 2,4-diacetylphloroglucinol (DAPG), a key factor in the antimicrobial activity of the biocontrol strain Pseudomonas fluorescens CHA0. FA production by 12 Fusarium oxysporum strains varied substantially. We measured the effect of FA production on expression of the phlACBDE biosynthetic operon of strain CHA0 in culture media and in the wheat rhizosphere by using a translational phlA'-'lacZ fusion. Only FA-producing F. oxysporum strains could suppress DAPG production in strain CHA0, and the FA concentration was strongly correlated with the degree of phlA repression. The repressing effect of FA on phlA'-'lacZ expression was abolished in a mutant that lacked the DAPG pathway-specific repressor PhlF. One FA-producing strain (798) and one nonproducing strain (242) of F. oxysporum were tested for their influence on phlA expression in CHA0 in the rhizosphere of wheat in a gnotobiotic system containing a sand and clay mineral-based artificial soil. F. oxysporum strain 798 (FA(+)) repressed phlA expression in CHA0 significantly, whereas strain 242 (FA(-)) did not. In the phlF mutant CHA638, phlA expression was not altered by the presence of either F. oxysporum strain 242 or 798. phlA expression levels were seven to eight times higher in strain CHA638 than in the wild-type CHA0, indicating that PhlF limits phlA expression in the wheat rhizosphere.


Defining memories by their distinct molecular traces.
It is often stated that short-term memory is consolidated in a protein-synthesis-dependent manner into long-term memory. Alternatively, memories might consist of distinct molecular traces that last for different periods of time. These traces can be graded by their 'volatility'; traces encoded by activation of protein kinases are more volatile than traces encoded by morphological changes at preexisting synapses. The least volatile ('static') traces are due to the generation and stabilization of new synapses. Importantly, whereas at the cellular level these traces are generated independently of each other, they might be linked at the network level where volatile memory traces are required to set up a cellular network that is in turn required to induce the static memory trace.


A kinetic model describing the pharmacokinetics of ethyl glucuronide in humans.
The glucuronide conjugation is a minor pathway of ethanol metabolism. The determination of ethyl glucuronide (EG) in serum and urine has gained importance in forensic and other legal decisions. To prospectively calculate the serum concentration of this non-oxidative ethanol metabolite, the computer program developed includes a parameter fitting routine. Multiple ethanol doses can be handled. The mathematical modeling was based on the following assumptions and simplifications, respectively. A single enzyme system is responsible for ethanol conjugation at one distinct site; the distribution of EG into the systemic circulation is delayed; the elimination of EG follows first-order kinetics. The concentration of EG was calculated using three kinetic parameters: a rate constant for the first-order formation of EG from serum ethanol, a transfer constant for an obstructed transfer of EG from the formation site (FS) into the central compartment (CC) and an exponential elimination constant. The program was applied to the data collected from 21 drinking experiments. The fitting algorithm optimized the three kinetic parameters, until the sum of concentration error squares of the data points was minimized. The means+/-standard deviation of the rate constant for the first-order formation of EG from serum ethanol was 0.0011+/-0.0006 h(-1), the transfer constant for an obstructed transfer of EG from the FS into the CC was 0.43+/-0.1996 h(-1) and the exponential elimination constant was 3.0+/-1.45 h(-1). Using the range of these parameters, it is now possible to calculate minimum and maximum serum concentrations of EG based on ethanol doses and drinking times. The comparison of calculated and measured concentrations can prove the plausibility of an alleged ethanol consumption. This can be crucial when the serum ethanol concentration (SEC) itself is not meaningful.


A partial augmented reality system with live ultrasound and registered preoperative MRI for guiding robot-assisted radical prostatectomy.
We propose an image guidance system for robot assisted laparoscopic radical prostatectomy (RALRP). A virtual 3D reconstruction of the surgery scene is displayed underneath the endoscope's feed on the surgeon's console. This scene consists of an annotated preoperative Magnetic Resonance Image (MRI) registered to intraoperative 3D Trans-rectal Ultrasound (TRUS) as well as real-time sagittal 2D TRUS images of the prostate, 3D models of the prostate, the surgical instrument and the TRUS transducer. We display these components with accurate real-time coordinates with respect to the robot system. Since the scene is rendered from the viewpoint of the endoscope, given correct parameters of the camera, an augmented scene can be overlaid on the video output. The surgeon can rotate the ultrasound transducer and determine the position of the projected axial plane in the MRI using one of the registered da Vinci instruments. This system was tested in the laboratory on custom-made agar prostate phantoms. We achieved an average total registration accuracy of 3.2 ± 1.3 mm. We also report on the successful application of this system in the operating room in 12 patients. The average registration error between the TRUS and the da Vinci system for the last 8 patients was 1.4 ± 0.3 mm and average target registration error of 2.1 ± 0.8 mm, resulting in an in vivo overall robot system to MRI mean registration error of 3.5 mm or less, which is consistent with our laboratory studies.


Flexion bonding transfer of multilayered graphene as a top electrode in transparent organic light-emitting diodes.
Graphene has attracted considerable attention as a next-generation transparent conducting electrode, because of its high electrical conductivity and optical transparency. Various optoelectronic devices comprising graphene as a bottom electrode, such as organic light-emitting diodes (OLEDs), organic photovoltaics, quantum-dot LEDs, and light-emitting electrochemical cells, have recently been reported. However, performance of optoelectronic devices using graphene as top electrodes is limited, because the lamination process through which graphene is positioned as the top layer of these conventional OLEDs is a lack of control in the surface roughness, the gapless contact, and the flexion bonding between graphene and organic layer of the device. Here, a multilayered graphene (MLG) as a top electrode is successfully implanted, via dry bonding, onto the top organic layer of transparent OLED (TOLED) with flexion patterns. The performance of the TOLED with MLG electrode is comparable to that of a conventional TOLED with a semi-transparent thin-Ag top electrode, because the MLG electrode makes a contact with the TOLED with no residue. In addition, we successfully fabricate a large-size transparent segment panel using the developed MLG electrode. Therefore, we believe that the flexion bonding technology presented in this work is applicable to various optoelectronic devices.


Ultrastructural demonstration of a projection from the flocculus to the nucleus prepositus hypoglossi in the cat.
Small electrolytic lesions were made in the flocculus of two adult cats by means of a stereotactic approach avoiding any damage to the cerebellar nuclei. After a survival time of 3 days the animals were killed and the brains fixed and prepared according to standard procedures for ultrastructural studies. The brains of two unoperated cats were similarly treated and served as normal controls. In the experimental animals a large number of boutons in the rostral part of the nucleus prepositus hypoglossi (Ph) ipsilateral to the floccular lesion showed degenerative changes. These were characterized by hypertrophy, a prominent aggregation of densely packed parallel tubules or concentric arrays of cisternae and a filamentous hyperplasia. Only very rarely were such abnormal boutons seen in the caudal half of the ipsilateral Ph, or on the contralateral side or in the unoperated animals. The degenerating boutons contain clusters of pleomorphic vesicles and they establish symmetrical synaptic contacts with somata, dendritic shafts and dendritic spines. Some of the degenerating boutons appear to be of the en passant type. These findings thus affirm the existence of a direct flocculo-prepositus projection in the cat. It is suggested that this pathway could be responsible for mediating information about eye position and velocity to Ph neurons.


Age- and sex-specific reference intervals for complete blood count parameters in capillary blood for Chinese neonates and infants: A prospective study.
The reference intervals (RIs) of laboratory tests are essential for disease diagnosis, therapy monitoring, and health assessment. They are also significant for clinicians to discriminate between subjects with disease and healthy subjects. However, RIs for complete blood count (CBC) parameters in capillary blood for children are deficient. This study aimed to establish capillary blood RIs for blood cell parameters in neonates and infants from birth to 2 years of age in Zhengzhou. We prospectively collected a total of 1840 capillary blood specimens from healthy subjects from birth to 2 years of age. Hematology RIs were established by analyzing capillary blood sample data, and RIs and 90 % confidence intervals (CIs) were calculated according to Clinical and Laboratory Standards Institute (CLSI) C28-A3 guidelines. RIs were established for hematological parameters of capillary blood in neonates and infants from birth to 2 years of age. The levels of almost all hematological parameters, except for the lymphocyte (LYMPH), platelet (PLT), and thrombocytocrit (PCT) parameters, peaked in the first month after birth and then decreased to lower levels within 6 months. There were significant sex differences in most erythrocyte-related parameters, with higher levels in males than in females. Erythrocyte-related parameters showed an increasing tendency with increasing age after the second month. Neutrophil (NEUT) levels were high on the third day of life, declined to a nadir in the first month, and then slowly increased with age. LYMPH levels were low at birth and began to increase after birth, peaked at approximately-six months of age and then gradually declined with age. PLT and PCT levels showed an increasing trend during the first month, while the other parameters showed a decreasing trend. All platelet-related and leukocyte-related parameters showed no significant difference with sex. We provide comprehensive age- and sex-specific RIs, including RIs for neonates in Henan. Our study provides more comprehensive reference ranges for Child Health Hospital and children's medical institutions, which may facilitate preliminary screening, diagnosis, and therapy.


Corrosion resistance of coupled sandblasted, large-grit, acid-etched (SLA) and anodized Ti implant surfaces in synthetic saliva.
The purpose of this study was to investigate the corrosion resistance of galvanically coupled SLA and anodized implant surfaces with a Co-Cr alloy. Three groups were included in this study. The first (SLA) was composed of SLA implants (Institut Straumann, Basel, Switzerland), the second (ANO) of NobelReplace® (Nobel Biocare, Göteborg, Sweden), and the third (MIX) of both implant systems combined. All groups were assembled with a single Co-Cr superstructure. Electrochemical testing included open-circuit potential, electrochemical impedance spectroscopy, cyclic potentiodynamic polarization, and chronoamperometric current-time measurements. The quantitative results (EOCP, ECORR, ICORR, EPROT, RP, and ICA) were statistically analyzed by one-way ANOVA and Tukey's post-hoc multiple comparison test (α = 0.05). All the aforementioned parameters showed statistically significant differences apart from ECORR and EPROT. The evaluation of qualitative and quantitative results showed that although SLA had higher corrosion resistance compared with ANO, it had less resistance to pitting corrosion. This means that SLA showed increased resistance to uniform corrosion but less resistance if pitting corrosion was initiated. In all cases, MIX showed intermediate behavior. The corrosion resistance of implant-retained superstructures is dependent on the electrochemical properties of the implants involved, and thus different degrees of intraoral corrosion resistance among different implant systems are anticipated.


Exosomes from microRNA 146a overexpressed bone marrow mesenchymal stem cells protect against spinal cord injury in rats.
This study aimed to investigate the effect of microRNA 146a (miR-146a) overexpressed bone marrow mesenchymal stem cells (BMMSCs) exosomes on spinal cord injury (SCI) recovery. Rat BMMSCs were isolated and transfected with miR-146a mimic (miR-mimic) and control mimic (NC-mimic), after which their exosomes were isolated. Afterward, SCI rat models were constructed, then treated with phosphate buffer saline (PBS), NC BMMSCs exosomes (separated from the culture medium of BMMSCs with NC-mimic), and miR-146a overexpressed BMMSCs exosomes (isolated from the culture medium of BMMSCs with miR-mimic), respectively; additionally, rats underwent sham surgery were treated with PBS as controls. MiR-146a was upregulated in BMMSCs, and BMMSCs derived exosomes post miR-mimic transfection. Then in SCI rats, BMMSCs exosomes elevated the Basso, Beattie, and Bresnahan (BBB) score and reduced hematoxylin&eosin-reflected spinal cord tissue injury. In addition, BMMSCs exosomes did not affect TUNEL positive cells rate while increased NeuN(+) cells/field in spinal cord tissue from SCI rats. As for inflammation, BMMSCs exosomes repressed pro-inflammatory cytokine expressions, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, in spinal cord tissue from SCI rats. Furthermore, miR-146a overexpressed BMMSCs exosomes presented with notably better effects regarding elevating BBB score in SCI rats and reducing tissue injury, neuron apoptosis, and inflammation while enhancing neuron viability in spinal cord tissue from SCI rats. MiR-146a overexpressed BMMSCs exosomes enhance locomotor capacity and neuron viability while reducing neuron apoptosis and spinal cord tissue inflammation in SCI rats.


Treating Obesity in Children and Adolescents with Special Healthcare Needs.
This paper aims to summarize the literature regarding treatment of obesity in children with special healthcare needs and provide examples of implementation based on the available scientific evidence and the clinical experience of the authors. Due to the complexity of providing treatment for children with obesity and special healthcare needs, multidisciplinary teams are recommended to adapt care to meet the children's unique needs and ensure coordination of care across settings/caregivers. Medication management is often required to assist with the side effects of psychotropic medications. Children with special healthcare needs (SHCN) such as intellectual and developmental disabilities (IDD) should be considered for metabolic and bariatric surgery as they have similar outcomes to children without SHCN. Children with special healthcare needs can be successful in weight management treatment when they have access to comprehensive care including dietary, behavioral, pharmacological, and surgical interventions. Each child requires a tailored approach to ensure their special healthcare needs are addressed within the treatment plan.


Genetic deficiency of complement factor H in a patient with age-related macular degeneration and membranoproliferative glomerulonephritis.
Age-related macular degeneration (AMD) and membranoproliferative glomerulonephritis type II (MPGN2) are dense deposit diseases that share a genetic association with complement genes and have complement proteins as important components of the dense deposits. Here, we present the case of a 64-year-old smoker male who developed both AMD and MPGN2 in his late 50s. The patient presented persistent low plasma levels of C3, factor H levels in the lower part of the normal range and C3NeF traces. Genetic analyses of the CFH, CFB, C3, CFHR1-CFHR3 and LOC387715/HTRA1 genes revealed that the patient was heterozygote for a novel missense mutation in exon 9 of CFH (c.1292 G>A) that results in a Cys431Tyr substitution in SCR7 of the factor H protein. In addition, he was homozygote for the His402 CFH allele, heterozygote for the Ser69 LOC387715 allele, homozygote for the Arg32 (BFS) CFB allele, heterozygote for the Gly102 (C3F) C3 allele and carried no deletion of the CFHR1/CFHR3 genes. Proteomic and functional analyses indicate absence in plasma of the factor H allele carrying the Cys431Tyr mutation. As a whole, these data recapitulate a prototypical complement genetic profile, including a partial factor H deficiency and the presence of major risk factors for AMD and MPGN2, which support the hypothesis that these dense deposit diseases have a common pathogenic mechanism involving dysregulation of the alternative pathway of complement activation.


Programming Levels and Speech Perception in Pediatric Cochlear Implant Recipients With Enlarged Vestibular Aqueduct or GJB2 Mutation.
To determine the relationship between hearing loss etiology, cochlear implant (CI) programming levels, and speech perception performance in a large clinical cohort of pediatric CI recipients. Retrospective chart review. Tertiary care hospitals. A total of 136 pediatric CI recipients (218 ears) were included in this study. All patients had diagnoses of either enlarged vestibular aqueduct (EVA) or GJB2 (Connexin-26) mutation confirmed via radiographic data and/or genetic reports. All patients received audiologic care at either Boston Children's Hospital or Massachusetts Eye and Ear in Boston, MA, between the years 1999 and 2020. Electrode impedances and programming levels for each active electrode and speech perception scores were evaluated as a function of etiology (EVA or GJB2 mutation). Children with EVA had significantly higher impedances and programming levels (thresholds and upper stimulation levels) than the children with GJB2 mutation. Speech perception scores did not differ as a function of etiology in this sample; rather, they were positively correlated with duration of CI experience (time since implantation). Differences in electrode impedances and CI programming levels suggest that the electrode-neuron interface varies systematically as a function of hearing loss etiology in pediatric CI recipients with EVA and those with GJB2 mutation. Time with the CI was a better predictor of speech perception scores than etiology, suggesting that children can adapt to CI stimulation with experience.


[Effects of glucosides on a spontaneously active vascular smooth muscle in vitro (author's transl)].
There is no support for the view that cardiac glucosides increase the resting tension in the rat portal vein, although such an effect on vascular smooth muscle might have been expected from the results of investigation on the coronary vessels. Glucosides in a concentration of 10(-4) m inhibit contractility while increasing the frequency of contractions. These changes of spontaneous activity are not accompanied by equivalent changes of the intracellular cation concentrations. There are no significant differences between the effects of g-strophanthine, k-strophanthoside and convallatoxin.


Widespread energy limitation to life in global subseafloor sediments.
Microbial cells buried in subseafloor sediments comprise a substantial portion of Earth's biosphere and control global biogeochemical cycles; however, the rate at which they use energy (i.e., power) is virtually unknown. Here, we quantify organic matter degradation and calculate the power utilization of microbial cells throughout Earth's Quaternary-age subseafloor sediments. Aerobic respiration, sulfate reduction, and methanogenesis mediate 6.9, 64.5, and 28.6% of global subseafloor organic matter degradation, respectively. The total power utilization of the subseafloor sediment biosphere is 37.3 gigawatts, less than 0.1% of the power produced in the marine photic zone. Aerobic heterotrophs use the largest share of global power (54.5%) with a median power utilization of 2.23 × 10-18 watts per cell, while sulfate reducers and methanogens use 1.08 × 10-19 and 1.50 × 10-20 watts per cell, respectively. Most subseafloor cells subsist at energy fluxes lower than have previously been shown to support life, calling into question the power limit to life.


Estimation of proportion of new mutants among cases of Duchenne muscular dystrophy.
Using a number of different methods, it is confirmed that approximately one third of all cases of X-linked Duchenne muscular dystrophy are new mutants, the remainder being sons of carriers.


A deeper understanding of noise effects on cetaceans.
Recent research with cetaceans under human care is illuminating just how dolphins are affected by human-made noise both in terms of their ability to cooperate as well as their ability to habituate to such noise. This research is providing granular detail to regulators assessing the problems associated with anthropogenic effects and is highlighting a role for behavior/cognition research in conservation.


Characterization of a spontaneous, recessive, missense mutation arising in the Tecta gene.
The TECTA gene encodes alpha-tectorin (TECTA), a major noncollagenous component of the tectorial membrane (TM). In humans, mutations in TECTA lead to either dominant (DFNA8/A12) or recessive (DFNB21) forms of nonsyndromic hearing loss. All missense mutations in TECTA that have been reported thus far are associated with the dominant subtype, whereas those leading to recessive deafness are all inactivating mutations. In this paper, we characterize a spontaneous missense mutation (c.1046C > A, p.A349D) arising in the mouse Tecta gene that is, unlike all previously reported missense mutations in TECTA, recessive. The morphological phenotype of the Tecta (A349D/A349D) mouse resembles but is not identical to that previously described for the Tecta(deltaENT)/(deltaENT) mouse. As in the Tecta(deltaENT/(deltaENT) mouse, the TM is completely detached from the surface of the organ of Corti and spiral limbus, lacks a striated-sheet matrix, and is deficient in both beta-tectorin (Tectb) and otogelin. A significant amount of Tecta is, however, detected in the TM of the Tecta (A349D/A349D) mouse, and numerous, electron-dense matrix granules are seen interspersed among the disorganized collagen fibrils. Mutated Tecta (A349D) is therefore incorporated into the TM but presumably unable to interact with either Tectb or otogelin. The Tecta (A349D/A349D) mouse reveals that missense mutations in Tecta can be recessive and lead to TM detachment and suggests that should similar mutations arise in the human population, they would likely cause deafness.


Impact of Connector Placement and Design on Bending Stiffness of Spinal Constructs.
To evaluate the stability of multiple rod-connector construct designs using a mechanical 4-point bending testing frame. A mechanical study was used to evaluate the bending stiffness of 3 connectors across 12 different configurations of rod-connector-rod constructs. Stability was evaluated in flexion-extension and lateral bending. Combinations of rods having 1 of 3 diameters (4.0 mm, 5.5 mm, and 6.0 mm) connected by 1 of 3 connector types (parallel open, snap-on, and hinged) were compared. Configurations with single connectors and with double connectors with variable spacing were also compared to simulate revision surgery conditions. Constructs consisting of 4.0-mm rods connected to 4.0-mm rods were significantly less stiff as the total number of connectors used in a series exceeded 2. When single-connector configurations were compared, parallel open rod connectors demonstrated greater stiffness in flexion-extension than hinged open connectors, whereas hinged open connectors demonstrated greater stiffness in lateral bending. Using double connectors increased stiffness of 4.0- to 4.0-mm rod configurations in flexion-extension and lateral bending, 4.0- to 6.0-mm rod configurations in flexion-extension, and 5.5- to 6.0-mm rod configurations in lateral bending. Spacing the double connectors significantly improved lateral bending stiffness of 4.0- to 4.0-mm and 5.5- to 6.0-mm rod configurations. Our data indicate that the design, number, and placement of rod connectors have a significant impact on the bending stiffness of a surgical construct. Such mechanical data may influence construct design in primary and revision surgeries of the cervical spine and cervicothoracic junction.


Changes of the prostaglandin F2a metabolism in early human placenta.
The quantitative metabolism of PgF2a was studied in different ages of early human placentae in vitro. The 15-OH-Pg-dehydrogenase became minimal at about the 9th week.