Retracted: Design of a Regional Economic Forecasting Model Using Optimal Nonlinear Support Vector Machines.
[This retracts the article DOI: 10.1155/2022/2900434.].


Water oxidation catalyzed by molecular di- and nonanuclear Fe complexes: importance of a proper ligand framework.
The synthesis of two molecular iron complexes, a dinuclear iron(iii,iii) complex and a nonanuclear iron complex, based on the dinucleating ligand 2,2'-(2-hydroxy-5-methyl-1,3-phenylene)bis(1H-benzo[d]imidazole-4-carboxylic acid) is described. The two iron complexes were found to drive the oxidation of water by the one-electron oxidant [Ru(bpy)3](3+).


Mapping a ligand binding site using genetically encoded photoactivatable crosslinkers.
G protein-coupled receptor (GPCR) signaling complexes are important for mediating many different biological processes. Uncovering the mechanism for how a ligand triggers a GPCR to elicit a specific response is an active area of research. One step toward understanding this mechanism is through identifying a ligand's binding site on a GPCR. We have optimized a targeted photocrosslinking technology to detect the residues in a receptor that are within a precise distance from a bound ligand in the receptor-ligand complex. Here, we describe the method for introducing photoactivable crosslinkers into a GPCR using the amber stop codon suppression technology. In addition, we review the steps to identify the binding site of a fluorescein-tagged peptide ligand and a tritium-labeled small molecule ligand.


Synergistic/antagonistic effects and mechanisms of Cr(VI) adsorption and reduction by Fe(III)-HA coprecipitates.
Widespread Fe(III)-humic acid (HA) coprecipitates (FHCs) have substantial impacts on the adsorption and reduction of Cr(VI) in soils and sediments, but whether this process is equal to the sum of their individual components remains unknown. In this study, ferrihydrite (Fh)- and HA-like FHCs (C/Fe<3 and C/Fe>3, respectively) were synthesized by controlling the initial C/Fe ratios (0.5-18) to explore the potential synergistic/antagonistic effects during the adsorption and reduction of Cr(VI). According to the results, antagonistic effects on Cr(VI) adsorption (5%-80%) were observed on Fh- and HA-like FHCs, where the antagonistic intensity increased with increasing HA proportions, respectively caused by the more serious occupation of adsorption sites and the stronger electrostatic repulsion to Cr(VI). Notably, significant synergistic reduction effects (5%-650%) occurred on Fh-like FHCs were found to be achieved by the activation of low-molecular HA (0.1-0.3 kDa) with primary/secondary hydroxylic groups, which might be induced by the inductive effect of Fh on complexed HA molecules according to density-functional theory (DFT) calculation. While slight antagonistic reduction effects (2%-45%) by HA-like FHCs were attributed to the decreasing accessibility of Cr(VI) to reductive phenolic groups, which might be blocked within FHC particles or complexed with Fe(III) ions through cation bridges.


Stress, inflammation, depression, and dementia associated with phosphate toxicity.
Depression and dementia are predicted to increase within aging global populations. Pathophysiological effects of phosphate toxicity, dysregulated amounts of accumulated phosphorus in body tissue, are under-investigated in association with stress, inflammation, depression, and dementia. A comparative analysis of concepts in cited sources from the research literature was used to synthesize novel themes exploring the disease-oriented neuroscience effects of phosphate toxicity. Phosphate toxicity is associated with activation of cellular stress response systems and inflammation. Cortisol released by the hypothalamic-pituitary-adrenal axis responds to stress and inflammation associated with phosphate toxicity and depression. In a reciprocal interaction, phosphate toxicity is capable of harming adrenal gland function, possibly leading to adrenal insufficiency and depression. Furthermore, Alzheimer's disease is associated with hyperphosphorylated tau which self-assembles into neurofibrillary tangles from excessive amounts of phosphate in the brain and central nervous system. Future research should investigate dietary phosphate modification to reduce potential pathophysiological effects of phosphate toxicity in stress, inflammation, depression, and cognitive decline which affects global populations.


Chemical Composition of the Essential Oils from Different Morphological Parts of Pinus cembra L.
The essential oils from needles, twigs, bark, wood, and cones of Pinus cembra were analyzed by GC-FID, GC/MS, and 1 H-NMR spectroscopy. More than 130 compounds were identified. The oils differed in the quantitative composition. The principal components of the oil from twigs with needles were α-pinene (36.3%), limonene (22.7%) and β-phellandrene (12.0%). The needle oil was dominated by α-pinene (48.4%), whereas in the oil from bark and in the oil from twigs without needles there were limonene (36.2% and 33.6%, resp.) and β-phellandrene (18.8% and 17.1%, resp.). The main constituents of the wood oil as well as cone oil were α-pinene (35.2% and 39.0%, resp.) and β-pinene (10.4% and 18.9%, resp.). The wood oil and the cone oil contained large amounts of oxygenated diterpenes in comparison with needle, twig, and bark oils.


Quality of patient-reported outcome reporting in randomised controlled trials of haematological malignancies according to international quality standards: a systematic review.
Patient-reported outcome (PRO) endpoints are increasingly considered for inclusion in randomised controlled trials (RCTs) involving patients with haematological malignancies. The aim of our systematic review was to investigate the quality of PRO reporting across these RCTs. We searched Ovid MEDLINE, Embase, the Cochrane Library, and PubMed for English language articles published between Jan 1, 2014, and Jan 31, 2019. Eligible articles were RCTs of cancer-directed therapy in adult patients with haematological malignancies that reported on PRO measures in the primary publication or in a subsequent publication, with a comparison of PROs among treatment groups. A total of 3678 records were assessed, and 71 RCTs, enrolling 24 701 patients, were included in our systematic review. Most RCTs (n=65 [92%]) had PRO measures as a secondary or exploratory endpoint. A PRO hypothesis and relevant PRO domains were specified in 36 (51%) RCTs. Statistical approaches for dealing with missing data were documented in 26 (37%) RCTs. Quality of PRO reporting was higher in RCTs citing the Consolidated Standards of Reporting Trials Statement-PRO extension (CONSORT-PRO) than in those not citing this checklist, as evidenced by the International Society for Quality of Life Research score (median score in studies citing the CONSORT-PRO extension [n=4] was 89 [IQR 75-94] vs 61 [44-78] in those not citing this extension). Independent factors significantly associated with higher reporting included having PROs as a primary endpoint (p=0·008) and the presence of a subsequent publication on PROs (p<0·0001). International guidelines for designing, reporting, and analysing PRO data are now available to further improve overall study quality. Our findings can help investigators to focus on key aspects most in need of attention when reporting PROs in future trials of haematological malignancies.


Radiofrequency current catheter ablation for control of supraventricular arrhythmias.
With the advent of radiofrequency energy, catheter ablation techniques have become an accepted form of treatment for a variety of supraventricular arrhythmias. The ablation of the atrioventricular (AV) node was performed first and is now widely used in patients with refractory atrial fibrillation or flutter. Ablation has also replaced surgery in patients with preexcitation syndromes, and as the complication rate in experienced centers is low, it has become the first line of treatment in these institutions. The results of catheter ablation in AV nodal reentrant tachycardia are excellent as well, although there is still debate about whether "slow" pathway ablation is superior to "fast" pathway ablation. Radiofrequency current ablation has also contributed to a better understanding of the pathophysiology of AV nodal reentrant tachycardia, as it has provided evidence for atrial participation in the reentrant circuit. Experience with atrial tachycardias and tachycardias due to Mahaim fibers remains limited. The ideal source of energy for specific arrhythmias is still unknown and improvement in catheter technology is needed.


Assessing the risk of disease transmission to patients when there is a failure to follow recommended disinfection and sterilization guidelines.
Medical devices that enter body tissues should be sterile, whereas devices that contact mucous membranes should be high-level disinfected between patients. Failure to ensure proper cleaning and sterilization or disinfection may lead to patient-to-patient transmission of pathogens. This paper describes a protocol that can guide an institution in managing potential disinfection and sterilization failures.


Neuropathology of Salla disease.
A neuropathological study was performed on two patients with Salla disease, one male and one female, from different families. They both died at the age of 41 years. Both patients showed increased excretion of free sialic acid in the urine, psychomotor retardation starting in the 1st year of life, ataxia and spasticity. Several family members of both families were affected with the same disease indicating the hereditary character of the disorder. The neuropathological investigation revealed strikingly similar changes in the two cases. Macroscopically the cerebral white matter was severely reduced. Histologically marked loss of axons and myelin sheaths was accompanied by pronounced astrocytic proliferation. The remaining axons frequently showed ovoid swellings surrounded by a myelin sheath. The reduction of the number of myelin sheaths seemed proportional to the numerical reduction of axons. Many cortical nerve cells displayed in relation to age an abnormal amount of lipofuscin. Neurofibrillary tangles were observed in nerve cells of the neo-cortex, nucleus basalis of Meynert and locus ceruleus. Cerebellum showed moderate loss of Purkinje cells. In the spinal cord axonal degeneration was observed in both ascending and descending tracts.


Effect of sympathetic de-activation on thermogenic function and membrane lipid composition in mitochondria of brown adipose tissue.
Male Long-Evans rats (9 weeks of age) were exposed to cold (5 degrees C) for 10 days. Then, sympathetic de-activation of brown adipose tissue (BAT) was performed either by BAT surgical denervation (Sy) or by warm re-exposure at 28 degrees C (WE) for 4 days. The incidence of the two treatments on thermogenic activity of BAT mitochondrial membranes and their lipid composition was investigated. Sy and WE induced a large decrease in GDP binding on the uncoupling protein (UCP) (43% and 82%, respectively). Several parameters of mitochondrial energization were investigated. Sy and WE substantially decreased UCP-dependent proton conductance (CmH+) over the whole range of protonmotive force. CmH+ showed greater variation than GDP binding. The low basal UCP-independent CmH+ was the same in all groups. Comparison of GDP binding and CmH+ with UCP content which is not modified revealed a masking of both the nucleotide binding site and the proton channel. Sy and WE induced the same increase of phosphatidylcholine to phosphatidylethanolamine ratio (16%) but had opposite effects on fatty acid unsaturation. The results were discussed with reference to functional significance of these variations in BAT mitochondrial thermogenic activity and lipid composition.


A novel ketone olefination via organozinc reagents in the presence of diphenyl phosphite.
Carbonyl compounds react with organozinc reagents in the presence of diphenyl phosphite to give the corresponding olefins. A variety of 1,3-dienes and unsaturated esters were obtained in moderate to excellent yields under mild conditions.


Control of lower incisor inclination with a completely customized lingual appliance for dentoalveolar compensation of class III malocclusion.
Bracket slots and orthodontic archwires offering high dimensional precision are needed for fully customized lingual appliances. We aimed to investigate whether high-precision appliances of this type enable dentoalveolar compensation of class III malocclusion so that lower incisor inclination at the end of treatment will closely match the anticipated situation as defined in a pretreatment setup. This retrospective study included a total of 34 consecutive patients who had worn a fully customized lingual appliance to achieve dentoalveolar compensation for class III malocclusion by intermaxillary elastics, or proximal enamel reduction, or extraction of teeth in one or both jaws. Casts fabricated at different points in time were three-dimensionally scanned to analyze how precisely the lower incisor inclinations envisioned in the setup were implemented in clinical practice. Aside from minor deviations of ±3.75°, the lower incisor inclinations were clinically implemented as planned even in patients with major sagittal discrepancies. Treatment goals predefined in a setup of dentoalveolar compensation for class III malocclusion can be very precisely achieved via a customized lingual appliance. Correct planning can prevent undesirable lingual tipping of the lower incisors. This finding should not encourage a more liberal use of dentoalveolar compensation, but it should heighten clinicians' awareness of how essential it is to sufficiently consider the individual anatomy of the dentoalveolar complex during treatment planning.


Self-administration of CNS stimulants by dog.
Drug-naive dogs were trained to respond for intravenous infusions of either d-amphetamine, phenmetrazine, or methylphenidate until a stable response rate per 4-hr daily session was achieved. The magnitude of reinforcement (i.e., mg/kg/infusion) was then varied systematically across a wide range for each drug. An inverse relationship between unit dose and number of self-administered infusions per session was seen. Thus, total drug intake per session remained relatively constant and was independent of unit dose. Using a parallel line bioassay design, the relative potencies of d-amphetamine, phenmetrazine, and methylphenidate to maintain self-administration were estimated. By comparing the unit doses of d-amphetamine which yielded the same rate of self-administration it was found that 1 mg of phenmetrazine is equivalent to 0.1 mg of d-amphetamine. It was also determined that 1 mg of methylphenidate is equivalent to 0.75 mg of d-amphetamine. These data indicate the dog can be used to assess the reinforcing properties of psychomotor stimulants.


DKK3 expression is associated with immunosuppression and poor prognosis in glioblastoma, in contrast to lower-grade gliomas.
We previously reported that expression of dickkopf-3 (DKK3), which is involved in the Wnt/β-catenin pathway, is significantly associated with prognosis in patients with glioblastoma multiforme (GBM). The aim of this study was to compare the association of DKK3 with other Wnt/β-catenin pathway-related genes and immune responses between lower grade glioma (LGG) and GBM. We obtained the clinicopathological data of 515 patients with LGG (World Health Organization [WHO] grade II and III glioma) and 525 patients with GBM from the Cancer Genome Atlas (TCGA) database. We performed Pearson's correlation analysis to investigate the relationships between Wnt/β-catenin-related gene expression in LGG and GBM. Linear regression analysis was performed to identify the association between DKK3 expression and immune cell fractions in all grade II to IV gliomas. A total of 1,040 patients with WHO grade II to IV gliomas were included in the study. As the grade of glioma increased, DKK3 showed a tendency to be more strongly positively correlated with the expression of other Wnt/β-catenin pathway-related genes. DKK3 was not associated with immunosuppression in LGG but was associated with downregulation of immune responses in GBM. We hypothesized that the role of DKK3 in the Wnt/β-catenin pathway might be different between LGG and GBM. According to our findings, DKK3 expression had a weak effect on LGG but a significant effect on immunosuppression and poor prognosis in GBM. Therefore, DKK3 expression seems to play different roles, through the Wnt/β-catenin pathway, between LGG and GBM.


Respiratory protein-generated reactive oxygen species as an antimicrobial strategy.
The evolution of the host-pathogen relationship comprises a series of invasive-defensive tactics elicited by both participants. The stereotype is that the antimicrobial immune response requires multistep processes. Little is known about the primordial immunosurveillance system, which probably has components that directly link sensors and effectors. Here we found that the respiratory proteins of both the horseshoe crab and human were directly activated by microbial proteases and were enhanced by pathogen-associated molecular patterns, resulting in the production of more reactive oxygen species. Hemolytic virulent pathogens, which produce proteases as invasive factors, are more susceptible to this killing mechanism. This 'shortcut' antimicrobial strategy represents a fundamental and universal mode of immunosurveillance, which has been in existence since before the split of protostomes and deuterostomes and still persists today.


Serodiagnostic potential of immuno-PCR using a cocktail of mycobacterial antigen 85B, ESAT-6 and cord factor in tuberculosis patients.
A novel indirect immuno-polymerase chain reaction (I-PCR) assay was developed for the detection of circulating anti-Ag85B (antigen 85B, Rv1886c), anti-ESAT-6 (early secretory antigenic target-6, Rv3875) and anti-cord factor (trehalose 6,6'-dimycolate) antibodies from the sera samples of pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) patients and the results were compared with an analogous enzyme-linked immunosorbent assay (ELISA). We covalently attached the amino-modified reporter DNA to the dithiothreitol (DTT)-reduced anti-human IgG antibody through a chemical linker succinimidyl 4-[N-maleimidomethyl]-cyclohexane-1-carboxylate (SMCC). The detection of cocktail of anti-Ag85B, anti-ESAT-6 and anti-cord factor antibodies was found to be superior to the detection of individual antibodies. The sensitivities of 89.5% and 77.5% with I-PCR and 70.8% and 65% with ELISA were observed in smear-positive and smear-negative PTB cases, respectively with high specificity (90.9%). On the other hand, a sensitivity of 77.5% with I-PCR and 65% with ELISA was observed in EBTB cases. The detection of cocktail of antibodies by I-PCR is likely to improve the utility of existing algorithms for TB diagnosis.


A thermostability perspective on enhancing physicochemical and cytological characteristics of octacalcium phosphate by doping iron and strontium.
Investigation of thermostability will lead the groundbreaking of unraveling the mechanism of influence of ion-doping on the properties of calcium phosphates. In this work, octacalcium phosphate (OCP), a metastable precursor of biological apatite, was used as a stability model for doping ions (Fe3+ and Sr2+) with different ionic charges and radii. After treated under hot air at different temperatures (110-200 °C), the phase, morphology, structure, physicochemical properties, protein affinity, ions release, and cytological responses of the ion-doped OCPs were investigated comparatively. The results showed that the collapse of OCP crystals gradually occurred, accompanying with the dehydration of hydrated layers and the disintegration of plate-like crystals as the temperature increased. The collapsed crystals still retained the typical properties of OCP and the potential of conversion into hydroxyapatite. Compared to the undoped OCP, Fe-OCP, and Sr-OCP had lower and higher thermostability respectively, leading to different material surface properties and ions release. The adjusted thermostability of Fe-OCP and Sr-OCP significantly enhanced the adsorption of proteins (BSA and LSZ) and the cytological behavior (adhesion, spreading, proliferation, and osteogenic differentiation) of bone marrow mesenchymal stem cells to a varying extent under the synergistic effects of corresponding surface characteristics and early active ions release. This work paves the way for understanding the modification mechanism of calcium phosphates utilizing ion doping strategy and developing bioactive OCP-based materials for tissue repair.


Developing and Mapping Entrustable Professional Activities with Saudi Meds Competency Framework: A Consensus Study.
This study aimed at developing a national consensus on entrustable professional activities (EPAs) for Saudi undergraduate medical education and mapping them with the "Saudi Meds" competency framework. A three phased approach was used. Phase 1 consisted of identifying and developing EPAs; Phase 2 consisted of building a national consensus on developed EPAs (validation process); and Phase 3 consisted of mapping the validated EPAs with the Saudi Meds competency framework. Nominal group and modified Delphi techniques were used to develop consensus on EPAs. Classical test theory-based item analysis was conducted to establish validity and reliability of finalized EPAs. Fifteen expert medical educationists and 109 academic leaders from 23 medical schools participated in the validation process. The study achieved a consensus on 10 core EPAs with an overall reliability (Cronbach's Alpha) of 0.814. The item-total correlation ranged from 0.341 to 0.642. This study results in a national consensus on generic, comprehensive and region-specific EPAs that have been mapped with Saudi Meds competency framework. Our study is the first step in the direction of facilitating EPA-based curricular reforms in Saudi medical schools.


Integrin β1, PDGFRβ, and type II collagen are essential for meniscus regeneration by synovial mesenchymal stem cells in rats.
Synovial mesenchymal stem cells (MSCs) injected into the knee promote meniscus regeneration in several animal models; however, the mode of action is unknown. Our purpose was to identify the molecules responsible for this meniscus regeneration. Rat synovial MSCs were treated with neutralizing antibodies for integrin β1, PDGFRβ, or CD44 or with the CRISPR/Cas9 system to delete Vcam1, Tnfr1, or Col2a1 genes. After partial meniscectomy, rat knees were injected with MSCs, and the regenerated meniscus area was quantified three weeks later. The in vivo and in vitro functions were compared between the treated and control MSCs. Anti-integrin β1 neutralizing antibody inhibited in vitro MSC adhesion to collagen-coated chambers, anti-PDGFRβ neutralizing antibody inhibited proliferation in culture dishes, and Col2a1 deletion inhibited in vitro chondrogenesis. In vivo, the regenerated meniscus area was significantly smaller after injection of MSCs treated with integrin β1 and PDGFRβ neutralizing antibodies or lacking type II collagen gene than after control MSC injection. By contrast, the regenerated areas were similar after injection of control, CD44-, Vcam1-, or Tnfr1 treated MSCs (n = 12-16) MSCs. Synovial MSCs injected into the knee joint promoted meniscus regeneration by adhesion to integrin β1 in the meniscectomized region, proliferation by PDGFRβ, and cartilage matrix production from type II collagen.


Induction of hapten-specific immunological tolerance and immunity in B lymphocytes. VII. Correlation between trinitrobenzenesulfonic acid administration, serum trinitrophenyl content, and level of tolerance.
The induction of immunological tolerance with trinitrobenzenesulfonic acid (TNBS) was studied by a comparison of the concentration of trinitrophenyl (TNP) in the serum of tolerant mice (TolS) and the degree of unresponsiveness induced as the dose and time of tolerogen injection were varied. The concentration of TNP in TolS was greater with a larger dose of TNBS, as expected, and decreased with time after tolerogen injection in a biphasic manner. The rapid initial decline followed on Day 10 by a more gradual decrease in TNP concentration suggests that there were two classes of TNP conjugates produced by TNBS injection. The serum TNP concentration appeared to correlate to the in vivo response of TNBS-treated mice to thymic-dependent and thymic-independent antigenic challenge while little correlation was evident with the in vitro response.


Studies on the accumulation and transformation of arsenic in freshwater organisms I. Accumulation, transformation and toxicity of arsenic compounds on the Japanese medaka, Oryzias latipes.
Accumulation, transformation and toxicity of arsenic compounds to Japanese Medaka, Oryzias latipes were investigated. For sodium arsenite [As(II)] and disodium arsenate [As(V)], the mean value for 7-day lethal concentration LC50 for O. latipes were 14.6 and 30.3 mg As/l, respectively. Direct accumulation of arsenic in O. latipes increased as a function of As(III) concentration in water. A small proportion of accumulated arsenic was transformed to methylated arsenic. As much as 70% of the total arsenic accumulated in tissue was depurated. Accumulation and transformation of As(III) by O. latipes in a simple freshwater food chain were also investigated. The transformation of As(III) to As(V) by organisms was more prevalent than biomethylation of accumulated arsenic in organisms of the three steps of the food chain.


Effects of Fibrin Sealant on Seroma Reduction for Patients with Breast Cancer Undergoing Axillary Dissection: Meta-Analysis of Randomized Controlled Trials.
Seroma formation is common in patients with breast cancer after axillary dissection. Fibrin sealant, containing fibrinogen and thrombin, has been developed to improve wound healing. We conducted a systematic review and meta-analysis to evaluate the efficacy of fibrin sealants in reducing seroma among patients with breast cancer undergoing axillary dissection. We searched the PubMed, EMBASE, and Cochrane Library databases for randomized controlled trials (RCTs) published up to April 2020. Pooled estimates of the outcomes were computed using a random-effects model. The primary outcomes were incidence and volume of seroma, while the secondary outcomes were volume and duration of drainage, incidence of infection, and length of hospital stay. We reviewed 23 RCTs that included 1640 patients. Compared with the control group, the fibrin sealant group had no significant differences in the incidence of seroma, length of hospital stay, or incidence of surgical site infection. Significant intergroup differences were discovered in lower volume of seroma (weighted mean difference [WMD] - 71.88, 95% confidence interval [CI] - 135.58 to - 8.19), volume of drainage (WMD - 73.24, 95% CI - 107.32 to - 39.15), and duration of drainage (WMD - 0.84, 95% CI - 1.50 to - 0.19). Fibrin sealants provide limited benefits in reducing the volume of seroma and the volume and duration of drainage. Therefore, after shared decision making, surgeons may apply fibrin sealants to patients with breast cancer undergoing axillary dissection.


The role of virtual sub-internships in influencing career perceptions: an international medical graduate perspective.
The SARS-CoV-2 pandemic has left a huge impact on the career perceptions of trainees and medical students globally. The cancellation and/or replacement of sub-internships in the United States (US) with a virtual alternative offer a different experience. We explore the impact of this issue on international medical graduates (IMGs) who are planning to apply to a US residency program in the near future.


Brain death due to fat embolism - could moderate hypercapnia and prone position be blamed for the tonsillar herniation?
Fat embolism to the systemic circulation in polytrauma patients is very common. The fat embolism syndrome (FES), however, is a rare condition. We describe a case of traumatic femur fracture with FES that was presented as acute tonsillar herniation (coning) and brain death postoperatively. We believe that in this case the prone position and moderate hypercapnia contributed to the acute coning.


Protective effect against alcohol dependence of the thermolabile variant of MTHFR.
Hyperhomocysteinemia is frequently observed in alcohol-dependent subjects, in particularly in those with marked withdrawal symptoms. The common C677T transition on the methylenetetrahydrofolate reductase (MTHFR) gene influences homocysteinemia. Our objective was to study the prevalence of the MTHFR C677T polymorphism in alcohol-dependent subjects and the influence of this polymorphism on symptoms associated with alcoholism. MTHFR C677T polymorphism was determined in 93 control subjects and 242 alcohol-dependent subjects. Serum homocysteine, folate and vitamin B12 levels together with hepatic biological parameters were determined in the control and alcohol-dependent subjects. Hyperhomocysteinemia is frequently observed in alcohol-dependent subjects, particularly in those with marked withdrawal symptoms. Alcohol-dependent subjects showed a significant decrease in MTHFR 677TT prevalence (9%, 21/242) compared to controls (18%, 17/93) (p<0.02). The relative risk estimated as an odds ratio for alcoholism in subjects with the TT genotype is 0.42 (odd ratio 95% confidence interval, 0.21-0.83). Moreover, drinkers with TT genotype presented lower values for markers of alcohol misuse (p<0.05), better liver function tests, a lower frequency of relapses and no marked withdrawal symptoms as assessed by the Lesch typology. MTHFR 677TT genotype could play a protective role against alcohol dependence. Moreover, when subjects with MTHFR 677TT genotype become dependent to alcohol, they seem to constitute a subgroup of alcoholic patients with a decreased risk for developing neurotoxic withdrawal symptoms and hepatic toxicity.


Repair of interrupted aortic arch and aortopulmonary window in an infant.
The diagnosis and repair in infancy of interrupted aortic arch and aortopulmonary window is described. Using deep hypothermia and circulatory arrest, aortic continuity was established with a prosthetic graft, which was anastomosed to the aortic orifice of the aortopulmonary window. The pulmonary artery side of the aortopulmonary window was closed directly. Postoperative cardiac catheterization demonstrated a good reconstruction. Previous experience with this rare variety of interrupted aortic arch complex is reviewed.


The geographic distribution of child abuse in an inner city borough.
The reported incidence of child abuse continues to rise. Present funding constraints make the introduction of child abuse intervention programs of proven effectiveness very difficult. This difficulty may lead to a change in direction away from population screening which looks for individuals at risk, towards the identification of geographic areas where child abuse is persistently concentrated (target areas). The method of plotting on a large scale map all registered cases of child abuse in an inner London borough is compared to three more complicated methods in its ability to accurately identify target areas. The geographic plotting of cases is favored because of its simplicity and our ability to update it annually as well as identify smaller areas such as housing estates.


Variability of the grass Phragmites australis in relation to the behaviour and mortality of the gall-inducing midge Giraudiella inclusa (Diptera, Cecidomyiidae).
Variability within and between shoots of the grass Phragmites australis proved to be important for both survival (successful gall induction) and reproduction (larval weight) of the gall-inducing midge Giraudiella inclusa. The ovipositing females and the migrating first instar larvae chose a predictable microhabitat within shoots and within internodes characterized by a high nutritional quality (nitrogen, mineral content, sugar, water) and reduced palnt defense properties (silicate). Clutch size increased with the shoot diameter, larval scramble competition could not be detected. Female shoot selection was random, although the chances of successful gall induction greatly differed between shoots. Thick and intact shoots (≥6 mm) led to a high larval mortality. But thick shoots destroyed apically by stem-mining caterpillars (of the noctuid moth Archanara geminipuncta) had on average large gall clusters. Accordingly, the adjustment of the clutch size to the shoot diameter resulted in an advantage for the gall midge females only when shoots were thin and short (i.e. stressed by water and nutrient deficiency) or heavily damage (i.e. stressed) by caterpillars. Thus, the monophagous gall maker G. inclusa did not compensate for all features of intershoot variation of P. australis, although grasses are well-known for their simple plant architecture and their low diversity and low concentration of secondary compounds.


Examining Cesarean Delivery Rates by Race: a Population-Based Analysis Using the Robson Ten-Group Classification System.
The Robson Ten-Group Classification System is widely considered to be the gold standard for comparing cesarean section (CS) delivery rates, despite limited adoption in the United States (US). When reporting overall CS rates, Blacks and other minorities are typically reported to have high CS rates but comparing overall CS rates may be misleading as CS may be more common in some higher risk populations. Improved understanding of how CS rates differ by race among standardized groups could highlight differences in care and areas for improvement. The current study examines racial differences in cesarean section delivery rates using the Robson Ten-Group Classification System in a nationwide sample. Data from US vital statistics live birth certificates were used to identify 3,906,088 births which were each classified into one of the ten groups based on five obstetric characteristics identifiable on presentation for delivery including parity, onset of labor, gestational age, fetal presentation, and number of fetuses. Results indicated that Black and Asian mothers had the highest CS rates in groups 1-4 which all contain single, cephalic pregnancies at term with no prior CS and are only differentiated by parity and onset of labor. Black mothers also had the lowest CS rates for groups 6 and 7, containing women with nulliparous and multiparous breech births. Black and Asian mothers show differences in CS rates among groups that could indicate lack of appropriate care. Efforts should be made to prevent unnecessary primary CS among low-risk mothers.


High refractive index monofunctional monomers as promising diluents for dental composites.
To evaluate high refractive index methacrylates as diluents for the formulation of radiopaque esthetic bulk-fill composites. 2-(4-Cumylphenoxy)ethyl methacrylate 1, 2-(2-phenylphenoxy)ethyl methacrylate 2 and 2-[2-(2-phenylphenoxy)ethoxy]ethyl methacrylate 3 were synthesized and characterized by 1H NMR spectroscopy. The reactivity of each monomer was studied using photo-DSC. Bulk-fill composites based on monomers 1-3 were formulated. Translucency (before and after light cure) was measured using a spectrophotometer. The depth of cure and the water sorption of these materials were determined according to ISO 4049. The flexural strength and modulus of elasticity were measured using a three-point bending setup, according to ISO 4049. The shrinkage force was assessed based on a method described by Watts et al. using a universal testing machine. Monomers 1-3 were easily synthesized in two steps. They exhibit a low viscosity and a high refractive index (1.553-1.573). Monofunctional methacrylates 1-3 were found to be more reactive than triethylene glycol dimethacrylate (TEGDMA). Bulk-fill composites based on these monomers were successfully prepared. They exhibit a high depth of cure and excellent esthetic properties (low transparency). These composites provide higher flexural modulus as well as lower water sorption than a corresponding material based on TEGDMA. Methacrylates 1 and 3 are particularly interesting as they led to composites showing lower shrinkage force. Methacrylates 1-3 are promising diluents for the formulation of highly esthetic radiopaque bulk-fill composites.


New relapse of multiple sclerosis and neuromyelitis optica as a potential adverse event of AstraZeneca AZD1222 vaccination for COVID-19.
We report on nine patients (eight cases of MS and one case of NMOSD) who presented a disease relapse in close temporal association with their first AZD1222 vaccination dose against COVID-19. These patients had been stable for a median period of six years, with no evidence of disease activity and no change in their medication. After a median of 13 days (7 to 25 days) from vaccination, they developed a new relapse with increased disability and new lesions on magnetic resonance imaging. Although this association may be rare, it might be an adverse event of AZD1222.


Single treatments with the antidepressant oxaprotiline and its (+) and (-) enantiomers increase behavioural responses to dopaminergic stimulation in the rat.
The effects of single doses of oxaprotiline and its (+)- and (-)-enantiomers (CGP 12 104 A and CGP 12 103 A, provisional generic name levoprotiline) on apomorphine- and amphetamine-induced stereotypies and amphetamine-induced hyperthermia were investigated in the rat. All 3 compounds enhanced and prolonged stereotyped responses to apomorphine and amphetamine at single doses of 10-30 mg/kg i.p. The most active appeared to be the (-)-enantiomer levoprotiline which is devoid of NA-uptake-inhibiting properties. Neither compound, however, potentiated amphetamine-induced hyperthermia, suggesting that enhanced behavioural effects are not due to the interference with metabolic degradation of amphetamine. The mechanism of the observed effect remains obscure, but in view of the reported clinical antidepressant action of levoprotiline these findings are interesting.


Genomic Dark Matter Illuminated: Anopheles Y Chromosomes.
Hall et al. have strategically used long-read sequencing technology to characterize the structure and highly repetitive content of the Y chromosome in Anopheles malaria mosquitoes. Their work confirms that this important but elusive heterochromatic sex chromosome is evolving extremely rapidly and harbors a remarkably small number of genes.


Subacute toxicity of mesoporous silica nanoparticles to the intestinal tract and the underlying mechanism.
The biological safety of mesoporous silica nanoparticles (MSNs) has gradually attracted attention. However, few studies of their toxicity to the intestine and mechanism are available. In this study, their primary structures were characterized, and their subacute toxicity to mice was investigated. After 2 weeks of intragastric administration of MSNs, they significantly enhanced serum ALP, ALT, AST and TNF-α levels and caused infiltration of inflammatory cells in the spleen and intestines. MSNs induced intestinal oxidative stress and colonic epithelial cell apoptosis in mice. Intestinal epithelial cells exhibited mitochondrial ridge rupture and membrane potential decrease after MSN treatment. Additionally, MSNs increased ROS and NLRP3 levels and inhibited expression of the autophagy proteins LC3-II and Beclin1. MSNs significantly changed the intestinal flora diversity in mice, especially for harmful bacteria, leading to intestinal microecology imbalance. Meanwhile, MSNs influenced the expression of metabolites, which were involved in a range of metabolic pathways, including pyrimidine metabolism, central carbon metabolism in cancer, protein digestion and absorption, mineral absorption, ABC transport and purine metabolism. These results indicated that the subacute toxicity of mesoporous silicon was mainly caused by intestinal damage. Thus, our research provides additional evidence about the safe dosage of MSNs in the clinical and food industries.


Genetic aberrations in prostate carcinoma detected by comparative genomic hybridization and microsatellite analysis: association with progression and angiogenesis.
In spite of increasing knowledge about the tumor biology of prostate cancer (PC), molecular events involved in tumor progression are not well characterized. There is evidence that a number of genetic alterations play a role in tumor progression and in addition, angiogenesis also contributes. In this study, comparative genomic hybridization (CGH), a sensitive method for detecting regional DNA copy number abnormalities, and microsatellite analysis was used to identify frequent genome changes in PC. Correlation of these data with microvessel density (MVD) and clinical follow-up data was performed to determine genetic alterations that are associated with angiogenesis and subsequent tumor progression. Fifty-seven paraffin embedded radical prostatectomy (RP) specimens were microdissected. DNA from the microdissected PC tissue was amplified by degenerate oligonucleoitide primed (DOP)-polymerase chain reaction (PCR), and CGH was performed on the PCR product. Quantitative analyses of the CGH profiles were performed using a t-statistic. Additionally, a microsatellite analysis of chromosome 13q was performed on a subgroup of 31 of the tumors. Using a polyclonal antibody against factor VIII, MVD was determined for all RP specimens. The results of CGH and microsatellite analysis were correlated with the clinical data of the patients and with MVD. Forty-two of the tumors (75%) showed one or more gains while 39 (70%) showed one or more losses per tumor. The most frequent DNA copy number gains were on chromosome 3, 4, 7, 8, 10, 11, 12, 13, and X. The most frequent losses were on chromosomes 2, 5, 6, 8, 10, 13, 15, and 16. Cancer recurrence occurred in 15 patients. The total number of DNA copy number losses was significantly higher in patients with this progression (86%) than without (52%) (P < 0.001). There was no significant difference in the number of gains in patients with or without progression. Contingency table analysis showed a significant correlation between progression and losses in regions of chromosomes 6q and 13q and a gain of chromosome 7q. In multivariate analysis, only loss of chromosome 6 was independently prognostic. The gains that correlated most closely with MVD > 35 were on chromosomes 2q, 7q, and Xq, while the losses most closely associated with MVD > 35 were on chromosomes 8q, 10q, and 13q. However, only the association between loss of chromosome 13q and MVD > 35 was statistically significant. Microsatellite analysis revealed a statistically significant correlation between MVD and instability of locus 171. This study indicates that the frequency of genetic alterations in PC as detected by CGH correlates with clinical outcome, and that losses of DNA from chromosomes 6q and 13q are important events that correlate with tumor progression, with loss of 13q, especially instability of locus 171, also associated with angiogenesis.


Specific inhibition of a calcium dependent activation of brain cyclic AMP phosphodiesterase activity by vinblastine.
Vinblastine selectively inhibits the activation of brain cyclic AMP phosphodiesterase activity by Ca++-protein activator (50% inhibition by 2 x 10(-5) M). This inhibitory effect was reversed by excessive amounts of the activator, whereas large quantities of Ca++ caused only a slight suppression of the vinblastine effect. This result of vinblastine suggests a new site of its action and also suggests the possible role of protein activator, phosphodiesterase proteins or cyclic nucleotides in the previously known effects of vinblastine in vivo and in vitro.


Anatomical and physiological characterization of avian sympathetic cardiac efferents.
In the preceding paper6 describing the right sympathetic cardiac nerve of the pigeon we reported a fast compound action potential component with no chronotropic effect, and single unit recordings from sympathetic postganglionic neurons demonstrated that this action potential component was not reflected in the antidromic postganglionic latencies. Electron microscopy then indicated the presence of numerous myelinated fibers in the nerve, and together these findings suggested the existence of a substantial number of sympathetic cardiac afferents in the right cardiac nerve. The present paper confirms this by demonstrating with retrograde transport of horseradish peroxidase that some fibers of the right sympathetic cardiac nerve have their cells of origin in dorsal root ganglia. This was also shown to be the case for the left sympathetic cardiac nerve. Selective activation of the myelinated fiber contingent was then shown to elicit a short latency decrease in arterial blood pressure that could be further augmented by the activation of the smaller unmyelinated fibers. This reflex depressor response to activation of sympathetic cardiac afferents survived bilateral vagotomy but was blocked by atropine. It is therefore concluded that both the left and right sympathetic cardiac nerves of the pigeon contain afferent fibers, both myelinated and unmyelinated, and that the reflex effect of activating these fibers is a sympathetically mediated vasodilation that is atropine-sensitive.


Primary clear cell sarcoma of the head and neck: a case series with review of the literature.
Clear cell sarcoma typically arises in deep soft tissues of the foot/ankle. Primary head and neck clear cell sarcoma is rare. We report three molecularly confirmed primary head and neck clear cell sarcoma and review the literature. Head and neck clear cell sarcoma with no primary elsewhere were retrieved from archival/consultation files. English language literature review of all reported head and neck clear cell sarcoma was performed. Three cases were identified. The tumors, all in men, presented on the scalp of a 33-year-old, face of a 20-year-old and tongue of a 44-year-old. Tumors ranged from 0.6 to 1.4 cm. All had typical features of clear cell sarcoma, including nests of tumor cells divided by fibrous septae. One had multinucleated wreath-like giant cells. One had a focal junctional component. Immunohistochemistry was positive for S100 (three out of three), HMB45 (three out of three) and Melan-A (two out of three). All had EWSR1 rearrangements by fluorescence in situ hybridization. Follow up available for one patient revealed no evidence of disease after wide excision and radiation. Seven additional reported cases were identified and tabulated. Head and neck clear cell sarcoma is rare but should be considered in the differential diagnosis of nested tumors with fibrous septae. Molecular analysis should be considered for definitive diagnosis regardless of location.


Exploring the Use of Hospital and Community Mental Health Services Among Newly Resettled Refugees.
Resettled refugees in high-income countries represent a vulnerable population. It is known that refugees have high rates of trauma-related mental health issues; however, ad hoc research has generally revealed low rates of health services use among refugees. Such research usually samples a population at a single point in time and is based on targeted surveys. Because refugee populations change over time, such research becomes expensive and time-consuming for agencies interested in routinely publishing statistics of mental health services use among refugees. The linking of large administrative data sets to establish rates of use of mental health services among resettled refugees is a flexible and relatively inexpensive approach. To use data linkage to establish rates of mental health services use among resettled refugees relative to the general population. This cross-sectional study implemented data linkage from the Refugee Health Nurse Program for 10 050 refugees who resettled in Sydney, Australia, from October 23, 2012, to June 8, 2017, with data concerning use of community mental health services and mental health hospitalization from New South Wales Health databases. Data were analyzed between June 1, 2019, and December 31, 2021. Rates of service contacts with community mental health services among the resettled refugees were compared with those of the general population by age, sex, and the most common International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis codes. Length of community mental health service sessions and rates of mental health hospitalizations were also compared. Among the 255 resettled refugees who had contacts with community mental health care services and were not missing data (median age, 35 [range, 4-80] years; 117 [64%] male and 138 [54%] female), 153 (60%) were born in Iraq and 156 (61%) were Arabic speaking. This population was less likely to use mental health services than the general population and had shorter community mental health consultations. The rate of contacts with community mental health services for depressive disorders among the resettled refugee population was 40% (95% CI, 33%-46%) lower than that among the general population. Rates of same-day hospitalization per 10 000 person-years were not significantly different between the refugee population (4 [95% CI, 2-8]) and the general Australian population (7 [95% CI, 7-7]). However, the refugee population was 17% (95% CI, 6%-29%) more likely than the general Australian population to interact with the community mental health system for severe stress- and adjustment disorder-related diagnoses. These findings suggest that refugees who have resettled in Australia tend to use fewer mental health services than the general population except for services devoted to stress- and adjustment disorder-related diagnoses. These findings also suggest that it is possible to successfully leverage data linkage to study patterns of mental health services use among resettled refugees.


End Stage Kidney Disease Patient Experiences of Renal Supportive Care in an Australian Teaching Hospital - A Qualitative Study.
Renal Supportive Care Services (RSCS) were introduced in Australia to provide patient-centred care with a focus on better symptom management and improved quality of life in end stage kidney disease (ESKD) patients managed with or without dialysis. While RSCS have demonstrated clinical benefits with reduced length of hospital stay and symptom burden, there is a gap in understanding the experience of patients referred to RSCS. To identify patient attitudes, beliefs, and perspectives on the RSCS. Qualitative interviews were conducted with 20 participants from both dialysis and conservative treatment pathways. Transcripts were then thematically analysed and primary themes identified, which were reviewed with a stakeholder group that included doctors, nurses and allied health staff to provide triangulation. Patients perceived the RSCS as a provider of multidisciplinary, holistic and patient-centred care that, in addition, helped to ensure prognostic awareness and timely end-of-life care planning. This contributed to an overall sense of patient empowerment with healthcare decisions. This study identified three major themes: (1) Expectations of care; (2) Experience of care; and (3) Understanding patient needs. The study found that RSCS support patient-centred and family-orientated initiatives in decision making and control over healthcare management. This is empowering for patients. Additional patient values, needs and wants from the RSCS were also identified and these could be addressed to improve the patient experience. Our findings support the ongoing use of RSCS to improve the experience of ESKD patients.


Binary mixing of micelles using Pluronics for a nano-sized drug delivery system.
Pluronics with different structural compositions and properties are used for several applications, including drug delivery systems. We developed a binary mixing system with two Pluronics, L121/P123, as a nano-sized drug delivery carrier. The lamellar-forming Pluronic L121 (0.1 wt%) was incorporated with Pluronic P123 to produce nano-sized dispersions (in case of 0.1 and 0.5 wt% P123) with high stability due to Pluronic P123 and high solubilization capacity due to Pluronic L121. The binary systems were spherical and less than 200-nm diameter, with high thermodynamic stability (at least 2 weeks) in aqueous solution. The CMC of the binary system was located in the middle of the CMC of each polymer. In particular, the solubilization capacity of the binary system (0.1/0.1 wt%) was higher than mono-systems of P123. The main advantage of binary systems is overcoming limitations of mono systems to allow tailored mixing of block copolymers with different physicochemical characteristics. These nano-sized systems may have potential as anticancer drug delivery systems with simple preparation method, high stability, and high loading capacity.


Antifungal resistance mechanisms in dermatophytes.
Although fungi do not cause outbreaks or pandemics, the incidence of severe systemic fungal infections has increased significantly, mainly because of the explosive growth in the number of patients with compromised immune system. Thus, drug resistance in pathogenic fungi, including dermatophytes, is gaining importance. The molecular aspects involved in the resistance of dermatophytes to marketed antifungals and other cytotoxic drugs, such as modifications of target enzymes, over-expression of genes encoding ATP-binding cassette (ABC) transporters and stress-response-related proteins are reviewed. Emphasis is placed on the mechanisms used by dermatophytes to overcome the inhibitory action of terbinafine and survival in the host environment. The relevance of identifying new molecular targets, of expanding the understanding about the molecular mechanisms of resistance and of using this information to design new drugs or to modify those that have become ineffective is also discussed.


Chromoblastomycosis: cure by cryosurgery.
Chromoblastomycosis was successfully treated by cryosurgery in a 55-year-old white man. Depigmentation within the scar precludes an entirely successful cosmetic result.


Severe paroxysmal hypertension. An automatic syndrome and its relationship to repressed emotions.
In most patients with severe and symptomatic paroxysmal hypertension, a pheochromocytoma or other medical cause is rarely identified. This article presents the psychosocial assessment of 10 such patients, in whom the absence of any emotional distress preceding paroxysms had discouraged consideration of any psychological basis. However, a causative role of repressed unreported emotions was strongly suggested by 1) a history of unusually severe emotional trauma in 8 of 10 patients, 2) the absence of feelings related to the trauma, and 3) the prompt and sustained response of 3 patients to psychotherapeutic or psychopharmacologic intervention. These observations suggest that some cases of unexplained paroxysmal hypertension have a psychosomatic etiology and result from repressed rather than perceived and reported emotions. Treatment options are explored.


A 90-day inhalation toxicity study with benomyl in rats.
Benomyl [methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate, CAS Registry No. 17804-35-2] is a fungicide and the possibility for inhalation exposure exists for field workers. To assess the toxicity of benomyl, groups of 20 male and 20 female CD rats were exposed nose-only 6 hr a day, 5 days a week, to concentrations of 0, 10, 50 or 200 mg/m3 of a benomyl atmosphere. At the midpoint (approximately 45 days on test) and at the end of the exposure period, blood and urine samples for clinical evaluation were collected from 10 rats/group/sex, and these animals were sacrificed for pathological examination. Similar evaluations were performed on all remaining rats at the end of the 90-day test period. After approximately 45 days on test, compound-related degeneration of the olfactory epithelium was observed in all males and in 8 of 10 female rats exposed to 200 mg/m3 benomyl. Two male rats exposed to 50 mg/m3 had similar, although less severe, areas of olfactory epithelial degeneration. After approximately 90 days of exposure, the remaining 10 rats/group/sex were sacrificed and examined. Of these rats, all of the males and females exposed to 200 mg/m3 had olfactory degeneration, along with 3 males exposed to 50 mg/m3 of benomyl. No other observed lesions were interpreted to have been caused by the benomyl exposure. In addition, male rats exposed to 200 mg/m3 benomyl had depressed mean body weights compared to controls and this finding correlated with a reduction in food consumption. Based on pathological observations, 10 mg/m3 represents the no-observable-effect level (NOEL) for the male rats, and 50 mg/m3 is the NOEL for the female rats.


Antitumour effects of streptococcal lipoteichoic acids on Meth A fibrosarcoma.
The antitumour effects of lipoteichoic acids (LTA) extracted from Streptococcus pyogenes were studied in comparison with other streptococcal cellular components. LTA suppressed the tumour growth of both solid- and ascites-type Meth A fibrosarcoma as did the whole cells of S. pyogenes (OK-432). No other cellular components, such as cell wall peptidoglycan, group-specific C-carbohydrate or type-specific M protein, suppressed the growth of Meth A. LTA, but not the other cellular components, induced tumour necrosis factor (TNF) in Propionibacterium acnes-primed mice. LTA had no direct killing effects on Meth A cells. These results indicate that LTA may be an important antitumour component of OK-432 and that one of the antitumour mechanisms by this streptococcal preparation is the induction of TNF.


Percutaneous 60-day peripheral nerve stimulation implant provides sustained relief of chronic pain following amputation: 12-month follow-up of a randomized, double-blind, placebo-controlled trial.
Peripheral nerve stimulation (PNS) has historically been used to treat chronic pain, but generally requires implantation of a permanent system for sustained relief. A recent study found that a 60-day PNS treatment decreases post-amputation pain, and the current work investigates longer-term outcomes out to 12 months in the same cohort. As previously reported, 28 traumatic lower extremity amputees with residual and/or phantom limb pain were randomized to receive 8 weeks of PNS (group 1) or 4 weeks of placebo followed by a crossover 4 weeks of PNS (group 2). Percutaneous leads were implanted under ultrasound guidance targeting the femoral and sciatic nerves. During follow-up, changes in average pain and pain interference were assessed using the Brief Pain Inventory-Short Form and comparing with baseline. Significantly more participants in group 1 reported ≥50% reductions in average weekly pain at 12 months (67%, 6/9) compared with group 2 at the end of the placebo period (0%, 0/14, p=0.001). Similarly, 56% (5/9) of participants in group 1 reported ≥50% reductions in pain interference at 12 months, compared with 2/13 (15%, p=0.074) in group 2 at crossover. Reductions in depression were also statistically significantly greater at 12 months in group 1 compared with group 2 at crossover. This work suggests that percutaneous PNS delivered over a 60-day period may provide significant carry-over effects including pain relief, potentially avoiding the need for a permanently implanted system while enabling improved function in patients with chronic pain. NCT01996254.


Multilayered Ceramic Membrane with Ion Conducting Thin Layer Induced by Interface Reaction for Stable Hydrogen Production.
Conventional methods for fabricating multilayered ceramic membranes with ion conducting dense thin layers are often cumbersome, costly, and limited by poor adhesion between layers. Inspired by the architectural structure of the rooted grasses in soil, here, we report an interface-reaction-induced reassembly approach for the direct fabrication of Ce0.9 Gd0.1 O2-δ (CGO) thin layers rooted in the parent multilayered ceramic membranes by only one firing step. The CGO dense layers are very thin, and adhered strongly to the parent support layer, ensuring low ionic transport resistance and structural integrity of the multilayered membranes. When using as an oxygen permeable membrane for upgrading fossil-fuel-derived hydrogen, it shows very long durability in harsh conditions containing H2 O, CH4 , H2 , CO2 and H2 S. Furthermore, our approach is highly scalable and applicable to a wide variety of ion conducting thin layers, including Y0.08 Zr0.92 O2-δ , Ce0.9 Sm0.1 O2-δ and Ce0.9 Pr0.1 O2-δ .


Advances in Topical Hemostatic Agent Therapies: A Comprehensive Update.
Severe hemorrhage causes significant metabolic and cellular dysfunction secondary to deficient tissue perfusion and oxygen delivery. If bleeding continues, hemodynamic destabilization, hypoxemia, multiple organ failure, and death will occur. Techniques employed to promote hemostasis include surgical suture ligatures, cautery, chemical agents, self-assembling nanoparticles, and physical methods, like mechanical pressure. Improved understanding of the natural clotting cascade has allowed newly designed agents to become more targeted for clinical and military use. Topically-applied hemostatic agents have enormous clinical applications in achieving hemostasis. This manuscript describes currently available and developing topical hemostatic materials, including topical active agents, mechanical agents, synthetic/hemisynthetic hemostatic agents, and external hemostatic dressings for clinical practice.


Aortic arch thrombosis in the neonate.
Aortic arch thrombosis (AAT) of the neonate is rare but life-threatening by fatal compromise associated with thrombotic obstruction of the ascending aorta. We report a neonate with AAT who demonstrated a severe coarctation of the aorta and cerebral hypo-perfusion immediately after birth. Echocardiography confirmed the diagnosis of AAT on the findings of a large thrombus located on the transverse arch and blocking the cervical arterial branches. Low-molecular-weight heparin reduced the size of the thrombus and improved the hemodynamics of coarctation and cerebral perfusion. Echocardiography is a powerful tool to make a diagnosis and to monitor the size and regression of AAT.


Field study on the efficacy of an extract of neem seed (Mite -Stop) against the red mite Dermanyssus gallinae naturally infecting poultry in Egypt.
Infestations with the poultry red mite Dermanyssus gallinae represent a major ectoparasite problem in poultry and affects egg and meat production worldwide. The effects of the neem seed product Mite-Stop against the red poultry mite were investigated. Five primitive poultry farms in two small villages in the Nile Delta and Giza district were selected for the study. The neem extract was diluted 1:40 and 1:50 with tap water just prior to use. Application of the two dilutions of the provided product was performed to soil, cracks and crevices of the examined area as well as to mite-infested birds on day 0 and day 7. Two hours after treatment soil dust was collected from sprayed regions of the stable and from unsprayed control regions of the same stable. The treated chickens were also checked for mites 2 h after each treatment. The examination of the chickens 2 h after spraying showed that they were free of mites. The examination of treated soil with the Tullgren funnel apparatus 2 h after the first spraying on day 0 already showed a considerable reduction of living mites compared to controls. Seven days after the first treatment of the soil the number of living mites was reduced for 80% in the treated soil and decreased even more after the second spraying, since those larvae that had hatched from eggs in the meantime were killed. The 1:40 dilution of the neem seed extract with tap water was superior to the 1:50 dilution. These results clearly show a very high killing rate of the extract, if the mites come in direct contact with the compound. However, in order to obtain extinction also of hidden and freshly hatched stages repeated spraying should be done three times within 8-10 days.


Cryptic effects of biological invasions: Reduction of the aggressive behaviour of a native fish under the influence of an "invasive" biomolecule.
The invasive green alga Caulerpa cylindracea has become an important component of the diet of the Mediterranean white seabream Diplodus sargus. As a consequence of this "exotic diet", the algal bisindolic alkaloid caulerpin accumulates in the fish tissues. Although the compound shows structural similarity to endogenous indolamines that modulate animal behaviour, the potential impact of caulerpin on fish behaviour still remains unexplored. In this report, behavioural experiments both on groups and on single fish responding towards a mirror were performed under different doses of dietary caulerpin. Differences between treated and control groups for each behaviour and for the overall aggressive pattern during the different experimental phases showed that the aggressiveness of D. sargus decreased with the administration of caulerpin. These results call the attention to a still unexplored potential ability of bioactive metabolites from marine invasive species, to alter the behaviour on native species, with putative negative effects on patterns of fish growth and population dynamics.


Cortical networks for rotational uncertainty effect in mental rotation task by partial directed coherence analysis of EEG.
Partial directed coherence (PDC) as a frequency-domain representation of Granger casuality (GC) could detect both strength and direction of cortical interactions by multivariate autoregressive (MVAR) model of electroencephalography (EEG). In the present study, we investigate the underlying neural networks mechanisms of "rotational uncertainty effect" during mental rotation (MR) task by PDC analysis of multichannel EEG signals before and after the visual stimuli presented, we found that (i) temporally the "rotational uncertainty effect" involved an activated network before the visual stimuli presented, which could also affect the cognitive process of MR later; (ii) the causality functional connectivity network indicated that the bi-directional frontal [symbol see text] parietal networks played critical roles in maintaining the readiness during the MR task. These findings suggest that functional networks of un-cued preparation before visual stimuli presented are worth to be paid more attention. And these networks provide crucial casuality information to understand the neural mechanism for "rotational uncertainty effect" in MR task.


Higher hospital volume predicts endoscopy but not the in-hospital mortality rate in patients with acute variceal hemorrhage.
Acute variceal hemorrhage (AVH) is an important complication of cirrhosis that carries a high mortality rate. Management of AVH requires early initiation of specialized care that may be more readily available at centers that deal with a high volume of AVH. Our purpose was to examine the relationship between the annual hospitalization volume and the in-hospital mortality rate for AVH. Cross-sectional study from a national representative sample. A 20% sample of all nonfederal short-term hospitals from 37 states participating in the Nationwide Inpatient Sample 2004. A total of 28,817 discharges with AVH identified through appropriate International Classification of Diseases, 9th Revision, Clinical Modification codes for bleeding esophageal varices. Hospitals were divided into low-, medium-, and high-volume hospitals if they had 1 to 15, 16 to 35, and 36 or more annual discharges related to AVH. In-hospital mortality rate. On multivariate analysis, there was no significant difference in the mortality rate either for medium- (odds ratio [OR] 0.84; 95% CI, 0.67-1.05) or high-volume hospitals (OR 1.06; 95% CI, 0.82-1.37). However, patients both at medium- (OR 1.27; 95% CI, 1.02-1.58) and high-volume hospitals (OR 1.40; 95% CI, 1.07-1.84) were more likely to undergo endoscopy for AVH. Endoscopic intervention for control of variceal hemorrhage was significantly more common in medium- (OR 1.20) and high- (OR 1.33) volume hospitals. Patients at medium- (OR 3.10; 95% CI, 2.09-4.60) and high-volume hospitals (OR 4.12; 95% CI, 2.52-6.75) were also more likely to undergo transjugular intrahepatic portosystemic shunt (TIPS). Higher hospital volume is associated with greater rates of endoscopy, endoscopic intervention, and higher utilization of TIPS in the management of AVH.


Coherent intensity fluctuation model for autocorrelation imaging spectroscopy with higher harmonic generating point scatterers-a comprehensive theoretical study.
We present a general analytical model for the intensity fluctuation autocorrelation function for second and third harmonic generating point scatterers. Expressions are derived for a stationary laser beam and for scanning beam configurations for specific correlation methodologies. We discuss free translational diffusion in both three and two dimensions. At low particle concentrations, the expressions for fluorescence are retrieved, while at high particle concentrations a rescaling of the function parameters is required for a stationary illumination beam, provided that the phase shift per unit length of the beam equals zero.


Reactions to peroral propylene glycol.
A peroral challenge test with 2--15 ml of propylene glycol (PG) was made in 38 patients with allergic-type epicutaneous test reactions to PG. Eight of 10 patients with a positive epicutaneous reaction to 2 % PG and seven of the other 28 patients with a positive epicutaneous reaction to 100-100 % PG developed an exanthem 3--16 h after ingestion of the drug. In all but one case the rash disappeared within 24--48 h without any medication. In one case the exanthem was treated with prednisone for 4 days, and the symptoms disappeared gradually in 6 days. None of the 20 control patients had skin symptoms. Nausea, vertigo and a curious sensation were recorded in four PG-sensitive patients and in three control patients. These symptoms were apparently due to the general pharmacodynamic effects of PG and they were regarded as non-allergic in nature. It was concluded that PG is a potential allergen and it must be added to the list of causes of drug exanthems.


Regional Distribution of Fluorine-18-Flubrobenguane and Carbon-11-Hydroxyephedrine for Cardiac PET Imaging of Sympathetic Innervation.
The aim of this study was to investigate the regional distribution of novel 18F-labeled positron emission tomographic (PET) tracer flubrobenguane (FBBG) (whose longer half-life could enable more widespread use) to assess myocardial presynaptic sympathetic nerve function in humans in comparison to [11C]meta-hydroxyephedrine (HED). The sympathetic nervous system (SNS) is vitally linked to cardiovascular regulation and disease. SNS imaging has shown prognostic value. HED is the most commonly used PET tracer for evaluation of sympathetic function in humans, but widespread clinical use is limited because of the short half-life of 11C. A total of 25 participants (n = 6 healthy; n = 14 ischemic cardiomyopathy, left ventricular [LV] ejection fraction [EF] = 34 ± 5%; and n = 5 nonischemic cardiomyopathy, EF = 33 ± 3%) underwent 2 separate PET imaging visits 8.7 ± 7.6 days apart. On 1 visit, participants underwent dynamic HED PET imaging. On a different visit, participants underwent dynamic FBBG PET imaging. The order of testing was random. HED and FBBG global innervation (retention index [RI] and distribution volume [DV]) and regional denervation (% nonuniformity) were quantified to assess regional presynaptic sympathetic innervations. FBBG RI (r2 = 0.72; ICC = 0.79; p < 0.0001), DV (r2 = 0.62; ICC = 0.78; p < 0.0001), and regional denervation (r2 = 0.97; ICC = 0.98; p < 0.0001) correlated highly with HED. Average LV RI values were highly similar between HED (7.3 ± 2.4%/min) and FBBG (7.0 ± 1.7%/min; p = 0.33). Post-hoc analysis did not reveal any between-tracer differences on a regional level (17-segment), suggesting equivalent regional distributions in both patients with and without ischemic cardiomyopathy. FBBG and HED yield equivalent global and regional distributions in both patients with and without ischemic cardiomyopathy. 18F-labeled PET tracers, such as FBBG, are critical for widespread distribution necessary for multicenter clinical trials and to maximize patient impact.


Chromosomal DNA content of sweet pepper determined by association of cytogenetic and cytometric tools.
The nuclear DNA content of sweet pepper (Capsicum annuum L. var. annuum, 2n = 24) has been measured by flow and image cytometries but the DNA content of each chromosome of this species has not yet been regarded. DNA content of individual chromosomes has been quantified by the flow karyotyping technique, which requires a great quantity of intact metaphasic chromosomes and methods that allow the characterization of individual chromosomes; however, the obtainment of adequate number of metaphases can be difficult in some species like C. annuum. In order to estimate the DNA content of each C. annuum var. annuum cv. "New Mexican" chromosome, flow and image cytometries were associated with the cytogenetic methodology. First, the DNA amount (2C = 6.90 pg) was established by flow cytometry. Integrated optical density (IOD) values were calculated by image cytometry for each Feulgen stained metaphasic chromosome. Then, by distributing the correspondent metaphasic value (4C = 13.80 pg) proportionally to average IOD values, the following chromosomal DNA contents were obtained in pg: 0.74 (chromosome 1), 0.67 (2), 0.61 (3, 4), 0.60 (5), 0.59 (6, 7), 0.58 (8), 0.57 (9), 0.56 (10) and 0.39 (11, 12). This study reports an alternative and reproducible technique that makes quantifying the chromosomal DNA content possible.


Response to comment on "Extinction debt and windows of conservation opportunity in the Brazilian Amazon".
Halley et al. purport to show a power-law relationship between fragment size and relaxation rates. We use a much more extensive data set to show that area dependence of relaxation rates exists only for very small fragment sizes (<60 hectares), which has limited relevance for our analyses conducted using 250,000-hectare grid squares. We also show that the example of Halley et al. is based on an unrealistic fragmentation model with an infinite number of fragments that have average size of zero hectares. A more realistic formulation of the model shows that relaxation is much less dependent on fragmentation than Halley et al. present.


Short-Chain Fatty Acids Produced by Ruminococcaceae Mediate α-Linolenic Acid Promote Intestinal Stem Cells Proliferation.
The proliferation and differentiation of intestinal stem cells (ISCs) are the basis of intestinal renewal and regeneration, and gut microbiota plays an important role in it. Dietary nutrition has the effect of regulating the activity of ISCs; however, the regulation effect of α-linolenic acid (ALA) has seldom been reported. After intervening mice with different doses of ALA for 30 days, it is found that ALA (0.5 g kg-1 ) promotes small intestinal and villus growth by activating the Wnt/β-catenin signaling pathway to stimulate the proliferation of ISCs. Furthermore, ALA administration increases the abundance of the Ruminococcaceae and Prevotellaceae, and promotes the production of short-chain fatty acids (SCFAs). Subsequent fecal transplantation and antibiotic experiments demonstrate that ALA on the proliferation of ISCs are gut microbiota dependent, among them, the functional microorganism may be derived from Ruminococcaceae. Administration of isobutyrate shows a similar effect to ALA in terms of promoting ISCs proliferation. Furthermore, ALA mitigates 5-fluorouracil-induced intestinal mucosal damage by promoting ISCs proliferation. These results indicate that SCFAs produced by Ruminococcaceae mediate ALA promote ISCs proliferation by activating the Wnt/β-catenin signaling pathway, and suggest the possibility of ALA as a prebiotic agent for the prevention and treatment of intestinal mucositis.


Palatal coverage and oral stereognosis: A systematic review and meta-analysis.
Complete denture wearers present with less sensory function than dentate individuals because of the loss of periodontal receptors. However, the role of the palatal receptors on such function is still unclear. The purpose of this systematic review and meta-analysis was to evaluate the influence of palatal coverage associated with complete dentures or palatal devices on oral stereognosis in edentulous or dentate adults. Eight major literature databases and the nonpeer-reviewed literature were searched up to December of 2021. Randomized clinical trials and nonrandomized clinical trials comparing oral stereognosis in edentulous or dentate participants using conventional complete dentures or implant-supported prostheses or those using palatal devices were included. Bias was assessed with Cochrane tools (ROBINS-I and RoB 2.0). Meta-analyses were conducted to compare oral stereognosis before and after palatal coverage (α=.05). Certainty of the evidence was verified using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Of 14 included studies, the risk of bias was considered low for 9 studies and moderate for 5 studies. Despite the very low certainty of evidence, meta-analyses showed no differences in oral stereognosis immediately after complete denture insertion (standardized mean difference [SMD]=0.302; 95% confidence interval [CI]: -0.124, 0.728; P=.165; I2=92.4%). Oral stereognosis scores improved after ≥1 month of complete denture use compared with initial evaluations without them. Qualitative analysis indicated that oral stereognosis was not influenced by palatal coverage shortly after complete denture installation and that oral stereognosis scores improved over time after prosthesis use. Oral stereognosis improved with the use of palate-covering prostheses over time. However, because of the very low certainty of evidence, the statement must be interpreted with caution.


Qualitative evaluation of a social media campaign to improve healthy food habits among urban adolescent females in Indonesia.
The current study focuses on how adolescent girls in urban Indonesia accept technology in a social media (SM) campaign to promote healthy eating habits. The study was a qualitative evaluation of the online campaign. In-depth interviews using semi-structured interview guidelines and focus group discussions were used to collect data. Data were analysed using a general inductive approach to provide simple and straightforward answers to our study questions. The study was conducted in two urban areas in Indonesia: Jakarta and Jogjakarta. Adolescent girls aged 16-19 years. The SM campaign was perceived as beneficial for increasing participants' knowledge. The campaign helped increase participants' awareness of healthy diets and the health risks of unhealthy diets as well as increase their motivation to change their behaviour and avoid foods containing salt, sugar and excess fat. The participants perceived information from the online campaign as complete and trustworthy. Instagram was cited as the easiest platform to use, while the website was cited as having the most complete information. YouTube provided the best viewing experience but was considered a data-heavy platform. The barriers to change were perceptions of taste, limited choices for healthy but affordable ingredients and family-related factors. The online nutrition campaign was well accepted by Indonesian urban adolescent females and motivated them to act to protect their health. Future nutrition-related SM campaigns aimed at this demographic should focus on platforms with the greatest benefit and ease of use.


Acute hyperlipidemia but not hyperhomocysteinemia impairs reflex regulation of the cardiovascular system.
Elevated circulating lipids and homocysteine may affect autonomic cardiovascular function by decreasing baroreflex sensitivity (BRS) and cardiovagal outflow and by increasing sympathetic drive. To test this hypothesis 25 clinically healthy men (mean age 24 ± 2 years) received 500 ml whipping cream (30% fat) and 0.1 g/kg l-methionine, respectively, at intervals of one week apart to induce hyperlipidemia and hyperhomocysteinemia, respectively. Cardiovascular parameters and endothelial function were assessed before and 2 h after the fat load and before and 4 h after the methionine load, respectively. Cardiovascular responses to sublingual application of a nitrovasodilator and a beta-agonist were also determined. Hyperlipidemia elicited a significant decline in BRS and an increase in heart rate and sympathetic drive. Reductions in BRS were associated with changes in total cholesterol but not with triglycerides or endothelial function. Autonomic and hemodynamic variables remained unaltered during transient hyperhomocysteinemia although there was a trend to lower BRS. Autonomic and hemodynamic responses to pharmacological vasodilation and beta-adrenoceptor stimulation were preserved under both conditions. These data provide experimental support for the concept that acute hyperlipidemia but not hyperhomocysteinemia impairs reflex regulation of the circulatory system.


Clinicopathological outcomes of preoperative chemoradiotherapy using S-1 plus Irinotecan for T4 lower rectal cancer.
To investigate the clinicopathological outcomes of patients with T4 lower rectal cancer treated using preoperative chemoradiotherapy with S-1 plus Irinotecan. Between 2005 and 2011, 35 patients with T4M0 lower rectal cancer, diagnosed initially as T4a in 12 and as T4b in 23, were treated with 45 Gy of radiotherapy concomitantly with S-1 plus Irinotecan. The median follow-up period was 50.6 months (range 2-123 months). A total of 32 patients (91.4 %) completed the radiotherapy and 26 (74.3 %) completed the full chemotherapy regimen. Radical surgery was then performed in 33 (94.3 %) of the 35 patients after the exclusion of two patients, who had macroscopic residual disease. The pathological diagnosis was downstaged from T4a to ypT0-3 in all 12 of those patients (100 %) and from T4b to ypT0-4a in 20 of those 23 patients (87.0 %). The tumor regression grade of 1a/1b/2/3 (complete response) was 10/8/15/2, respectively. In terms of long-term survival, the 5-year local relapse-free survival rate was 74.8 % and the recurrence-free survival rate was 52.0 %. This regimen may result in favorable downstaging. Moreover, in this series, pathological evidence of involvement of adjacent organs was rare following preoperative chemoradiotherapy, in the patients with disease diagnosed as T4b at the initial staging.


Robot-assisted vs laparoscopic pyeloplasty in children with uretero-pelvic junction obstruction (UPJO): technical considerations and results.
Although both laparoscopic pyeloplasty (LP) and robot-assisted laparoscopic pyeloplasty (RALP) have reported excellent clinical outcomes, no evidence is currently available about the best surgical approach for surgical treatment of children with uretero-pelvic junction obstruction (UPJO). This study aimed to compare the outcomes of LP and RALP in children with UPJO. The medical records of all patients with UPJO, who underwent LP or RALP in three pediatric urology units over a 2-year period, were retrospectively reviewed. The authors excluded open pyeloplasty and cases with complex anatomy such as horseshoe kidney. A dismembered Anderson-Hynes pyeloplasty was performed in all cases. Sixty-seven patients (39 boys and 28 girls) with a median age of 4 years (range 8 months-14 years) were included. Thirty-seven patients (55.2%) underwent RALP, and 30 patients (44.8%) underwent LP. Three patients of RALP group presented a recurrent UPJO. No significant difference was found in the median total operative time between RALP (133 min) and LP (139 min) (P = 0.33). The median anastomotic time was significantly shorter in RALP (79 min) compared with LP (105.5 min) (P = 0.001). Overall surgical success rate was 96.7% for LP and 100% for RALP (P = 0.78). As for postoperative complications, the authors recorded re-stenosis of UPJO in one LP patient (3.3%), who underwent redo-RALP. According to the authors experience, robotic surgery should be indicated in patients older than 18-24 months with a body weight > 10-15 Kgs. Laparoscopic pyeloplasty requires advanced laparoscopic skills related to intracorporeal suturing. However, the learning curve of suturing in robotics is much shorter compared with laparoscopy. In fact, during LP, the authors have to place 2-3 transabdominal stay sutures to stabilize the uretero-pelvic junction, before performing the anastomosis. Conversely, the authors never needed to place stay sutures in RALP. The study experience suggested that RALP and LP give excellent results in children with UPJO. Laparoscopic pyeloplasty can be considered more minimally invasive than RALP because 3-mm trocars are adopted instead of 8-mm robotic ports. However, LP is technically challenging and has a bad ergonomics for the surgeon. Conversely, RALP is technically easier compared with LP, especially in redo procedures, with an excellent ergonomics. The main disadvantages of RALP remain high costs and size of robotic instruments. The choice to perform LP or RALP should be tailored to the individual case, considering patient's age and surgeon's experience.


Statistical comparison of Pearl rates.
Statistical procedures for hypothesis testing and interval estimation of the difference in a pair of Pearl rates are presented. The p value of the test statistic is evaluated exactly from the binomial distribution or approximately from the standard normal distribution. Interval estimation is provided by the test-based method of Miettinen. The procedures are applied to two published data sets, and the conceptual link between the Pearl rate and life-table methods is discussed.


Tosta Evans, 1953 (Lepidoptera: Hesperiidae): a new species from northeast Brazil, first description of the female of Tosta tosta Evans, 1953, and placement of the genus within Achlyodini.
A new species of Tosta Evans, 1953 from northeast Brazil is described: T. pseudospeculum Siewert, Mielke & Casagrande, sp. nov. Additionally, the female of Tosta tosta Evans, 1953, the type species of the genus, is described for the first time. Illustrations of adults and male and female genitalia for all studied species are provided, as well as a discussion of the placement of the genus within the tribe Achlyodini.


Icariin delays homocysteine-induced endothelial cellular senescence involving activation of the PI3K/AKT-eNOS signaling pathway.
Homocysteine-induced endothelial cellular senescence may contribute to some cardiovascular disorders. Icariin (ICA), a flavonoid derived from Epimedium sagittatum Maxim. (Berberidaceae), has been reported to increase production of nitric oxide (NO) and reduce reactive oxygen species (ROS) levels in human umbilical vein endothelial cells (HUVECs). To observe the effects of ICA on homocysteine-induced senescence and the underlying mechanisms in HUVECs. ICA at concentrations of 0.1, 1, and 5 μM was added into homocysteine pretreated HUVECs. Cellular senescence was assayed by senescence-associated β-galactosidase (SA-β-gal) staining and cumulative population doublings (CPDs). ICA (5 μM) was given orally to homocysteine-treated rats, luminal surface of aortic artery of rats was subjected to SA-β-gal staining. Protein expression was measured by western blot. Homocysteine significantly increased cellular senescence both in vitro and in vivo. After treatment by ICA, the percentage of SA-β-gal-positive cells, and the ROS level significantly decreased. The CPDs were partially restored. ICA also significantly reduced the mean density of SA-β-gal staining in vivo. We found that NO production and phosphorylation of AKT, ERK, and endothelial NO synthase (eNOS) were elevated by ICA in HUVECs. Furthermore, the increased level of NO production was fully abolished by the phosphatidylinositol-3-kinase (PI3K) inhibitor wortmannin. The mitogen-activated protein kinase (MEK) inhibitor PD98059, which can inhibit phosphorylation of ERK, did not show this ability. Our results indicate that ICA delays homocyteine-induced endothelial senescence in vitro and in vivo. Activation of PI3K/Akt-eNOS-dependent signaling pathway may be responsible for this efficacy of ICA.


Time-of-day-dependent responses of cyanobacterial cellular viability against oxidative stress.
As an adaptation to periodic fluctuations of environmental light, photosynthetic organisms have evolved a circadian clock. Control by the circadian clock of many cellular physiological functions, including antioxidant enzymes, metabolism and the cell cycle, has attracted attention in the context of oxidative stress tolerance. However, since each physiological function works in an integrated manner to deal with oxidative stress, whether or not cell responses to oxidative stress are under circadian control remains an open question. In fact, circadian rhythms of oxidative stress tolerance have not yet been experimentally demonstrated. In the present work, we applied an assay using methyl viologen (MV), which generates reactive oxygen species (ROS) under light irradiation, and experimentally verified the circadian rhythms of oxidative stress tolerance in photosynthetic cells of the cyanobacterium Synechococcus elongatus PCC 7942, a standard model species for investigation of the circadian clock. Here, we report that ROS generated by MV treatment causes damage to stroma components and not to the photosynthetic electron transportation chain, leading to reduced cell viability. The degree of decrease in cell viability was dependent on the subjective time at which oxidative stress was applied. Thus, oxidative stress tolerance was shown to exhibit circadian rhythms. In addition, the rhythmic pattern of oxidative stress tolerance disappeared in mutant cells lacking the essential clock genes. Notably, ROS levels changed periodically, independent of the MV treatment. Thus, we demonstrate for the first time that in cyanobacterial cells, oxidative stress tolerance shows circadian oscillation.


Dichotomy between Receptor-Interacting Protein 1- and Receptor-Interacting Protein 3-Mediated Necroptosis in Experimental Pancreatitis.
Pancreatic acinar cell necrosis and inflammatory responses are two key pathologic processes in acute pancreatitis (AP), which determines the severity and outcome of the disease. Recent studies suggest that necroptosis, a programed form of necrosis, is involved in the pathogenesis of AP, but the underlying mechanisms remain unknown. We investigated the expression of necrosome components, including receptor-interacting protein (RIP) 1, RIP3, and mixed lineage kinase domain-like (MLKL), and the molecular mechanisms in pancreatitis-associated necroptosis. We found that RIP3 and phosphorylated MLKL expression was positively related to the degree of necrosis, whereas RIP1 expression was negatively related to the degree of necrosis. Pharmacologic inhibition of RIP1 kinase activity exerted no protection against caerulein/cholecystokinin-8-induced AP, but knockdown of RIP1 with siRNA increased acinar cell necrosis and inhibition of NF-κB activation. RIP1 inhibition led to enhanced RIP3 expression. RIP3 and MLKL inhibition decreased acinar cell necrosis, in which the inhibition of RIP3 reduced the phosphorylation level of MLKL. RIP3 inhibition had no effect on trypsinogen activation but partly inhibited inflammasome activation. Our study strongly suggests that the imbalance between RIP1 and RIP3 shifts the cell death to necrosis, which unravels a new molecular pathogenesis of mechanism of AP and may provide insight into the development of novel therapeutic agent for other necrosis-related diseases.


Regulating evolution.
Because genes encode instructions for building animal bodies, biologists once expected to find significant genetic differences among animals, reflecting their great diversity of forms. Instead very dissimilar animals have turned out to have very similar genes. Mutations in DNA "switches" that control body-shaping genes, rather than in the genes themselves, have been a significant source of evolving differences among animals. If humans want to understand what distinguishes animals, including ourselves, from one another, we have to look beyond genes.


Amylase release from rat parotid glands. I. General characteristics.
The involvement of calcium, ATP, and cyclic AMP-dependent protein kinase activity in the release of amylase from rat parotid glands was examined. Pretreatment of the glandular tissue in 11.25 mM Ca2+ medium potentiated the secretory responses to: dibutyryl cyclic AMP, elevation of the extracellular K+ concentration, reduction of the H+ concentration, La3+, and caffeine. Uncoupling of oxidative phosphorylation blocked release induced by dibutyryl cyclic AMP, K+, and reduction of H+, but had no effect on La3+, caffeine or tolbutamide-stimulated release. Inhibition of cyclic AMP-dependent protein kinase activity blocked only dibutyryl cyclic AMP-induced release and did not inhibit the responses to K+, reduction of H+ or caffeine. The loss of lactate dehydrogenase was used to access the integrity of the tissue during amylase release. No significant increase in the release of lactate dehydrogenase was observed during the secretory responses to: dibutyryl cyclic AMP, La3+, caffeine, or tolbutamide. Triton X-100 and ethanol increased the efflux of both amylase and lactate dehydrogenase. The differential involvement of Ca2+, ATP, and cyclic AMP-dependent protein kinase activity in amylase release induced by the various secretagogues suggests that three types of reactions are involved in the release of amylase.


Do individual allocyclic chromosomes in metaphase reflect their interphase domains?
Individual S phase allocyclic chromosomes have been analyzed in Bloom syndrome lymphocytes, in cells with an r(9), and in hypotetraploid Ehrlich mouse ascites cells treated with 1-methyl-2-benzyl hydrazine. On the basis of the following observations, we conclude that such chromosomes more or less reflect their domains in interphase: (1) The S phase allocyclic chromosomes have the same structure as S phase prematurely condensed chromatin (PCC) in fused cells; in other words they form limited areas of chromatin dots; (2) the allocyclic chromosome is the only chromosome in a metaphase plate which synthesizes DNA simultaneously with interphase nuclei; (3) the size of the allocyclic chromosomes is related to the size of the corresponding metaphase chromosome; and (4) the S phase allocyclic chromosomes resemble closely the chromosome domains in interphase made visible with biotinylated human DNA. A variety of evidence shows that most allocyclic chromosomes are simply left behind in their cycle, which presumably is caused by a deletion or inactivation of a hypothetical coiling center situated on each chromosome arm.


Induction or suppression of a B cell-specific response to self antigen in vivo is dependent upon dendritic cell activation via the TNF-alpha receptor at the time of antigen uptake.
In this study we show that the retinal autoantigen, S-antigen, contains a functional TNF-alpha homologous domain which stimulates maturation and differentiation of cultured dendritic cells (DC) or tissue DC via the p55 TNF-alpha receptor. Tissue DC became more dendritiform in shape, and migrated into culture supernatant. S-antigen also stimulated accumulation of cell surface MHC class II antigen with a corresponding loss of acidic intracellular vesicles, and induced IL-1beta and IL-12 mRNA expression in cultured bone marrow-derived DC. In addition, cultured splenic DC primed immune responses to S-antigen in vivo in the absence of other, exogenous cytokine sources. DC pulsed with either retinal S-antigen or another retinal autoantigen, interphotoreceptor retinoid binding protein (IRBP), were able to stimulate naive T cell proliferation in vitro, but only S-antigen-pulsed DC were able to induce an immune response in vivo and initiate antibody class switching. In contrast, IRBP-pulsed DC had no detectable in vivo priming effect and IgG antibody levels remained suppressed even after immunization with IRBP in complete Freund's adjuvant. These results indicate that DC from the same precursor population can either induce or suppress a B cell-specific response to self antigen in vivo, the outcome being dependent upon DC activation at the time of antigen uptake and presentation.


Managing patients on extracorporeal membrane oxygenation support during the COVID-19 pandemic - a proposal for a nursing standard operating procedure.
Extracorporeal membrane oxygenation (ECMO) is effective in a selected critically ill patient population with promising results in refractory hypoxemia related to the novel coronavirus disease (COVID-19). However, it requires specialized clinicians and resources in advanced technology. Moreover, the COVID-19 remains an ongoing global emergency, and there is no evidence-based practice in preparedness. This article proposes an innovative and optimized nursing care protocol, the Standard Operating Procedure (SOP), that regulates safety and efficiency in using personal protective equipment (PPE) during ECMO-relevant procedures while providing ECMO therapy for patients with COVID-19. After performing a narrative literature search, we developed a high-fidelity translational simulation scenario. It included practicing appropriate donning and doffing PPE during work organization, ECMO-related procedures, and routine daily nursing care and management of ECMO over nine hours. In addition, we held supplementary constructive debrief meetings to consult international expert in the field. A proposal for nursing standardized operating procedures was created, divided into categories. They included work organization, workload references, competences, infrastructural conditions, cannulation equipment, daily routine nursing care, and procedures during ECMO. High-fidelity medical simulation can play an important role in staff training, improvement in previously gained proficiency, and development of optimal SOP for nursing care and management during ECMO in patients with COVID-19. Optimal SOPs may further guide multidisciplinary teams, including intensive care units and interventional departments.