Comparative cost of ART and conventional treatment within a dental school clinic.
The changing oral health needs in South Africa require that both the teaching and clinical techniques of atraumatic restorative treatment (ART) form a part of the restorative undergraduate curriculum. This study was undertaken to establish and compare the estimated costing of an amalgam, composite resin and ART restoration within the Board of Health Funders (BHF) recommended scale of benefits at the School of Oral Health Sciences Oral and Dental Hospital, University of the Witwatersrand (SOHS). Fixed and variable costs were calculated by pricing items and equipment used in each procedure. The output values were established according to the recommended scale of benefits (BHF, 1999). This enabled the calculation of contribution margins and net income for each of the three restorations. The annual capital cost for the ART approach is approximately 50% of the other two options (e.g. per multiple surface restoration ART = R1.58; amalgam and composite resin restorative procedures: R3.12 and R3.10 respectively), despite the fact that ART restorations are rendered in a modern dental setting. Our study shows that implementation of the ART approach within the clinic setting of the SOHS can be accomplished without additional cost. Furthermore ART can be performed as an economically viable alternative to conventional treatment procedures within the clinic setting. The study represents a first step towards determining the cost efficiency of implementing ART as a pragmatic and cost-effective restorative option within the SOHS, University of the Witwatersrand.


Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study.
Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUCτ) and maximum plasma concentration (Cmax) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed. A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUCτ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.


Post-translational modification of a tryptophan biosynthetic enzyme. Precursor-product relationships in vivo and carbon-energy source dependence.
Purified preparations of the bifunctional, tryptophan biosynthetic enzyme N-(5'-phosphoribosyl)anthranilate isomerase/indole-3-glycerol phosphate synthase of Escherichia coli K12 contain five forms of the protein (molecular mass = 49 kDa) which can be separated by isoelectric focusing or two-dimensional gel electrophoresis. The stability of the enzyme and its different forms was studied in exponentially growing, ammonium-starved and energy-depleted cultures using a dual-labeling, pulse-chase method. Labeled enzyme was isolated by standard purification techniques and by immunoprecipitation from crude extracts. The results demonstrated the following: 1) post-translational modification occurred in vivo, 2) modification occurred to the same extent in growing and ammonium-starved cells, 3) modification was dependent on a carbon-energy source for the cells, and 4) the enzyme was not degraded in growing or nongrowing cells. The pulse-chase data also indicated that one form of the protein (band 1) was the precursor of three other forms (bands 3-5) and that the relative amount of one form (band 2) remained constant.


Residual nodal disease in patients with advanced-stage oropharyngeal squamous cell carcinoma treated with definitive radiation therapy and posttreatment neck dissection: Association with locoregional recurrence, distant metastasis, and decreased survival.
Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in frequency. We reviewed patients with advanced-stage OPSCC treated with chemoradiation to assess the impact of residual neck disease on survival. We reviewed 202 patients with OPSCC between 1990 and 2010 treated with primary chemoradiation followed by neck dissection. Imaging was analyzed using RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 criteria. Survival was evaluated using both univariate and multivariate analyses. Overall survival at 5 years was 89%. Forty-two patients (21%) had residual disease in the neck (pN+). pN+ was associated with greater locoregional recurrence (LRR) and distant metastasis (DM) and decreased survival. No clinicopathologic factors were predictive of pN+. Contrasted posttreatment CT had low sensitivity and specificity. In advanced OPSCC pN+, patients have higher rates of LRR and DM. Neither clinicopathologic factors nor posttreatment imaging was predictive of pN+, although increased use of modern imaging may reduce the rate of negative neck dissections.


Comparison of the cardiac force-time integral with energetics using a cardiac muscle model.
Several investigators have found experimentally that the force-time integral varies non-linearly with energy expenditure over the course of a cardiac contraction. Also, recent research findings have indicated that the crossbridge cycle to ATP hydrolysis ratio in muscle fiber systems may not be coupled with a one-to-one ratio. In order to investigate these findings, Huxley's sliding filament crossbridge muscle model coupled with parallel and series elastic components was simulated to examine the behavior of the crossbridge energy utilization and force-time integral vs time. Crossbridge (CB) energy utilization was determined by considering the ATP hydrolysis for the crossbridge cycling, and this CB energy was compared with the force-length energy in a contraction. This CB energy was calculated in both isometric and isotonic contractions as a function of contraction time and compared to the force-time integral. Simulation results demonstrated that the ratio of the force-time integral to CB energy varies strongly throughout the cardiac cycle for both isometric and isotonic cases, as has been observed experimentally. Simulations also showed that using the force-length energy component of energy vs the CB energy gave a better correlation between the total energetic predictions and the force-time integral, agreeing with recent finding that the crossbridge cycle to ATP hydrolysis ratio may not be coupled one-to-one, especially at lower force levels.


Another ten stories in antiviral drug discovery (part C): "Old" and "new" antivirals, strategies, and perspectives.
The ten stories told here deal with (i) ribavirin as an inhibitor of IMP dehydrogenase and (ii) ribavirin, in combination with pegylated interferon, as the present "standard of care" for hepatitis C; (iii) S-adenosylhomocysteine hydrolase inhibitors as antiviral agents; (iv) new adamantadine derivatives for the treatment of influenza A virus infections; (v) 5-substituted 2'-deoxyuridines (i.e. IDU, TFT) for the treatment of herpes simplex virus (HSV) infections; (vi) acyclic guanosine analogues (e.g. acyclovir) for the treatment of HSV infections; (vii) OMP decarboxylase inhibitors (i.e. pyrazofurin) and CTP synthetase inhibitors (i.e. cyclopentenylcytosine) as possible antiviral agents; (viii) the future of cidofovir (and alkoxyalkyl esters thereof) and ST-246 as potential antipoxvirus agents; (ix) the two decade journey from tivirapine to rilpivirine in the ultimate therapy of HIV infections; and (x) the extension of the therapeutic application of tenofovir disoproxil fumarate (Viread) to the treatment of hepatitis B virus infection, in addition to HIV infection.


[Prevention of Cardiovascular Complications in Patients With Arterial Hypertension While Use of Angiotensin II Receptor Antagonists. Possibilities of Candesartan].
The article demonstrates advantages of angiotensin II receptor antagonists in treatment of arterial hypertension (AH). Subjects for consideration are evidences of antihypertensive efficacy of candesartan and possibilities of the product in prevention of cardiovascular complications in patients with AH.


Parkinson's disease: Research puts spotlight on thiamine deficiency and cardiovascular health.
The manuscript is a commenting on the article "Effects of vitamin B12, folate, and entacapone on homocysteine levels in levodopa-treated Parkinson's disease patients: A randomized controlled study", recently published by Anamnart and Kitjarak (2021), in this prestigious journal. The authors demonstrated that combination supplementation with vitamin B12 and folate was associated with significantly decreased plasma homocysteine (Hcy), suggesting that plasma Hcy levels should be monitored during levodopa treatment, and supplementation with inexpensive vitamin B12 and folate is beneficial for levodopa-treated PD patients. Considering some evidences - i) that it has to be indicated that dietary and supplemental thiamine intake has a protective effect on various medical conditions, including PD; ii) that several studies highlighted a possible relationship between PD low levels of thiamine in the serum, suggesting that elevated thiamine levels might protect against PD; iii) that thiamine deficiency is not just a common finding in patients with cardiovascular dysfunctions, but it might also have a role in the development and prognosis of PD - our research group believes that some comprehensive cardiovascular screening protocols should be developed for PD patients in order to reduce fatal events in these individuals.


Late-onset Rasmussen Encephalitis: A literature appraisal.
Rasmussen Encephalitis (RE) is classically described as a childhood encephalopathy due to a unilateral inflammation of the cerebral cortex with a presumed immune-mediated pathophysiological basis. Unusual variant forms, including adolescent and adult-onset RE have been described but there is still a doubt whether these atypical cases correspond to classical RE patients. To review evidence, a systematic PubMed search was conducted to retrieve papers addressing late onset RE to assess (i) the positivity rate of classical childhood-onset diagnostic criteria for RE in late-onset RE, (ii) the specific clinical and radiological features that could help earlier diagnosis and therapeutic interventions, (iii) the arguments for an autoimmune pathophysiology including (iiia) the association with autoimmune markers or diseases and (iiib) the effects of immunomodulatory or immunosuppressive treatments. A total of 50 papers were considered. We identified 102 late-onset RE patients with a sex ratio of 8 women for 2 men. 67% fulfilled the consensus diagnostic criteria for RE. As compared to classical RE, the late-onset RE patients exhibited: i) more frequent focal complex partial seizures, ii) less frequent epilepsia partialis continua throughout evolution, iii) a slower evolution with a delayed occurrence of cortical deficit, iv) less cognitive deterioration and v) a better outcome. A specific association with autoimmune markers or diseases was not found. Immunomodulatory therapies, even performed in a late stage, improved late-onset RE patients in 61% of cases. This review proves that late-onset RE is a reality with specific clinical and radiological features. The good response to immunomodulatory treatments brings further arguments for an immune-regulated process.


Influence of the Stern layer on electrokinetic phenomena in porous media.
The Stern layer has been included in the description of electrolytes in a charged porous medium, with possibly large zeta potentials. The surface charge density, the conductivity, and the electroosmotic coupling coefficient are calculated for various porous structures and various physico-chemical conditions. The saturation of the Stern layer is analyzed, as well as its consequences for the macroscopic properties of the medium. The discontinuous character of the solid interface has an important influence on the macroscopic conductivity and the electroosmotic coefficient.


Rheological properties of cellulose nanofiber hydrogel for high-fidelity 3D printing.
Optimization of the rheological properties of the matrix is critical for high-fidelity matrix-assisted 3D printing (MAP), which enables the free-form fabrication of fluidic soft materials. This report describes the generic criteria observable in the printing process of cellulose nanofiber (CNF) hydrogels: the sharpness of an angled line, the cross-sectional ratio of a feature, the surface roughness of features, and the completeness of multi-line writing. The concentration and physical properties of the CNF affects the printing fidelity by changing the values of the four criteria, which are closely related to the rheological properties of the matrix. The printing fidelity can be enhanced by the optimal combination of the inks and the CNF matrix. Hydrophilic and hydrophobic inks are printed in the CNF matrix demonstrating as a universal matrix for free-form fabrication with liquid inks.


Conducting clinical trials during the COVID-19 pandemic-a collaborative trial network response.
The unprecedented demand placed on healthcare systems from the COVID-19 pandemic has forced a reassessment of clinical trial conduct and feasibility. Consequently, the Australasian Kidney Trials Network (AKTN), an established collaborative research group known for conducting investigator-initiated global clinical trials, had to efficiently respond and adapt to the changing landscape during COVID-19. Key priorities included ensuring patient and staff safety, trial integrity and network sustainability for the kidney care community. New resources have been developed to enable a structured review and contingency plan of trial activities during the pandemic and beyond.


Relationship between formaldehyde exposure, respiratory irritant effects and cancers: a review of reviews.
Formaldehyde is an organic compound used in the production of resins, paper, wood plywood, solvents and cleaning products. Formaldehyde is also present when tobacco is smoked. Formaldehyde has been defined as an irritant and is classified as a human carcinogen by the International Agency for Research on Cancer. The purpose of this study was to demonstrate the following two distinct correlations: (1) the association between formaldehyde exposure and development of irritant diseases affecting the respiratory tract, mainly asthma; and (2) the association between formaldehyde exposure and development of neoplastic diseases. This was an umbrella review. A search was conducted in the three main electronic databases of scientific literature: PubMed, Scopus and Web of Science. The search included systematic reviews and meta-analyses published in the previous 10 years. Initially, titles and abstracts of retrieved articles were evaluated, then full-text assessments of selected articles took place. Data extraction and quality assessment were performed according to Assessing the Methodological Quality of Systematic Reviews (AMSTAR) score. A total of 630 articles were initially collected. Nine articles concerning the association between formaldehyde exposure and asthma were included in the present review, and the majority of these reported good association. In addition, 27 articles investigating the association between formaldehyde exposure and neoplastic diseases were included in the review. These studies showed that nasopharyngeal cancer and leukaemia were the most represented neoplastic diseases; however, only a weak association was reported between formaldehyde exposure and cancer. Although the studies included in this review did not show a strong association between exposure to formaldehyde and irritant or neoplastic diseases, the World Health Organisation recommends that levels of formaldehyde do not exceed the threshold value of 0.1 mg/m3 (0.08 ppm) for a period of 30 min. It is recommended that preventive measures, such as ventilation in workplaces with high exposure to formaldehyde and environmental monitoring of formaldehyde concentrations, are implemented.


Extraocular sebaceous carcinoma of the chest wall: A case report.
Sebaceous carcinoma is a rare malignancy that is most commonly found in the head and neck region, particularly in the periocular region. Extraocular lesions are rarer, however are thought to have a higher association with Muir-Torre Syndrome, a variant of Lynch Syndrome, that affects both sebaceous glands and visceral organs. Our patient was a 54 year old male with a past medical history of hypertension, stroke, and vertigo who presented to the emergency department with paresthesias concerning for a transient ischemic attack in the setting of a hypertensive emergency. After admission, the patient reported an abscess on the chest that was present for four months prior. Subsequent physical exam incidentally revealed a fungating mass located on the chest wall. The mass was noted to have central ulceration and necrosis. CT scan of the chest with intravenous contrast revealed that the mass did not invade the chest wall, therefore a surgical excision was performed. A final diagnosis of sebaceous carcinoma was made after microscopic examination of the resected mass. Immunohistochemistry revealed loss of expression of mismatch repair genes. The patient was lost to follow-up before any additional work up could be performed. Extraocular sebaceous carcinomas should be tested using immunohistochemistry for loss of expression of mismatch repair genes. Patients with loss of expression should be risk stratified using the Mayo Muir-Torre risk score to determine if they should undergo germline genetic testing for Lynch Syndrome. Patients with issues in adherence represent a unique diagnostic challenge in potentially evolving diseases.


Imaging of the Vestibular Schwannoma: Diagnosis, Monitoring, and Treatment Planning.
Appropriate imaging strategies for the detection, treatment planning, and posttreatment monitoring of vestibular schwannomas will be discussed. The typical and variant imaging appearances of vestibular schwannomas, as well as the imaging features that should prompt consideration of differential diagnoses, will be illustrated. Understanding the natural history of vestibular schwannomas, optimal measurement and definition of tumour growth helps the radiologist evaluate for the failure of conservative management and requirement for surgery or radiotherapy. In order to determine the success of conservative management, the radiologist is required to understand the natural history of vestibular schwannomas and how tumour growth is defined. Finally, the imaging features which help guide appropriate treatment with surgery or radiotherapy will be highlighted, and the expected posttreatment imaging changes will be described.


Routine abdominal magnetic resonance imaging can determine psoas muscle area in paediatric Crohn's disease and correlates with bioelectrical impedance spectroscopy measures of lean mass.
Paediatric Crohn's disease (CD) has been associated with undernutrition. Accurate and accessible measures of body composition would provide data to personalise nutritional therapy. We assessed feasibility of MRI-derived measures of psoas cross-sectional area (PCSA) in paediatric CD and correlated with anthropometric and bioelectrical impedance spectroscopy (BIS) measures. MRI small bowel/pelvis images of patients with CD, aged <18 years, were retrieved. Patients with concurrent anthropometric and BIS measurements were eligible for inclusion. The PCSA at L3 was calculated by two assessors and combined. To assess reproducibility of measures we calculated the coefficient of variation (CoV). Age, height-Z-scores, weight-Z-scores and BIS measures were correlated with PCSA. Using normal paediatric data from CT-scans we derived psoas area Z-scores for our cohort. 10 patients were included. Mean age at MRI scan was 14.6 years (11.7-16.3). PCSA was calculated for all MRI scans. There was high reproducibility between measurers, mean CoV 0.099. There was a significant positive correlation between PCSA and BIA-derived fat free mass, Pearson correlation coefficient (PCC) 0.831, p = 0.003. Correlation coefficients for PCSA and Height-for-age Z-score, weight-for-age -Z-score and age were PCC 0.343- p = 0.33, PCC = 0.222- p = 0.54, and PCC 0.6034- p = 0.065, respectively. The mean PCSA Z-score was -1.81, with 70% of the patients having a Z-score < -2.0. These data demonstrate the feasibility of deriving measures of body composition from routine MRI imagine. There was significant positive correlation between PCSA and BIS-derived lean mass. Further studies are required to confirm applicability of normal ranges prior to routine clinical implementation.


Nomogram Prediction Model for Diabetic Retinopathy Development in Type 2 Diabetes Mellitus Patients: A Retrospective Cohort Study.
This study is aimed at investigating the systemic risk factors of diabetic retinopathy and further establishing a risk prediction model for DR development in T2DM patients. This is a retrospective cohort study including 330 type 2 diabetes mellitus (T2DM) patients who were followed up from December 2012 to November 2020. Multivariable cox regression analysis identifying factors associated with the hazard of developing diabetic retinopathy (DR) was used to construct the DR risk prediction model in the form of nomogram. 50.6% of participants (mean age: 58.60 ± 10.55) were female, and mean duration of diabetes was 7.09 ± 5.36 years. After multivariate cox regression, the risk factors for developing DR were age (HR 1.068, 95%Cl 1.021-1.118, P = 0.005), diabetes duration (HR 1.094, 95%Cl 1.018-1.177, P = 0.015), HbA1c (HR 1.411, 95%Cl 1.113-1.788, P = 0.004), albuminuria (HR 6.908, 95%Cl 1.794-26.599, P = 0.005), and triglyceride (HR 1.554, 95%Cl 1.037-2.330, P = 0.033). The AUC values of the nomogram for predicting developing DR at 3-, 4-, and 5-year were 0.854, 0.845, and 0.798. Combining age, diabetes duration, HbA1c, albuminuria, and triglyceride, the nomogram model is effective for early recognition and intervention of individuals at high risk of DR development.


Absence of pupil response to blur-driven accommodation.
The drive to the pupil constriction associated with near fixation has generally been attributed to accommodation with convergence and fusional convergence having secondary roles. However, our previous investigations have shown that significant changes in accommodation can take place without concomitant pupil response. To investigate further, the present study recorded pupil and accommodation responses to a blur-only accommodative stimulus using a target moved sinusoidally at a range of temporal frequencies. Care was taken to minimise target size change and apparent lateral or vertical target displacement. Results show that pupil response could be very much reduced or absent irrespective of stimulus temporal frequency and despite maintained accommodation response. The results suggest that blur-driven accommodation alone is not sufficient to drive pupil near response and that the presence of cues such as size change and lateral or vertical displacement of an approaching object may be necessary to elicit a response.


Embolization and Open Decompression of a Giant Aneurysm Involving the P2 Segment of the Posterior Cerebral Artery.
A 5-year-old girl was brought to the clinic because of chronic intermittent left-sided headaches. The patient underwent computed tomographic angiography, which demonstrated a giant aneurysm that involved the P2 segment of the left posterior cerebral artery. Before treatment proceeded, consent was obtained from the patient's legal guardian. A trapping-evacuation technique was used for proximal control and decompression so that a clip could be placed on the proximal inflow artery of the aneurysm. First, embolization was performed for aneurysm trapping and for sacrifice of the parent vessel. Two days later, the patient was taken to the operating room for open surgical decompression, clipping, and reconstruction. Heparin was administered during the embolization stage of the operation. The patient did well postoperatively and was discharged home. The 3-month follow-up evaluation demonstrated a right superior homonymous quadrantanopia and no other neurologic deficits. The patient's clinical course is summarized in Video 1.


The Clinical Nursing Pathway on Prevention of Catheter Slippage with Intensive Care Unit Patients: A Systematic Review and Meta-Analysis.
To evaluate the prevention effect of the clinical nursing pathway (CNP) of catheter slippage with intensive care unit (ICU) patients. Primary databases were electronically searched from the inception up to June 25, 2021. Randomized clinical trials of CNP versus routine nursing for prevention of catheter slippage with ICU patients were included. The risk of bias was assessed using the Cochrane risk of bias tool and the quality of included studies using the Jadad rating scale. A meta-analysis was conducted using the Cochrane collaboration's RevMan5.3 software. Eight studies met the inclusion criteria. The findings of the meta-analysis revealed that the comparison of CNP and routine nursing was applied in ICU patients, the catheter slippage incidence rate odds ratio (OR) was 0.11, with 95% confidence interval (CI) (0.05, 0.24), and the difference was statistically significant (P < 0.00001). The catheter infection rate OR was 0.15, with 95% CI (0.06, 0.37), and the difference was statistically significant (P < 0.0001). The nursing satisfaction OR was 14.06, with 95% CI (5.71, 34.63), and the difference was statistically significant (P < 0.00001). Compared with routine nursing, the application of CNP in ICU patients can effectively reduce the incidence of catheter slippage, reduce the infection rate of the catheter, and improve the nursing satisfaction.


Radioimmunoassay for toxoplasmosis.
A solid-phase radioimmunoassay for toxoplasmosis has been developed, and the results show good correlation with the indirect hemagglutination test.


Evaluating lower limb tendinopathy with Victorian Institute of Sport Assessment (VISA) questionnaires: a systematic review shows very-low-quality evidence for their content and structural validity-part I.
The Victorian Institute of Sport Assessment (Achilles tendon-VISA-A, greater trochanteric pain syndrome-VISA-G, proximal hamstring tendinopathy-VISA-H, patellar tendon-VISA-P) questionnaires are widely used in research and clinical practice; however, no systematic reviews have formally evaluated their content, structural, and cross-cultural validity evidence. The measurement properties referring to content, structural and cross-cultural validity of the VISA questionnaires were appraised and synthesized. The systematic review was conducted according to Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) methodology. PubMed, Cochrane, CINAHL, EMBASE, Web of Science, SportsDiscus, grey literature, and reference lists were searched. Development studies and cross-cultural adaptations (12 languages) assessing content or structural validity of the VISA questionnaires were included and two reviewers assessed their methodological quality. Evidence for content (relevance, comprehensiveness, and comprehensibility), structural, and cross-cultural validity was synthesized. A modified Grading of Recommendations Assessment Development and Evaluation (GRADE) approach was applied to evidence synthesis. The VISA-A presented very-low-quality evidence of sufficient relevance, insufficient comprehensiveness, and inconsistent comprehensibility. VISA-G displayed moderate-quality evidence for sufficient comprehensibility and very-low-quality evidence of sufficient relevance and comprehensiveness. The VISA-P presented very-low-quality evidence of sufficient relevance, insufficient comprehensiveness, and inconsistent comprehensibility, while VISA-H presented very-low evidence of insufficient content validity. VISA-A displayed low-quality evidence for structural validity concerning unidimensionality and internal structure, while VISA-H presented low-quality evidence of insufficient unidimensionality. The structural validity of VISA-G and VISA-P were indeterminate and inconsistent, respectively. Internal consistency for VISA-G, VISA-H, and VISA-P was indeterminate. No studies evaluated cross-cultural validity, while measurement invariance across sexes was assessed in one study. Only very-low-quality evidence exists for the content and structural validity of VISA questionnaires when assessing the severity of symptoms and disability in patients with lower limb tendinopathies. IV. PROSPERO reference-CRD42019126595.


Differential regulation of phospholipase A2 by cytokines inhibiting bone formation and mineralization.
Treatment of fetal rat calvarial cells with interleukin-1 alpha, tumor necrosis factor-alpha, transforming growth factor-beta 1, or group II phospholipase A2 inhibits the number of bone nodules formed in long-term cultures. These same mediators also inhibit the mineralization of fully developed bone nodules in a time and dose-dependent fashion. The pro-inflammatory cytokines interleukin-1 alpha and tumor necrosis factor-alpha cause a dose-dependent induction of rat calvarial cell phospholipase A2-II mRNA levels, suggesting that their effects on bone formation may be mediated indirectly by activation of this enzyme. In contrast, transforming growth factor-beta 1, which has more potent effects on bone formation than interleukin-1 alpha or tumor necrosis factor-alpha, suppresses basal levels of phospholipase A2-II mRNA, indicating a different mechanism of action for this cytokine.


Factors affecting hospital readmission heart failure patients in Japan: a multicenter retrospective cohort study.
The purpose of this study was to examine factors influencing readmission to hospital in patients with heart failure. This multicenter, retrospective cohort study analyzed 197 heart failure patients admitted to the research cooperation facilities between January 2017 and November 2017. We defined the readmission group as being readmitted to hospital in ≤ 6 months of discharge and the non-readmission group as > 6 months after discharge. Cox proportional hazards analysis was performed to explore the predictors of readmission. The incidence of readmission was calculated using Kaplan-Meier curves for the extracted factors. Intergroup differences were estimated using the log-rank test. The results of Cox proportional hazards analysis indicated that chronic renal dysfunction (hazard ratio (HR) = 4.729), dementia (HR = 7.105), HFrEF (HR = 8.138), walking without support (HR = 4.031), and walking with a cane (HR = 11.857) significantly contributed to the model. In the survival analyses using the Kaplan-Meier log-rank test, chronic renal dysfunction, dementia, and HFrEF were significant (P < 0.05), but walking without support and walking with a cane after discharge were not significant (P > 0.05). This study suggests that early involvement after discharge is important for lowering the readmission rates in patients with heart failure, even when their walking ability is good.


Virtual Away Rotations Increase Access to Radiation Oncology.
The COVID-19 pandemic altered the workplace for medical education. As restrictions ease, the opportunities provided by virtual rotations remain. Radiation oncology rotations based on virtual participation with patients (consultations, follow-ups, and brachytherapy), contouring and reviewing external beam plans, didactics, and unstructured office hours have been well received at multiple institutions. Virtual rotations decrease barriers to access including lack of a radiation oncology department at one's home institute and the high cost of travel and housing. Furthermore, rotations can be adapted to preclinical students and those with prior radiation oncology rotation experience. However, the virtual format creates and exacerbates several challenges including technical difficulties with electronic medical record or treatment planning software, lack of the spontaneous interactions common to in-person rotations, and unexpected delays in the clinic. We recommend early scheduled time with information technology services to troubleshoot any potential issues, scheduled office hours with faculty and videoconferencing with nonphysician team members to mitigate omission of in-person introductions, and provision of complete contact information for all staff scheduled to meet with students to facilitate communication when unexpected clinic issues arise. Although we are all excited for quarantine restrictions to safely be lifted, we support the continued development of virtual away rotations as a flexible, more affordable option to increase exposure to the field.


Reversal of Advanced Directives in Neurologic Emergencies.
Patients with advanced directives or Medical Orders for Life-Sustaining Treatment (MOLST), including "Do Not Resuscitate" (DNR) and/or "Do Not Intubate" (DNI), may be candidates for procedural interventions when presenting with acute neurologic emergencies. Such interventions may limit morbidity and mortality, but typically they require MOLST reversal. We investigated outcomes of patients with MOLST reversal for treatment of neurologic emergencies. We conducted a retrospective chart review from July 1, 2019 to April 30, 2021 of patients with MOLST reversal treated in our NeuroMedicine Intensive Care Unit. Variables collected include neurologic disease, MOLST reversal decision maker, procedural interventions, and outcomes. Twenty-seven patients (18 female, median age 78 years (IQR 73-85 years), median baseline modified Rankin score 1 [IQR 0-2.5] were identified with MOLST reversal. The most common pre-procedural MOLST was DNR/DNI (n=22, 81%), and 93% (n=25) pre-procedural MOLSTs were completed by the patient. MOLSTs were reversed by surrogates in n=23 cases (85%). The median time from MOLST completion to MOLST reversal was 603 days (IQR 45 days to 4 years). The most common neurologic emergency was ischemic stroke (n=14, 52%). Most patients died (n=14, 52%), 26% (n=7) were discharged to skilled nursing, and 22% (n=6) returned to home or assisted living. In neurologic emergencies, urgent shared decision making is needed to ensure goal-concordant care, which may result in reversal of existing advanced directives. Outcomes of patients with MOLST reversal were heterogeneous, emphasizing the importance of deliberate patient-centered care weighing the risks and benefits of each intervention.


Carrier diversity and chemical ligations in the toolbox for designing tumor-associated carbohydrate antigens (TACAs) as synthetic vaccine candidates.
This review highlights the recent development in the use of carriers of increasing simplicities and versatile chemical ligation processes leading to synthetic vaccine candidates against tumor-associated carbohydrate antigens (TACAs). After briefly covering their structures, functions, occurrence, and biosynthesis, an overview of common conjugation chemistry is described with an emphasis on the versatile alkenyl glycosides as starting materials toward glycoconjugate syntheses. This is followed by a successive description of the numerous scaffolds and carriers used to progressively improve and simplify glycovaccine formulations. Throughout a systematic investigation of the various architectures involved, a critical description of the basic principles discovered en route to effective immune responses is disclosed wherein it is found that size, shape, densities, and carriers are all key factors involved towards successful vaccines.


Longitudinal analyses of serum neurofilament light and associations with obesity indices and bioelectrical impedance parameters.
Neurofilament light is a constituent of the neuronal cytoskeleton and released into the blood following neuro-axonal damage. It has previously been reported that NfL measured in blood serum is inversely related to body mass index. However, no reports exist with regard to body composition assessed using bioelectrical impedance analysis or other indicators of obesity beyond BMI. We analyzed the relationship between sNfL and body composition according to the three compartment model. Additionally, associations between sNfL, body shape index, waist-to-height ratio, and BMI were examined. The sample consisted of 769 participants assessed during the baseline examination and 693 participants examined in the course of the follow-up of the BiDirect Study. Associations between sNfL, BMI, BSI, and WtHR were separately analyzed using linear mixed models. Body compartments operationalized as fat mass, extracellular cell mass, and body cell mass were derived using BIA and the relationship with sNfL was analyzed with a linear mixed model. Lastly, we also analyzed the association between total body water and sNfL. We found significant inverse associations of sNfL with BMI and WtHR. The analysis of the three compartment model yielded significant inverse associations between sNfL, body cell mass and body fat mass, but not extracellular mass. Furthermore, total body water was also inversely related to sNfL. A potential mechanism could involve body cell mass and body fat mass as highly adaptive body constituents that either directly absorb sNfL, or promote the formation of new vasculature and thereby increase blood volume.


Dopaminergic signals for improved parental behavior.
In this issue of Neuron, Xie et al.1 record and manipulate dopaminergic activity as mice engage in parental care. Dopaminergic prediction error signals previously implicated in food rewards were associated with retrieving isolated pups to the nest, showing that neural mechanisms long associated with reinforcement learning can be repurposed for aspects of parenting.


Finding the best separation in situations of extremely low chromatographic resolution.
Samples with a large number of compounds or similarities in their structure and polarity may yield insufficient chromatographic resolution. In such cases, however, finding conditions where the largest number of compounds appears sufficiently resolved can be still worthwhile. A strategy is here reported that optimises the resolution level of chromatograms in cases where conventional global criteria, such as the worst resolved peak pair or the product of elementary resolutions, are not able to detect any separation, even when most peaks are baseline resolved. The strategy applies a function based on the number of "well resolved" peaks, which are those that exceed a given threshold of peak purity. It is, therefore, oriented to quantify the success in the separation, and not the failure, as the conventional criteria do. The conditions that resolve the same amount of peaks are discriminated by either quantifying the partial resolution of those peaks that exceed the established threshold, or by improving the separation of peaks below it. The proposed approach is illustrated by the reversed-phase liquid chromatographic separation of a mixture of 30 ionisable and neutral compounds, using the acetonitrile content and pH as factors.


Sevoflurane inhibits angiotensin II-induced Rho kinase-mediated contraction of vascular smooth muscle from spontaneously hypertensive rat.
Angiotensin II (Ang II)-induced vasoconstriction is mediated by changes in intracellular free Ca(2+) concentration ([Ca(2+)](i)) and myofilament Ca(2+) sensitivity. Protein kinase C- and Rho kinase-mediated signaling pathways are proposed for the regulation of the Ca(2+) sensitization mechanisms. We have demonstrated that sevoflurane inhibits Rho kinase-mediated contraction of isolated rat aortic smooth muscle. A recent study demonstrated that Rho-kinase mediated Ca(2+) sensitization was involved in the pathophysiology of hypertension. This study was designed to investigate the effects of sevoflurane on Ang II-induced Rho kinase-mediated vascular contraction in spontaneously hypertensive rats (SHR). The effects of sevoflurane on vasoconstriction, increase in [Ca(2+)](i), and membrane translocation of Rho kinase in response to Ang II were investigated in normotensive Wistar-Kyoto rats (WKY) and SHR, using an isometric force transducer, a fluorometer, and Western blotting, respectively. The inhibitory effects of sevoflurane on Ang II (10(-7)M)-induced contraction were greater (P < 0.05) in SHR than in WKY at the highest concentration of sevoflurane (5.1%). Y27632 (3 × 10(-7)M), a specific inhibitor of Rho kinase, inhibited the Ang II-induced contraction in SHR, but not in WKY. Sevoflurane did not affect the increases in [Ca(2+)](i) in response to Ang II in either strain. Ang II stimulated Rho kinase activity in SHR, which was almost abolished by sevoflurane at a concentration of 5.1% (P < 0.05). These findings suggest that the inhibition of the Ang II-induced contraction by sevoflurane in SHR may be, at least in part, due to the attenuation of the Rho kinase-mediated signaling pathway.


Tremor due to sodium valproate.
Four patients developed postural tremor after ingestion of sodium valproate. The tremor was recorded by a variable-capacitance transducer and was of the "benign essential" type. The dosages of sodium valproate varied between 1000 mg and 2000 mg daily and serum levels were between 34.9 microgram per milliliter and 154.3 microgram per milliliter. Tremor was ameliorated in two cases when the dosage was reduced. In only one case was the serum level in the toxic range for our laboratory. The pharmacology of essential tremor is unknown; production of a similar tremor by a drug could serve as a biochemical model.


Closed reduction of the traumatic posterior-dislocation of hip joint using a novel sitting technique: A case series.
Traumatic hip dislocation is a common joint dislocation. Delayed reduction has been shown to increase the risk of avascular necrosis of the femoral head. Most of the traditional methods must be performed under general anesthesia or spinal anesthesia to relax hip muscles. Anesthesia will prolong the interval between the injury and the reduction. 16 patients presented with hip pain and a leg shortened, flexed, internally rotated and adducted. X-ray and CT-scan showed acute closed posterior dislocation of hip. Closed reduction of the traumatic posterior-dislocation of hip joint using a novel sitting technique. Among these 16 patients, 15 hips were successfully reduced using the Sitting Technique (table 1), indicating the success rate was 93.8%(15/16). A total of 12 patients were followed up, with a mean period of 23.5 months (range, 6-72 months). Among these 12 patients, 10 patients (83.3%) had excellent grade, 2 patients (16.7%) had good grade. Sitting technique for treatment of traumatic posterior dislocation of hip joint does not need anaesthesia, which it shortens the interval between the injury and the reduction and saves valuable time for 6 hours of joint reduction. On the other hand, this method does no harm to the physicians' low back.


Clinical outcome of radioiodine treatment of hyperthyroidism: a follow-up study.
To study the clinical outcome of treatment of hyperthyroid patients with radioiodine. Records of patients treated for hyperthyroidism with radioiodine from 1989 to 1992 were examined in 1994, and a questionnaire was sent to patients < or = 70 years with Graves' disease (GD) and toxic nodular goitre (TNG) to obtain information regarding thyroxine substitution, smoking habits and present state of health. Outpatients in a thyroid unit; follow-up by primary care. Seven hundred and fifty-four patients with hyperthyroidism treated with radioiodine, 327 receiving the questionnaire, 72% response rate. Radioiodine treatment using a delivered absorbed dose method, aiming at an absorbed dose to the thyroid of 100-120 Gy. Statistical analysis of clinical records and results from questionnaire. Only 10% of the patients needed more than one treatment. At the time of follow-up, thyroxine supplementation was given to 178 (93%) of the GD and to 21 (47%) of the TNG patients. Smoking was more common in GD patients than in the general population (44% vs. 26%; P < 0.001). Smoking GD patients experienced eye discomfort more often than smoking TNG patients (53% vs. 7%; P < 0.001). Weight gain after therapy was a problem in 79% of the hyperthyroid individuals. Few patients needed retreatment and most of the GD patients had thyroxine after 1-5 years after therapy. Smoking patients, especially those with GD, had more eye symptoms. At follow-up, the euthyroid patients still consider themselves having a poorer health than individuals in the general population.


Low TGF-β1 in Wound Exudate Predicts Surgical Site Infection After Axillary Lymph Node Dissection.
Surgical site infection (SSI) after axillary lymph node dissection (ALND) for breast cancer increases morbidity and delays the onset of adjuvant treatment. Only a few studies have investigated the feasibility of wound exudate analysis in SSI prediction. This study assessed changes in cytokine levels in postsurgical wound exudate after ALND and examined their predictive value for the early diagnosis of SSI. An observational prospective pilot study was conducted in 47 patients with breast cancer undergoing ALND. Wound exudate samples were collected on the first and sixth postoperative days (POD). Interleukin (IL)-1α, IL-1β, IL-4, IL-10, IL-13, tumor necrosis factor alpha (TNF-α), transforming growth factor beta1 (TGF-β1) and vascular endothelial growth factor (VEGF) C and D levels were measured by immunoassay. Patients were followed to detect SSI. SSI was diagnosed in 8/47 (17.0%) patients. Four SSI patients were hospitalized and treated with intravenous antibiotics. The concentration of TGF-β1 in wound exudate was significantly lower on POD#1 in the SSI group compared to the no SSI group (p=0.008). The receiving operator characteristics (ROC) curve for TGF-β1 showed an area under curve of 0.773 (p=0.0149) indicating good diagnostic potential. On POD#6, the concentration of TGF-β1 remained significantly lower (p=0.043) and the concentrations of IL-10 (p=0.000) and IL-1β (0.004) significantly higher in the SSI group compared to the no SSI group. To our knowledge, this is the first study suggesting a predictive role of wound exudate TGF-β1 levels for SSI. Our results suggest that the risk for SSI can be detected already on POD#1 and that the assessment of TGF-β1 levels in the wound exudate after ALND can provide a usefull method for the early detection of SSI. The key findings of this pilot study warrant verification in a larger patient population.


Robotic Retrograde Intrarenal Surgery: A Journey from "Back to the Future".
The introduction of robotics has revolutionized surgery. Robotic platforms have also recently been introduced in clinical practice specifically for flexible ureteroscopy. In this paper, we look at the robotic platforms currently available for flexible ureteroscopy, describing their advantages and limitations. The following robotic platforms are discussed: Roboflex Avicenna®, EasyUretero®, and ILY® robot. Finally, potential future advancements in this field are presented.


Parenting practices and dysregulation profile in a sample of Italian children.
emotional dysregulation is a transdiagnostic factor linked to a heightened risk for psychopathology. A dysregulation profile (DP) derived from the Strenght and Difficulties Questionnaire (SDQ) is often used to indirectly assess emotional dysregulation in children and adolescents. Theoretical models account for parenting as a causal and maintaining factor for emotional dysregulation. Notwithstanding, empirical data are scant. 547 students (47.5% males) aged between 9 and 11 years of age (mean age = 9.66, SD = 0.64) were assessed with the SDQ-DP (teacher and parent-reported) and their parents self-reported on their own parenting practices with the Alabama Parenting Questionnaire. as expected, SDQ-DP teacher-rated was positively associated with maternal and paternal negative parenting practices; SDQ-DP mother and father-rated were both negatively associated with maternal and paternal positive parenting and positively associated with maternal and paternal negative parenting practices. the age range is limited to pre-adolescents. The cross-sectional nature of the study precludes inferences on causality. youth's emotional dysregulation is linked to parenting practices. These findings support the need to include families in the intervention for emotionally dysregulated youths.


Androgenic control of N-acetyltransferase activity in the harderian glands of the Syrian hamster is mediated by 5 alpha-dihydrotestosterone.
N-acetyltransferase (NAT) activity in the Harderian glands of intact and gonadectomized male and female Syrian hamsters was evaluated. The exogenous administration of 5 alpha-dihydrotestosterone (DHT) to castrated males and intact females produced an increase in NAT values, which reached the values present in the glands of intact males. The administration of a 5 alpha-reductase inhibitor to intact males led to a decrease in NAT activity, suggesting that testosterone is converted in DHT within the glands. It is concluded that NAT activity in the Syrian hamster Harderian glands is under androgenic control, the active steroid being DHT.


Conditioned medium from keloid keratinocyte/keloid fibroblast coculture induces contraction of fibroblast-populated collagen lattices.
Keloid scars represent a pathological response to cutaneous injury. Overproliferation of fibroblasts and overproduction of collagen characterize these abnormal scars. The pathology of these scars remains poorly understood. The role of epithelial-mesenchymal interactions in keloid pathogenesis and scar contracture has recently been explored. To test our hypothesis that epithelial-mesenchymal interactions play a major role in modulating keloid scar contracture. A coculture model was employed wherein keloid and normal keratinocytes were cocultured with keloid or normal fibroblasts, and the conditioned media from day 5 cocultures were collected to study the effect of the paracrine secretions on contraction of an in vitro fibroblast-populated collagen lattice (FPCL) model. Keloid keratinocyte/keloid fibroblast coculture conditioned media brought about increased contraction of the collagen lattice compared with non-cocultured conditioned media. When keloid fibroblasts populated the collagen lattice, significantly increased lattice contraction was induced compared with lattices populated by normal fibroblasts. The addition of antitransforming growth factor (TGF)-beta neutralizing antibody to the conditioned media produced an attenuation of the contraction of the FPCLs. When keloid and normal fibroblasts were cultured on chamber slides and treated with conditioned media from coculture and non-coculture series, immunohistochemical analysis demonstrated an increased expression of alpha-smooth muscle actin (a marker for fibroblast differentiation into myofibroblasts) in fibroblasts exposed to conditioned media from coculture. These data indicate that epithelial-mesenchymal interactions are likely to play a major role in scar contracture and scar pathogenesis, and underscore the role of TGF-beta1 as a key player in keloid pathogenesis.


Polymorphic membrane protein 20G: A promising diagnostic biomarker for specific detection of Chlamydia psittaci infection.
Psittacosis is a zoonotic disease caused by Chlamydia psittaci (C. psittaci), leading to high risk for animal industry and human health. Lack of reliable commercial kits and effective vaccines is hampering control of C. psittaci infection. Polymorphic outer membrane protein Gs (PmpGs) are enriched in diverse C. psittaci, and its role are unclear during C. psittaci infection. In the present study, pmp20G gene was cloned into pET-28a vector and then the constructed plasmid was transferred into Escherichia coli Rossetta (DE3). After denaturation and renaturation, the recombinant Pmp20G-N was identified by SDS-PAGE and Western blot. Afterwards Pmp20G-N was used as the coating antigen to develop an indirect ELISA (I-ELISA) assay. Both the specificity and sensitivity of Pmp20G-N ELISA were 100%, while the MOMP-ELISA had 93.65% sensitivity and 98.94% specificity, respectively. The concordance between MOMP-ELISA and Pmp20G-N ELISA assay was 98.1%. Hence, Pmp20G-N ELISA has the potential to be a diagnostic antigen for detection C. psittaci antibody. However, further studies are needed to be done for differentiating C. psittaci from Chlamydia spp. and other C.psittaci-specific serovars using Pmp20G-N ELISA.


Spatial effects, sampling errors, and task specialization in the honey bee.
Task allocation patterns should depend on the spatial distribution of work within the nest, variation in task demand, and the movement patterns of workers, however, relatively little research has focused on these topics. This study uses a spatially explicit agent based model to determine whether such factors alone can generate biases in task performance at the individual level in the honey bees, Apis mellifera. Specialization (bias in task performance) is shown to result from strong sampling error due to localized task demand, relatively slow moving workers relative to nest size, and strong spatial variation in task demand. To date, specialization has been primarily interpreted with the response threshold concept, which is focused on intrinsic (typically genotypic) differences between workers. Response threshold variation and sampling error due to spatial effects are not mutually exclusive, however, and this study suggests that both contribute to patterns of task bias at the individual level. While spatial effects are strong enough to explain some documented cases of specialization; they are relatively short term and not explanatory for long term cases of specialization. In general, this study suggests that the spatial layout of tasks and fluctuations in their demand must be explicitly controlled for in studies focused on identifying genotypic specialists.


Higher cardiovascular risk scores and liver fibrosis risk estimated by biomarkers in patients with metabolic-dysfunction-associated fatty liver disease.
The definition of metabolic-dysfunction-associated fatty liver disease (MAFLD) allows identification of metabolically complicated patients. Fibrosis risk scores are related to cardiovascular risk (CVR) scores and could be useful for the identification of patients at risk of systemic complications. To evaluate the relationship between MAFLD and CVR using the Framingham risk score in a group of Mexican patients. Cross-sectional, observational and descriptive study carried out in a cohort of 585 volunteers in the state of Veracruz with MAFLD criteria. The risk of liver fibrosis was calculated with aspartate aminotransferase-to-platelet ratio index, nonalcoholic fatty liver disease score and fibrosis-4, as well as with transient hepatic elastography with Fibroscan®. The CVR was determined by the Framingham system. One hundred and twenty-five participants (21.4%) with MAFLD criteria were evaluated, average age 54.4 years, 63.2% were women, body mass index 32.3 kg/m2. The Framingham CVR was high in 43 patients (33.9%). Transient elastography was performed in 55.2% of volunteers; 39.1% with high CVR and predominance in advanced fibrosis (F3-F4). The logistic regression analysis showed that liver fibrosis, diabetes and hypertension independently increased CVR. One of every three patients with MAFLD had a high CVR, and in those with high fibrosis risk, the CVR risk was even greater.


1-Chloromethylpyrene: a reference skin sensitizer and genotoxin.
1-Chloromethylpyrene (1-CMP) has been evaluated as a model mutagen and toxin related to the ultimate electrophiles derived from benzo[a]pyrene and 1-nitropyrene. It was mutagenic to Salmonella (greater than 100 pg/plate) and exceptionally reactive to DNA when assessed by the 32P-postlabelling technique. 1-CMP was inactive in a mouse bone micronucleus assay when administered by gavage, probably due to hydrolysis, whose kinetics have been studied (t1/2 approximately 23 min at 37 degrees C). However, as expected, it was a potent skin toxin as determined by its activity as a mitogen to mouse skin and its contact allergenicity, as determined using the local lymph node proliferative assay. It is concluded that 1-CMP will probably be a potent human skin carcinogen and contact allergen.


Understanding Psychological Distress and Protective Factors Amongst Older Adults During the COVID-19 Pandemic.
This study examined the emotional distress and loneliness during COVID-19 and the roles of resiliency and activities. A cross-sectional national survey. Amazon Mechanical Turk (mTurk) and Prolific Research Platforms. Five hundred and one U.S. dwelling English-speaking adults 60 years old and older. Participants completed an online survey with the PHQ-9; GAD-7; Short Health Anxiety Inventory; 3-item UCLA Loneliness scale; PROMIS measures of global health, instrumental, and emotional support; 10-item Connor-Davidson Resilience Scale; and COVID-19 needs assessment. Across the sample 13% reported moderate depressive symptoms, 9% reported moderate anxiety symptoms, and 26% endorsed being "lonely." The emotionally distressed group endorsed more loneliness, lower resiliency, less physical exercise, and worse physical health. The low Socio-Economic Status group endorsed less loneliness, less likely to engage in physical exercise and worse physical health.The lonely group endorsed less resilience, less physical exercise, and worse physical health. A multiple logistic regression found that resilience, socioeconomic status, and physical health were significant predictors of loneliness, whereas global health was the best predictor of emotional distress. Even after prolonged social distancing, older adults in this study did not report greater psychological distress compared to earlier studies of older adults during COVID-19. Older adults with lower SES, worse physical health, and less resiliency, were more likely to report more loneliness. It is this group that should be the focus of intervention.


A Review on Chitosan in Drug Delivery for Treatment of Neurological and Psychiatric Disorders.
Neurological diseases are known as global health problems with a growing number of patients annually. Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease as well as spinal cord injury, hypoxic ischemia injury, epilepsy, depression and etc., are some examples of neurological diseases. One of the main problems in the treatment of these diseases is the delivery of drugs across the blood-brain barrier (BBB). These days, researchers have tended to find non-invasive and non-toxic strategies for solving this problem. As a non-toxic, safe, and potential agent, chitosan has attracted attention for use in drug delivery systems. Recently, numerous studies have been designed to develop drug delivery systems by using chitosan to treat various neurological diseases. In this paper, the latest developments of chitosan and its derivatives utilization in the drug delivery systems for the treatment of different neurological and psychiatric diseases were reviewed.


Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from the nuclear pore complex.
The novel human betacoronavirus SARS-CoV-2 has caused an unprecedented pandemic in the 21st century. Several studies have revealed interactions between SARS-CoV-2 viral proteins and host nucleoporins, yet their functions are largely unknown. Here, we demonstrate that the open-reading frame 6 (ORF6) of SARS-CoV-2 can directly manipulate localization and functions of nucleoporins. We found that ORF6 protein disrupted nuclear rim staining of nucleoporins RAE1 and NUP98. Consequently, this disruption caused aberrant nucleocytoplasmic trafficking and led to nuclear accumulation of mRNA transporters such as hnRNPA1. Ultimately, host cell nucleus size was reduced and cell growth was halted.


Physiological responses of Dunaliella salina and Dunaliella tertiolecta to copper toxicity.
Species differences in heavy metal tolerance were investigated by comparing the responses of Dunaliella tertiolecta and Dunaliella salina to elevated concentrations of CuCl2. Although both species showed reduced cell number ml(-1) of algal culture, D. salina was more affected by increase in CuCl2. This reflects higher sensitivity of D. salina to CuCl2 compared to D. tertiolecta. Total chlorophyll in terms of microg ml(-1) was higher in D. tertiolecta at all tested CuCl2 levels, but in terms of microg cell(-1) no significant difference was observed between the two species. Total carotenoids in microg cell(-1) increased with increase in CuCl2 in both species and it was about five times higher in D. salina at all CuCl2 concentrations. While both species showed significant increase in lipid peroxidation at elevated CuCl2, the malondialdehyde content of D. salina cells was about three times higher at most CuCl2 concentrations. Although ascorbate peroxidase (APX) activity increased with increase in CuCl2 levels in both species, higher activity was observed in D. tertiolecta at all tested CuCl2 concentrations. Cu content of D. salina cells was higher than D. tertiolecta which may be due to larger volume of D. salina cells. In conclusion, since hydroxyl radical (HO*) produced from H2O2 by Cu2+ (Haber-Weiss cycle) is involved in lipid peroxidation, higher ascorbate peroxidase activity in D. tertiolecta may partly account for lower sensitivity of this species to CuCl2 compared to D. salina.


The influence of the host sex on parasitemia of parasite lineages belonging to Haemoproteus majoris in a natural bird community.
Immunological capability shows a sexual dimorphism in diverse animal species. Females are generally more immunocompetent than males, leading to the higher susceptibility of males to infection compared to females and thus greater infection-related pathology in males. These sex-differences in immunity remain understudied in birds. Here, we compared the percentage of parasitemia of three different parasite lineages belonging to the morphological species Haemoproteus majoris (namely, PARUS1, PHSIB1 and WW2) in terms of the sex of birds living in a natural community. We found that parasitemia (percentage of erythrocytes infected with parasites) of WW2 lineage, but not of the other two lineages of H. majoris, is higher in male birds compared to female birds. Similarly, we showed that the total parasitemia of these three H. majoris lineages is higher in male birds compared to female birds. Our study points out that male birds at the community level may be more susceptible to infection by certain parasites than female birds. We propose that sexual dimorphism in parasitemia of certain parasites in host birds might be more common than previously thought, similar to what is observed in other species, influencing host population dynamics in a sex-specific manner. Therefore, it can be speculated that infection by certain parasites might differentially affect male and female birds, possibly resulting in a bias in survival rates between sexes due to infections, in certain contexts.


Preparation of magnetic molecularly imprinted polymer based on multiwalled carbon nanotubes for selective dispersive micro-solid phase extraction of fenitrothion followed by ion mobility spectrometry analysis.
A novel molecularly imprinted polymer based on magnetic multiwalled carbon nanotubes was fabricated and applied for selective dispersive micro-solid phase extraction of fenitrothion prior its determination by ion mobility spectrometry. The composite was synthesized using magnetic multiwalled carbon nanotubes as the support. Methacrylic acid was used as the functional monomer, fenitrothion as the template, ethylene glycol dimethacrylate as the cross-linker, and 2,2-azoisobutyronitrile as the initiator. The resultant polymer was characterized by FTIR spectroscopy, X-ray diffraction, field emission scanning electron microscopy, Brunauer-Emmet-Teller analysis, thermogravimetric analysis, and vibrating sample magnetometer techniques. Experimental factors affecting the extraction efficiency such as pH and amount of sorbent were evaluated. Under optimum experimental conditions, the developed method displayed the linear range of 5-220 μg/L with a detection limit of 1.3 μg/L. The intra- and interday relative standard deviations for determination of fenitrothion were 3.6 and 4.7% (n = 6), respectively. Ultimately, the proposed method was used to monitor trace amounts of fenitrothion in fruits, vegetables, and water samples.


Prevalence of lung cancer in Isfahan Province, Iran.
To describe for the first time period prevalence (PP) and incidence rate (Ir) for patients with lung cancer in Isfahan Province/Iran. Data associated to the Surveillance, Epidemiology, and End Results; (SEER) was collected from the Isfahan Cancer Registry from March 2011 to March 2015. Lung cancer was distinguished by the related established topography code. PP and Ir were calculated and expressed per 100,000 persons. In all, 548 females and 1399 males were identified. For the total population the PP was calculated as 39.1 (distinguished as: 30.7 for bronchus and lung, 7.9 for larynx and 0.5 for trachea). This value corresponded to a PP of 55.3 for males and 22.3 for females (p < 0.001). Irs versus mortality rates were calculated for each year, i.e. 2011-2012, 2012-2013, 2013-2014, and 2014-2015, as 9.3 vs 6.3, 10.1 vs 6.6, 9.9 vs 6.3, 9.6 vs 6.4, respectively. The mean (SD, range) age of the patients was 65.8 (14.7, 1-103) years. In relation to the age of study population, lung cancer occurred in 94% of patients aged between 40 and 90 years. The PP for lung cancer in male population was 2.5 times higher than females. There was a 3.2% increase in the Irs over the study period. To facilitate early diagnosis for better management associated to pharmacotherapy or surgical care, our findings emphasized the advantage of further research and greater effort toward environmental, job related exposure, genetic and geographical factors in Isfahan Province/Iran.


Teaching with collective resilience during COVID-19: Korean teachers and collaborative professionalism.
This study applies system-focused resilience and collaborative professionalism to examine how teachers in Korea collectively developed resilience and transformed teaching during COVID-19. Using qualitative data from seven individual interviews and four focus groups, we found Korean teachers navigated complex challenges (rapidly changing policies, online teaching, exacerbated learning gaps, and excessive social pressure) and utilized contextual resources (collective autonomy and flexibility, solidity and solidarity, and collective responsibility) to develop strategies (collaborative inquiry, timely communication, and envisioning the future of schooling). The study extends teacher resilience toward more collective and communal, from the individual level, by linking resilience to collaborative systemic changes.


MRI findings of sciatic endometriosis.
Endometriosis is a rare cause of sciatic mononeuropathy. We report a woman with cyclic, menstruation-related hip pain associated with right leg weakness and sensory loss. Examination and electrodiagnostic studies suggested sciatic nerve dysfunction. Magnetic resonance imaging (MRI) revealed abnormal signal consistent with endometriotic tissue in the region of the right sciatic nerve. The abnormal signal partially regressed after treatment of the endometriosis. This case further illustrates the utility of MRI in the assessment of rare pelvic disorders.


Economic growth and environmental technology simultaneously important for reducing energy poverty and ecological footprint in E7 economies: do political institutions play a role?
Energy poverty and climate change are major concerns for the emerging seven countries. Therefore, this study explores the economic growth impact on reducing energy poverty and ecological footprint in the emerging seven economies from 2000 to 2019. Energy poverty is measured using three disciplines: availability poverty, accessibility poverty, and affordability poverty. We applied a new dynamic method, "bias-corrected method of moments estimators (2021)," for long-run outcomes. This study used the environmental Kuznets curve-approach to measure economic growth's scale effect and technique effect to reduce energy poverty and ecological footprint. Importantly, the study explores the mediating role of politically stable institutions in mitigating environmental and energy poverty. Our findings validate that energy poverty and ecological footprint could not reduce at the initial stage of economic growth. However, the later development stage shows a positive effect on reducing energy poverty and ecological footprint. These results validated an inverted U-shaped Kuznets curve hypothesis for emerging seven. Further, the result found that strong political systems are more quick-witted and have the legislative power to swiftly implement beneficial policies to pull out of the vicious circle of energy poverty. Further, environmental technology significantly reduced energy poverty and ecological footprint. The causality analysis entails that a bidirectional exists between energy poverty, income, and ecological footprint.


Reply to Alberts, P. Comment on "Hietanen et al. Cytolytic Properties and Genome Analysis of Rigvir® Oncolytic Virotherapy Virus and Other Echovirus 7 Isolates. Viruses 2022, 14, 525".
Our work focused on comparing the cellular effects of Rigvir to other echovirus 7 isolates, because originally Rigvir is also an echovirus 7 isolate [...].


Bet v 1 contiguous overlapping peptides anchored to virosomes with TLR4 agonist enhance immunotherapy efficacy in mice.
Whereas sublingual allergen immunotherapy (AIT) is routinely performed without any adjuvant or delivery system, there is a strong scientific rationale to better target the allergen(s) to oral dendritic cells known to support regulatory immune responses by using appropriate presentation platforms. To identify a safe presentation platform able to enhance allergen-specific tolerance induction. Virosomes with membrane-integrated contiguous overlapping peptides (COPs) of Bet v 1 and TLR4 or TLR2/TLR7 agonists were assessed for induction of Bet v 1-specific IgG1, IgG2a and IgE antibodies, hypersensitivity reactions and body temperature drop following subcutaneous injection in naive CD-1 mice. The most promising candidate, Bet v 1 COPs anchored to virosomes with membrane-incorporated TLR4 agonist (Vir.A-Bet v 1 COPs), was further evaluated by the sublingual route in a therapeutic setting in BALB/c mice with birch pollen-induced allergic asthma. Airway hyperresponsiveness, pro-inflammatory cells in bronchoalveolar lavages and polarization of Th cells in the lungs and spleen were then assessed. Both types of adjuvanted virosomes coupled to Bet v 1 COPs triggered a boosted Th1 immunity. Given a more favourable safety profile, Vir.A-Bet v 1 COPs were further evaluated and shown to able to fully reverse asthma symptoms and lung inflammation in a sublingual therapeutic model of birch pollen allergy. We report herein for the first time on the capacity of a novel and safe presentation platform, that is virosomes with membrane-integrated TLR4 agonist, to improve dramatically sublingual AIT efficacy in a murine model due to its intrinsic dual properties of targeting and stimulating to further promote anti-allergic immune responses. As such, our study paves the ground for further clinical development of this allergen presentation platform for patients suffering from respiratory allergies.


Long-term endoscopic follow-up in small bowel transplant recipients: single-center series.
The reliability of endoscopic findings after adult intestinal transplantation on short-term follow-up has been shown. The aim of this study was to evaluate in a long-term follow-up the diagnostic value of endoscopies compared with the biopsy value. We evaluated 52 endoscopies over a period of 2 years (2 in each patient in 2010 and 1 in each patient in 2011, plus 1 endoscopy for suspected post-transplant lymphoproliferative disease [PTLD]) on 17 recipients transplanted between the years 2000 and 2006 (more than 5 years of follow-up). All the 52 endoscopic findings were comparable to biopsy definitive results: only 1 case of mild enteritis and 1 case of Epstein-Barr virus (EBV) chronic infection at biopsy were not diagnosed by endoscopy. One case of rectal PTLD and 1 of EBV-related enteritis were diagnosed by use of both procedures. Specificity was 98%: we did not calculate sensitivity because no episodes of rejection were diagnosed because recipients were stable in long-term follow-up. Endoscopy is a reliable procedure even on a long-term follow-up after intestinal transplantation, allowing a support to biopsy for diagnosis on adult recipients, especially for EBV infections and PTLD surveillance.


Effect of killed autogenous polyvalent vaccines against Vibrio harveyi, V. alginolyticus and Streptococcus iniae on survival and immunogenicity of Asian seabass (Latescalcarifer).
Vibriosis and Streptococcosis are the most important bacterial diseases that infect Asian seabass (Lates calcarifer) in various stages of its life cycle. Vaccination is a cost-effective strategy to prevent the occurrence of infectious diseases and increase sustainability in the aquaculture industry. This study was aimed to develop and evaluate a killed polyvalent vaccine against Vibrio harveyi, V. alginolyticus and Streptococcus iniae, delivered by intraperitoneal injection in Asian seabass. The fish were divided into three groups with 60 fish in triplicate: I) a control group injected with phosphate-buffered saline (PBS), II) a group vaccinated by polyvalent vaccine (V. alginolyticus + V. harveyi + S. iniae) and III) a group vaccinated with the same polyvalent vaccine plus an oral booster. Immunological parameters and antibody titer were measured before and at three, five-, and eight-weeks post-vaccination. The efficacy of the killed vaccine was assessed five weeks post-vaccination by challenging with each isolate separately. The vaccinated groups had higher survival rate than control group. The highest relative percentage survival rate, 85.71 ± 3.57 % was observed in group III when challenged with V. harveyi. The vaccinated fish produced significantly higher antibody titers against V. alginolyticus, V. harveyi and S. iniae than the control group (P < 0.05). Non-specific immune parameters were significantly enhanced in the vaccinated groups, especially group III, compared to the control. The results demonstrated that the administration of a killed polyvalent vaccine can effectively protect Asian seabass against V. alginolyticus, V. harveyi and S. iniae.


DNA damage in bronchial epithelial and mesothelial cells with and without associated crocidolite asbestos fibers.
Mesothelioma is induced almost exclusively by exposure to asbestos fibers. We have investigated whether the induction of DNA damage in human bronchial epithelial BEAS 2B cells and human mesothelial MeT 5A cells by crocidolite asbestos (2 microg/cm2) requires the presence of asbestos fibers in the cells. DNA damage was measured microscopically by the Comet assay, and the presence of fibers in the same cells was assessed using bright-field illumination. After treatment times of 6-72 hr, damage levels were, on the average, two times higher in cells with fibers than in cells without fibers. It was further found that DNA damage decreased with time in BEAS 2B cells both with and without fibers. No decrease in damage with time was seen in MeT 5A cells, suggesting that these mesothelial cells repair the initial damage poorly, lack induction of protective systems, or constantly produce high levels of damaging species. Our results indicate that crocidolite-treated human mesothelial MeT 5A and bronchial epithelial BEAS 2B cells show an elevated level of DNA damage if they contain a fiber. In comparison with epithelial BEAS 2B cells, mesothelial MeT 5A cells have more DNA damage after the crocidolite treatment and the damage is more persistent.


The ontogeny of electrical activity associated with absorption of solutes across the developing small intestine of the chick (Gallus domesticus).
1. Electrical potentials across the developing intestine of the chick were measured in vitro 3-4 days before and up to 32 days after hatching.2. Embryonic intestine had a very high endogenous p.d. (serosa positive to mucosa) which decreased up to hatching. This decrease continued during intestinal maturation, reaching a basal level several days after hatching.3. Transfer potential differences were caused only by the actively transferred hexoses both in embryonic and post-embryonic intestine. These potentials decreased concomitantly with the decrease in the endogenous p.d. Kinetic analysis showed that the ;apparent K(m)' of glucose for the glucose transfer p.d. generating mechanism did not change over the period of hatching.4. Both the embryonic and post-embryonic transmural p.d. either in the presence or absence of metabolizable hexose was dependent upon aerobic metabolism.5. The transmural p.d. of hatched chick small intestine (with and without hexoses) was linearly related to log(10)[Na(+)] of the mucosal fluid. The magnitude of the glucose transfer p.d. both in embryonic and post-embryonic small intestine, however, was not lowered by decreasing the mucosal [Na(+)].6. Amino acid transfer potentials were of small magnitude at all stages of development.


Fourth degree perineal tears: Surgical repair technique in 10 steps.
Obstetrical anal sphincter injury (OASIS) may lead to significant comorbidities, including anal incontinence, rectovaginal fistula, and pain. A correct repair is required to avoid improper healing, as a persistent defect in the external anal sphincter after delivery can increase the risk of complications and worsening of symptoms following subsequent vaginal deliveries. Herein is described the surgical repair technique for a fourth degree perineal tear. Regarding resident education, there are challenges associated with the proper training in OASIS repair. The procedure is illustrated by an instructive video article that standardizes the essential steps to make the technique ergonomic and easy to perform with step-by-step explanations.


Transcriptional profiling distinguishes inner and outer annulus fibrosus from nucleus pulposus in the bovine intervertebral disc.
Cells in the intervertebral disc have unique phenotypes and marker genes that separate the nucleus pulposus (NP), annulus fibrosus (AF) and articular cartilage (AC) have been identified. Recently, it was shown that phenotypic marker genes exhibit variable expression in humans. In this study, the bovine tail was used to determine the ability of marker genes to distinguish the outer and inner AF from NP tissue and isolated cells. Bovine tail intervertebral discs from 13 donors were dissected and correct isolation of tissue was confirmed. mRNA was isolated directly from tissue or passage 0 monolayer cells and used for gene expression measurements (qPCR). Conventional marker genes (bAcan, bCol1a1, bCol2a1) and novel marker genes (bAdamts17, bBrachyury/T, bCD24, bCol5a1, bCol12a1, bFoxf1, bKrt19, bPax1, bSfrp2) were evaluated. As expected bAcan, bCol2a1 and bCol1a1 distinguished outer AF from NP tissue, while inner AF and NP could not be discriminated. The NP markers bT, bCd24 and bKrt19 were significantly higher expressed in NP than inner and outer AF tissue. bFoxF1 and bPax1 only distinguished IVD tissues from AC. The AF markers bAdamts17, bCol5a1, bCol12a1 and bSfrp2 were higher expressed in the outer AF compared with inner AF and NP tissue. Monolayer culturing strongly decreased bAcan, bCol2a1, bCD24 and bCol5a1 expression, while bCol1a1, bT, bKrt19 and bSfrp2 were not affected. The IVD phenotypic marker genes bT, bKrt19, bSfrp2 and bCol12a1 convincingly distinguished NP from outer AF in situ and in vitro.


Phosphatidylinositol metabolism of the renal proximal tubule S3 segment is disturbed in response to diabetes.
Diabetes is a main risk factor for kidney disease, causing diabetic nephropathy in close to half of all patients with diabetes. Metabolism has recently been identified to be decisive in cell fate decisions and repair. Here we used mass spectrometry imaging (MSI) to identify tissue specific metabolic dysregulation, in order to better understand early diabetes-induced metabolic changes of renal cell types. In our experimental diabetes mouse model, early glomerular glycocalyx barrier loss and systemic metabolic changes were observed. In addition, MSI targeted at small molecule metabolites and glycero(phospho)lipids exposed distinct changes upon diabetes in downstream nephron segments. Interestingly, the outer stripe of the outer medullar proximal tubular segment (PT_S3) demonstrated the most distinct response compared to other segments. Furthermore, phosphatidylinositol lipid metabolism was altered specifically in PT_S3, with one of the phosphatidylinositol fatty acid tails being exchanged from longer unsaturated fatty acids to shorter, more saturated fatty acids. In acute kidney injury, the PT_S3 segment and its metabolism are already recognized as important factors in kidney repair processes. The current study exposes early diabetes-induced changes in membrane lipid composition in this PT_S3 segment as a hitherto unrecognized culprit in the early renal response to diabetes.


Response of prokaryotic, eukaryotic and algal communities to heavy rainfall in a reservoir supplied with reclaimed water.
The global climate change made the heavy rainfall happen more frequently, and the non-point source pollution caused by it would exacerbate the risk to the water ecological environment. In this study, we took a reservoir (Shahe reservoir, Beijing, China) supplied with reclaimed water as an exapmle to investigate how spatiotemporal changes in the quantity and diversity of prokaryotic, eukaryotic, and algal communities respond to heavy rainfall. Results showed that heavy rainfall could directly impact the composition of the prokaryotic community by introducing amounts of runoff closely associated bacterium especially for the human potential pathogens such as Aliarcobacter, Aeromonas and Pseudomonas in the Shahe reservoir area. While the eukaryotic community was rather stable, and the development and changes in algal communities occurred in the last few days after heavy rainfall. The microbial source tracking through FEAST indicated that Nansha river (S) was the major contributor to the development of all the three concerned communities in the reservoir. The co-occurrence analysis showed that the modules with the highest cumulative abundance in each community were all strongly and positively connected with Chl-a, pH, turbidity, COD and TOC, but negatively correlated with NO3-N (p < 0.01). The network analysis showed that the eukaryotes played a key role in the interaction network among the three communities, and were more likely to interact with algae and prokaryotes. It was suggested that the controlling of human potential pathogens associated with prokaryotic community should be emphasized at the beginning of the heavy rainfall, but the prevention of the eutrophication bloom should be another focus after the heavy rainfall. This study provided valuable information concerning the role of heavy rainfall on the water ecological environment from the perspective of microbial community.


New insights regarding Acinetobacter genomic island-related elements.
The objective of this study was to mobilise the Acinetobacter genomic island 1-A (AGI1-A) from Enterobacter hormaechei EclCSP2185 (E. cloacae complex) and to search for the distribution and structure of AGI1-related elements in the NCBI database. AGI1-A was transferred to Escherichia coli. Analysis of the attachment (att) sites could locate the possible recombination crossover in the att sequences at position 10-11 (GG) in the last 18 bp of trmE. In silico detection of AGI backbones in the WGS database identified AGI variants in Salmonella enterica (83 strains), Vibrio cholerae (33), E. hormaechei (12), Acinetobacter baumannii (2), most belonging to prevalent clones (ST40, ST69, ST114 and ST25, respectively), but also in E. coli (1) and Klebsiella pneumoniae (1). Two groups of backbone were identified: one similar to AGI1, the other with a short segment from a Shewanella element upstream of ORF A022. The MDR regions were inserted by transposition at the res site in four different positions ATAGG (A. baumannii), CATAG (S. enterica and V. cholerae), TAGGT (S. enterica and K. pneumoniae) and TGCAC (S. enterica) representing four different lineages. In some V. cholerae, E. hormaechei and E. coli, deletion events occurred that eliminated part of the backbone at the left junction. Analysis of the right junction identified a fifth lineage in V. cholerae and E. hormaechei (CCATA). In conclusion, based on the position of the MDR region, AGI-related elements belonged to five groups of closely related genomic islands (AGI1-AGI5), with differences in backbones that evolved independently over time.


Efficacy of high-frequency jet ventilation in cardiac tamponade.
To evaluate the effects of high-frequency jet ventilation (HFJV) (f = 60, 120 breaths/min) and conventional mechanical ventilation (CMV) (f = 10, 20) during equivalent conditions of cardiac tamponade, stroke index (SI), intrapericardial pressure (IPP), airway pressure (P(aw)), and cardiac pressures were measured in anesthetized, paralyzed, chest-closed dogs with the same levels of PaCO2. Cardiac tamponade was produced by infusing normal saline into the intrapericardial space to increase IPP to either 8 mm Hg (group 1, n = 8) or 12 mm Hg (group 2, n = 8). Stroke index in group 1 was 7.3 +/- 0.8 during CMV (f = 10), 8.1 +/- 0.7 during CMV (f = 20), 10.9 +/- 1.4 during HFJV (f = 60), and 10.7 +/- 1.2 (mL.beat-1.m-2) during HFJV (f = 120). Stroke index in group 2 was 4.1 +/- 0.7, 5.1 +/- 0.5, 7.2 +/- 0.5, and 6.7 +/- 0.5 (mL.beat-1.m-2), respectively. In both IPP groups, stroke index values during HFJV were significantly higher than during CMV; however, there were no significant differences in mean left and right atrial transmural pressures between HFJV and CMV. Peak IPP, mean P(aw), and peak P(aw) during HFJV were significantly lower than those during CMV. The results indicate that HFJV with lower mean and peak Paw, and with lower mean and peak IPP, can result in higher cardiac output than CMV in cardiac tamponade. Thus, HFJV may be superior to CMV in the clinical management of cardiac tamponade.


Immunosenescence and human vaccine immune responses.
The age-related dysregulation and decline of the immune system-collectively termed "immunosenescence"-has been generally associated with an increased susceptibility to infectious pathogens and poor vaccine responses in older adults. While numerous studies have reported on the clinical outcomes of infected or vaccinated individuals, our understanding of the mechanisms governing the onset of immunosenescence and its effects on adaptive immunity remains incomplete. Age-dependent differences in T and B lymphocyte populations and functions have been well-defined, yet studies that demonstrate direct associations between immune cell function and clinical outcomes in older individuals are lacking. Despite these knowledge gaps, research has progressed in the development of vaccine and adjuvant formulations tailored for older adults in order to boost protective immunity and overcome immunosenescence. In this review, we will discuss the development of vaccines for older adults in light of our current understanding-or lack thereof-of the aging immune system. We highlight the functional changes that are known to occur in the adaptive immune system with age, followed by a discussion of current, clinically relevant pathogens that disproportionately affect older adults and are the central focus of vaccine research efforts for the aging population. We conclude with an outlook on personalized vaccine development for older adults and areas in need of further study in order to improve our fundamental understanding of adaptive immunosenescence.


Tranilast abrogates cisplatin-induced testicular and epididymal injuries: An insight into its modulatory impact on apoptosis/proliferation.
Cisplatin is a chemotherapeutic agent whose therapeutic use is greatly limited by the associated organs' toxicity and particularly, testicular toxicity. Cisplatin-induced testicular damage reported being mediated through mitochondria-mediated apoptosis, inflammation, and oxidative stress. Evidence showed that tranilast (TRN) has the ability to restore the oxidative status and modulate TRAIL/caspase-8 signaling. This led us to hypothesize that TRN could abrogate cisplatin-induced testicular and epididymal injuries via inhibiting oxidative stress and modulating proliferation and TRAIL/caspase-8/cJNK signaling. Cisplatin injection induced oligospermia and abnormalities in testicular and epididymal structure along with impaired oxidative status. TRN administration (100 or 300 mg/kg) for 7 days post-cisplatin injection preserved spermatogenesis and restored testicular and epididymal architecture, but restoration was more so in TRN300 than TRN100. This was in line with the restoration of balanced oxidative status as indicated by the increased total antioxidant capacity, glutathione and superoxide dismutase activity, and the decreased malondialdehyde content in testes (p < 0.05 vs. cisplatin). TRN increased the cell proliferation revealed by the increased expression of proliferating cell nuclear antigen in a dose-dependent manner (p < 0.05 vs. cisplatin) whereas only TRN300 decreased testicular cJNK, TRAIL, and caspase-8 expression (p < 0.05 vs. cisplatin). Moreover, TRN dose-dependently inhibited the pro-inflammatory transcription factor NF-kB and the cytokine TNF-α expressions in testes. In conclusion, TRN300 was more effective than TRN100 in alleviating cisplatin-induced testicular and epididymal injuries and in enhancing spermatogenesis. This curative effect of TRN might be mediated through its antioxidant and anti-inflammatory impacts along with its modulatory impact on cJNK/TRAIL/caspase-8 signaling favoring proliferation rather than apoptosis.


Predictors of communication attitude in preschool-age children who stutter.
Although preschool-age children who stutter report more negative attitudes toward communication than their typically fluent peers, few investigations have explored factors that may contribute to the differences observed in communication attitude. The purpose of the present study was to explore whether behavioral characteristics of stuttering severity (frequency, duration, physical concomitants) and time since onset of stuttering predict communication attitude in preschool-age children. Fifty-nine preschool-aged children who stutter completed two speaking samples and the KiddyCAT, a self-report assessment of communication attitude. Speech samples were analyzed for stuttering frequency (measured by percentage of stuttered syllables), duration, and presence of physical concomitants. Linear regression models were used to assess if these behavioral measures of stuttering and time since onset of stuttering predicted self-reported communication attitude. Results indicate stuttering behavioral measures and time since onset do not predict KiddyCAT scores of preschool-age children who stutter. Preliminary data suggest children who have presented with stuttering for a longer period of time are no more likely to report a negative communication attitude than children who have a shorter time since onset. Additionally, in contrast to school-age children who stutter, but similar to adults and adolescents who stutter, communication attitude is not linearly related to stuttering severity in preschool-age children.


Comparison of real-time PCR methods for quantification of European hake (Merluccius merluccius) in processed food samples.
The quantification of species in commercial products is limited by analytical shortcomings, as most of them provide semiquantitative results. An exception is real-time PCR, which can provide quantitative results using hybridization probes. In the present work, this technique has been applied to the absolute, absolute-relative and relative quantification of the most valued hake species in European markets, Merluccius merluccius (European Hake). The best quantification results for this species in binary mixtures with non-target species (Merluccius capensis) and using a species-specific real-time PCR MMER_VIC system was achieved using a relative quantification approach (MLL as reference system). Absolute quantification using the MLL nuclear system has been demonstrated as appropriate for the quantification of the Merluccius genus in food model samples. This study reveals the impact of different reference systems (MLL and HAKE) in the absolute-relative and relative quantification approaches, showing that the nuclear MLL system performed better than the mitochondrial HAKE system.


A mild case of acromesomelic dysplasia, type Maroteaux with novel natriuretic peptide receptor B (NPR2) variants.
Acromesomelic dysplasia, type Maroteaux is caused by variants in NPR2. It is a severe chondrodysplasia resulting in shortening of the middle and distal segments of the limbs. Limb length at birth may be normal but decreased growth becomes obvious in the first 2 years of life. Here we present an 11-year-old male with mild but typical skeletal features of acromesomelic dysplasia, type Maroteaux. Whole exome sequencing has identified two likely pathogenic variants in NPR2 which have not previously been reported in individuals with acromesomelic dysplasia, type Maroteaux. Given these findings, a diagnosis of AMDM should be considered in individuals with characteristic radiological findings, even if stature is only modestly affected.


Association of meteorological parameters with intussusception in children aged under 2 years: results from a multisite bidirectional surveillance over 7 years in India.
The study aimed to document the association between intussusception in Indian children and meteorological parameters and examine regional variations. A bidirectional (retrospective and prospective) surveillance between July 2010 and September 2017. At 20 hospitals in India, retrospective case record review during July 2010 and March 2016 and prospective surveillance during April 2016 and September 2017 were performed. 2161 children aged 2-24 months with first intussusception episode were included. The monthly mean meteorological parameters (temperature, sunshine, rainfall, humidity and wind speed) for the study sites were collected. The association between monthly intussusception cases and meteorological parameters was examined at pooled, regional and site levels using Pearson (r) and Spearman's rank-order (ρ) correlation, factorial analysis of variance, and Poisson regression or negative binomial regression analyses. The intussusception cases were highest in summer and lowest in autumn seasons. Pearson correlation analysis showed that temperature (r=0.056; p<0.05), wind speed (r=0.134; p<0.01) and humidity (r=0.075; p<0.01) were associated with monthly intussusception cases. Spearman's rank-order correlation analysis found that temperature (ρ=0.049; p<0.05), wind speed (ρ=0.096; p<0.01) and sunshine (ρ=0.051; p<0.05) were associated with monthly intussusception cases. Poisson regression analysis resulted that monthly intussusception case was associated with rising temperature (North region, p<0.01 and East region, p<0.05), sunshine (North region, p<0.01), humidity (East region, p<0.01) and wind speed (East region, p<0.01). Factorial analysis of variance revealed a significant seasonal difference in intussusception cases for pooled level (p<0.05), 2-6 months age group (p<0.05) and North region (p<0.01). Significant differences in intussusception cases between summer and autumn seasons were observed for pooled (p<0.01), children aged 2-6 months (p<0.05) and 7-12 months (p<0.05). Significant correlations between intussusception cases and temperature, humidity, and wind speed were observed at pooled and regional level in India. A peak in summer months was noted, which may be used for prediction, early detection and referral for appropriate management of intussusception.


Evolution of isotype switching.
This review discusses evolution of the process of Ig heavy chain class switching, relating it to the first appearance of somatic hypermutation (SHM) of variable region genes. First, we discuss recent findings on the mechanism of class switch recombination (CSR) in mice and humans, and then review the mechanisms of expression of Ig heavy chain isotypes from fishes to mammals. Importantly, activation-induced cytidine deaminase (AID), which is essential for CSR and somatic hypermutation, is found in fishes. Although at least some fishes are likely to undergo SHM, CSR is highly unlikely to occur in this group. We discuss the first appearance of CSR in amphibians and how it differs in birds and mammals.