Polyunsaturated fatty acids and risk of Alzheimer's disease: a Mendelian randomization study.
Observational studies have suggested that polyunsaturated fatty acids (PUFAs) may decrease Alzheimer's disease (AD) risk. In the present study, we examined this hypothesis using a Mendelian randomization analysis. We used summary statistics data for single-nucleotide polymorphisms associated with plasma levels of n-6 PUFAs (linoleic acid, arachidonic acid) and n-3 PUFAs (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid), and the corresponding data for AD from a genome-wide association meta-analysis of 63,926 individuals (21,982 diagnosed AD cases, 41,944 controls). None of the genetically predicted PUFAs was significantly associated with AD risk; odds ratios (95% confidence interval) per 1 SD increase in PUFA levels were 0.98 (0.93, 1.03) for linoleic acid, 1.01 (0.98, 1.05) for arachidonic acid, 0.96 (0.88, 1.06) for alpha-linolenic acid, 1.03 (0.93, 1.13) for eicosapentaenoic acid, 1.03 (0.97, 1.09) for docosapentaenoic acid, and 1.01 (0.81, 1.25) for docosahexaenoic acid. This study did not support the hypothesis that PUFAs decrease AD risk.


Engineering, delivery, and biological validation of artificial microRNA clusters for gene therapy applications.
The cellular machinery regulating microRNA biogenesis and maturation relies on a small number of simple steps and minimal biological requirements and is broadly conserved in all eukaryotic cells. The same holds true in disease. This allows for a substantial degree of freedom in the engineering of transgenes capable of simultaneously expressing multiple microRNAs of choice, allowing a more comprehensive modulation of microRNA landscapes, the study of their functional interaction, and the possibility of using such synergism for gene therapy applications. We have previously engineered a transgenic cluster of functionally associated microRNAs to express a module of suppressed microRNAs in brain cancer for therapeutic purposes. Here, we provide a detailed protocol for the design, cloning, delivery, and utilization of such artificial microRNA clusters for gene therapy purposes. In comparison with other protocols, our strategy effectively decreases the requirements for molecular cloning, because the nucleic acid sequence encoding the combination of the desired microRNAs is designed and validated in silico and then directly synthesized as DNA that is ready for subcloning into appropriate delivery vectors, for both in vitro and in vivo use. Sequence design and engineering require 4-5 h. Synthesis of the resulting DNA sequence requires 4-6 h. This protocol is quick and flexible and does not require special laboratory equipment or techniques, or multiple cloning steps. It can be easily executed by any graduate student or technician with basic molecular biology knowledge.


Adsorption process modeling to reduce COD by activated carbon for wastewater treatment.
Investigations have been carried out on the utilization of Activated Carbon (AC) in adsorption processes for the wastewater treatment of industry and municipal. Sulfides materials, phenols and furfural is a toxic compounds in wastewater from refineries can adversely affect the performance of biological aeration basins in reducing COD levels. This work aims to provide the effectiveness of AC in reducing the COD level of the effluent from the Dissolved Air Flotation (DAF) unit to meet standards of environments protecting and pass the design of wastewater treatment plants. A dynamic adsorption model was developed based on the dispersion of axial in the AC packed bed, assuming that the LDF (linear driving force) model in to the adsorbents is agreed to mass transfer. The model's predictions of chemical oxygen demand breakthrough curve concentrations showed excellent agreement with experimental data. The sensitivity analysis of operational conditions such as flow rate, inlet concentration of COD and bed length was used to gain a better understanding of the optimal design of an AC fixed bed. The results suggest that an AC fixed bed can complement biological treatment of wastewater and address the challenges faced by biological basins in oil refineries.


Meloidogyne incognita: molecular cloning and characterization of a cDNA encoding a cathepsin D-like aspartic proteinase.
Herein we describe the cloning and characterization of a cDNA encoding an aspartic proteinase from the root-knot nematode Meloidogyne incognita. Using PCR techniques, a 1471-bp cDNA fragment encoding a cathepsin D-like (Mi-asp1) transcript was isolated from second-stage larvae mRNA. Its predicted amino acid sequence comprises a pro-region of 71 amino acid residues and a mature protease of 378 amino acid residues with a predicted molecular mass of 41.502kDa. Protein sequence comparisons of Mi-asp1 with GenBank (DQ360827) sequences showed 59-71% identity with nematode-specific cathepsin D-like aspartic proteinases. Southern blot analysis, RT-PCR amplification and EST mining suggest the existence of a developmentally expressed gene family encoding aspartic proteinases in M. incognita. Mi-asp1 may represent a potential target for molecular intervention for the purposes of plant-parasitic nematode control.


The mechanism of molecular cross-linking against nonenzymatic degradation in the body wall of ready-to-eat sea cucumber.
Ready-to-eat sea cucumbers (RSC) treated by high pressure steam were easily degraded during storage. Celery (Apium graveolens, AG) and chlorogenic acid (CA) were screened for enhancing the stability of RSC. After RSC cross-linked by AG or CA, the hardness was significantly increased by 108% or 254% at 30 d, and the relaxation time decrease by 31.90 or 39.89 ms, and the proportion of T23 reduced by 0.40% or 1.15%. The crosslinked RSC exhibited smaller pore size with finer collagen fibrils. CA treatment caused the secondary structure changes in RSC. In addition, it also inhibited the break of peptide bonds in RSC collagen, observing the decrease of free hydroxyproline level from 46.63 to 34.53 μg/g, and the reduction of free ammonia nitrogen from 20.96 to 15.30 μmol/g. Therefore, AG and CA will have an important application in RSC processing industry.


Left ventricular outflow tract obstruction masked by severe aortic stenosis.
An 81-year-old woman developed severe hemolytic anemia after aortic valve replacement. The anemia was not caused by paravalvular leakage, as in most cases. Instead, it occurred secondary to left ventricular outflow tract obstruction that had not been seen preoperatively and was induced by afterload reduction following aortic valve replacement. The hemolytic anemia was drug-refractory and finally treated with dual-chamber pacing, as for hypertrophic cardiomyopathy.


Evaluation and outcomes of women with a breast lump and a normal mammogram result.
Many women experience a breast lump. Clinical guidelines suggest that a normal mammogram result alone is not adequate to exclude a diagnosis of cancer. To examine the characteristics of women with a breast lump and a normal mammogram that were associated with receiving further evaluation, and to examine cancer outcomes. Observational cohort. Women aged 35 to 70 years who participated in a population-based mammography registry and who did not have a history of breast cancer noted at the time of their mammogram that they had a breast lump, and had a "normal" (Breast Imaging Reporting and Data System 1 or 2) mammogram result (n=771). Telephone survey performed 6 months after the mammogram to ascertain information about evaluation. Cancer outcomes within 12 months of the index mammogram were confirmed through linkage with a cancer registry. Only 56.9% of women reported receiving an adequate evaluation for their breast lump, including a subsequent clinical breast exam, a visit to a breast specialist, an ultrasound, a biopsy, or aspiration. Latinas were less likely than white women to have received adequate evaluation, as were obese women compared with normal-weight women, and uninsured women compared with women with insurance. Among women with at least 12 months of follow-up, 1.4% were diagnosed with cancer. Many women do not receive adequate evaluation for a recent breast lump. Interventions should be designed to improve the follow-up of women with this common clinical problem.


Social insect histology from the nineteenth century: the magnificent pioneer sections of Charles Janet.
Charles Janet (1849-1932) was the leading pioneer in the histological description of the internal anatomy of social insects, in particular of ants and wasps. Because many of the original Janet sections still exist, this article is able to illustrate the amazing skills through some selected pictures taken from this more than a century old material, and thus to pay tribute to this French founder of insect morphology.


Understanding Chronic Aggression and Its Treatment in Children and Adolescents.
Youth aggression is common and has a significant burden on individuals, families, and society. However, its treatment is often a challenge for clinicians. Thus, this review will examine the current understanding of youth aggression, conceptualize aggression as a symptom rather than its own disorder, and provide an overview of treatment strategies. Youth aggression is associated with complex genetic, neurobiological, and environmental risks. Prevention strategies are of the utmost importance for at-risk families and youth. Psychosocial interventions are the first line treatment. But if not fully effective, then pharmacologic interventions-including psychostimulants, alpha-2 agonists, atomoxetine, and risperidone-have shown benefits. Other medications, such as SSRIs, can be useful in certain scenarios. It is important to conceptualize youth aggression as being a trans-diagnostic symptom in psychopathology. Determining the underlying cause of aggression will help to guide treatment.


Introduction: microbes, networks, knowledge-disease ecology and emerging infectious diseases in time of COVID-19.
This is an introduction to the topical collection Microbes, Networks, Knowledge: Disease Ecology in the twentieth Century, based on a workshop held at Queen Mary, University London on July 6-7 2016. More than twenty years ago, historian of science and medicine Andrew Mendelsohn asked, "Where did the modern, ecological understanding of epidemic disease come from?" Moving beyond Mendelsohn's answer, this collection of new essays considers the global history of disease ecology in the past century and shows how epidemics and pandemics have made "microbes complex".


How Do J-Proteins Get Hsp70 to Do So Many Different Things?
Hsp70 chaperone machineries have pivotal roles in an array of fundamental biological processes through their facilitation of protein folding, disaggregation, and remodeling. The obligate J-protein co-chaperones of Hsp70s drive much of this remarkable multifunctionality, with most Hsp70s having multiple J-protein partners. Recent data suggest that J-protein-driven versatility is substantially due to precise localization within the cell and the specificity of substrate protein binding. However, this relatively simple view belies the intricacy of J-protein function. Examples are emerging of J-protein interactions with Hsp70s and other chaperones, as well as integration into broader cellular networks. These interactions fine-tune, in critical ways, the ability of Hsp70s to participate in diverse cellular processes.


In vivo incorporation of labeled fatty acids in rat liver lipids after oral administration.
Striking differences were found in the compartmentalization of fatty acids into liver lipid fractions. The saturated fatty acids--lauric, myristic, palmitic and stearic--were incorporated into phosphoglycerides at faster rates with increasing chain lengths, while triglyceride incorporation was almost uniform. The degree of incorporation of the unsaturated fatty acids into phosphoglycerides (structural) compared to triglyceride (storage and energy) was the converse of their oxidation rates. The incorporation of oleic, linoleic and alpha-linolenic acids was mainly into triglyceride, whereas dihomo-gamma-linolenic acid and arachidonic acid were preferentially incorporated into phosphoglycerides. The data suggest that distribution of each fatty acid is different depending on its destination for structural or energy function.


[Reports on two species of Pegohylemyia tibetana group in Xiling snow mountain of Dayi county, Sichuan, China (Anthomyiidae, Diptera)].
Male:Body 7mm. in length. Having a pair of bristles on the distal part of cercal plate, a blunt round angle of postgonite, the new species being less related to Pegohylemyia macrospini gera Deng, 1990, but having 4 pairs of large spines on the 5th sternite, a spherical point of postgonite and biconcave surstyli at apex, thus differing from the relative species. Holotype male, paratypes 18 male male, Xiling snow mountain of Dayi county, Sichuan, 17, July 1993, coll. Geng Lin, Deng Anxiao. Male:Body 7mm. in length. Having 4 pairs of spines on the 5th sternite being similar to Pegohylemyia nigribella above, but having legs with yellow color and round apex of surstyli resembling Pegohylemyia setisilva Jin, 1983; however, broadening postgonite and slender surstyli may be distinguished from all yellow leg species in this group. Holotype male:paratypes 63 male male, date and place of collection being the same as the first species above, coll Geng Lin, Li Ling, Deng Anxiao. Holotype and paratypes are kept in author's laboratory.


Prognostic Factors in the Midterm Results of Pullout Fixation for Posterior Root Tears of the Medial Meniscus.
To identify predictors of unfavorable clinical and radiologic outcomes a minimum of 5 years after pullout fixation for medial meniscus posterior root tears (MMPRTs). In total, 40 patients who were followed for >5 years after pullout fixation in MMPRT were recruited. The mean follow-up duration was 71.1 months. Clinical outcomes, including Lysholm score and International Knee Documentation Committee (IKDC) score, and radiographic results, including Kellgren-Lawrence (K-L; 0/1/2/3/4) grade and medial joint space width, were evaluated preoperatively and at final follow-up. Preoperative prognostic factors, including age, sex, body mass index, degree of varus alignment, K-L grade, medial joint space width, meniscal extrusion, and cartilage status, by the modified Outerbridge classification (grades 1 or 2 v 3 or 4), for relatively unfavorable (fair or poor grade) Lysholm or IKDC score, and progression of K-L grade were investigated by multivariate logistic regression analysis. The mean Lysholm score (52.1 ± 8.8 to 83.8 ± 11.9) and IKDC score (40.1 ± 7.6 to 73.3 ± 10.9) were improved significantly (P < .001), although the loss of medial joint space width (4.8 ± 1.1 to 3.9 ± 1.1 mm) and K-L grade (6/25/9/0/0 to 0/11/20/9/0) progressed significantly (P < .001). Unfavorable prognostic factors of the Lysholm score were grade ≥3 chondral lesions (odds ratio [OR] = 5.993; P = .028) and varus mechanical alignment (OR = 1.644; P = .017), for IKDC score were grade ≥3 chondral lesions (OR = 11.146; P = .038) and older age (OR = 1.200; P = .017). Preoperative chondral lesion grade ≥3 increased the risk of K-L grade progression (OR = 11.000; P = .031). Clinically, modified Outerbridge classification grade ≥3 chondral lesions, varus alignment, and older age were found to predict a poor prognosis after MMPRT fixation. In terms of radiographic K-L grade progression, grade ≥3 chondral lesions were identified as a poor prognostic factor. Level IV, case series.


A clinical assessment of cochlear implant recipient performance: implications for individualized map settings in specific environments.
Individual speech intelligibility was measured in quiet and noise for cochlear Implant recipients upgrading from the Freedom to the CP900 series sound processor. The postlingually deafened participants (n = 23) used either Nucleus CI24RE or CI512 cochlear implant, and currently wore a Freedom sound processor. A significant group mean improvement in speech intelligibility was found in quiet (Freiburg monosyllabic words at 50 dBSPL) and in noise (adaptive Oldenburger sentences in noise) for the two CP900 series SmartSound programs compared to the Freedom program. Further analysis was carried out on individual's speech intelligibility outcomes in quiet and in noise. Results showed a significant improvement or decrement for some recipients when upgrading to the new programs. To further increase speech intelligibility outcomes when upgrading, an enhanced upgrade procedure is proposed that includes additional testing with different signal-processing schemes. Implications of this research are that future automated scene analysis and switching technologies could provide additional performance improvements by introducing individualized scene-dependent settings.


Home-Based Infusion of Alglucosidase Alfa Can Safely be Implemented in Adults with Late-Onset Pompe Disease: Lessons Learned from 18,380 Infusions.
Enzyme replacement therapy (ERT) with alglucosidase alfa is the treatment for patients with Pompe disease, a hereditary metabolic myopathy. Home-based ERT is unavailable in many countries because of the boxed warning alglucosidase alfa received due to the risk of infusion-associated reactions (IARs). Since 2008, home infusions have been provided in The Netherlands. This study aimed to provide an overview of our experience with home-based infusions with alglucosidase alfa in adult Pompe patients, focusing on safety, including management of IARs. We analysed infusion data and IARs from adult patients starting ERT between 1999 and 2018. ERT was initially given in the hospital during the first year. Patients were eligible for home treatment if they were without IARs for multiple consecutive infusions and if a trained home nurse, with on-call back-up by a doctor, was available. The healthcare providers graded IARs. We analysed data on 18,380 infusions with alglucosidase alfa in 121 adult patients; 4961 infusions (27.0%) were given in hospital and 13,419 (73.0%) were given at home. IARs occurred in 144 (2.9%) hospital infusions and 113 (0.8%) home infusions; 115 (79.9% of 144) IARs in hospital and 104 (92.0% of 113) IARs at home were mild, 25 IARs (17.4%) in hospital and 8 IARs (7.1%) at home were moderate, and very few severe IARs occurred (4 IARs in hospital [2.8%] and 1 IAR at home [0.9%]). Only one IAR in the home situation required immediate clinical evaluation in the hospital. Given the small numbers of IARs that occurred with the home infusions, of which only one was severe, we conclude that alglucosidase alfa can be administered safely in the home situation, provided the appropriate infrastructure is present.


Additive and synergistic antifungal effects of copper and phenolic extracts from grape cane and apples.
Organic viticulture seeks sustainable alternatives for eco-toxic copper fungicides to control downy mildew caused by Plasmopara viticola. (Poly)phenol-rich extracts of agricultural byproducts are known to possess antifungal activity, but high production costs often limit their actual implementation. We developed and produced novel ligninsulfonate-based grape cane extract (GCE) formulations and an apple extract on a pilot plant scale, including a detailed (poly)phenol characterization by high-performance liquid chromatography photodiode array mass spectrometry (HPLC-PDA-MS). Our GCE formulations alone reduced downy mildew disease severity in greenhouse trials by 29%-69% in a dose-dependent manner, whereas a standard application of the copper-based agent alone reached ~56%. When applied together, disease severity was diminished by 78%-92%, revealing a synergistic effect that depended on the mixture ratio. Combining GCE formulations with the apple extract, additive effects were found (80% disease severity reduction). The studied plant extracts are proposed to both substitute for and synergistically reinforce copper fungicides in grapevine downy mildew control. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Sn-MOF@CNT nanocomposite: An efficient electrochemical sensor for detection of hydrogen peroxide.
A novel approach for the assembly of Sn-based metal organic framework (Sn-MOF) via solvothermal method and its composite (Sn-MOF@CNT) with electroactive material, carbon nanotubes (CNT) by sonochemical means, is described that is useful for hydrogen peroxide sensing; large surface area and pore volume of Sn-MOF were exploited where in the crystallinity of the Sn-MOF was preserved upon inclusion of CNT over its surface. The surface morphology and structural analysis of Sn-MOF and its composite form, Sn-MOF@CNT, were determined analytically through Fourier-transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), Scanning electron microscopy (SEM), Brunauer-Emmett-Teller and Energy-dispersive X-ray spectroscopy (EDX). The developed Sn-MOF@CNT sensor was expansively used to determine and optimize the effect of scan rate, concentration and detection limits including the EDX and SEM analysis of used Sn-MOF@CNT nanocomposite's post hydrogen peroxide sensing. The electrochemical sensing with Sn-MOF@CNT revealed a lower limit of detection ~4.7 × 10-3 μM with wide linear range between 0.2 μM and 2.5 mM. This study has explored a new strategy for the deposition of CNT over Sn-MOF via a simple sonochemical methodology for successful electrochemical detection of H2O2, an approach that can be imitated for other applications.


Solitary metastasis to the skull as the first sign of hepatocellular carcinoma in a patient in long-term remission.
Hepatocellular carcinoma (HCC) is a common malignant tumor with a 5-year survival rate of 10%, presenting with extrahepatic metastases in 15-17% of patients. HCC-bone metastases represent approximately one-quarter of all HCC metastases, most frequently in the spine, pelvis, ribs, or femur. HCC-skull metastases, however, make up 0.4-1.6% of all HCC- bone metastases. Furthermore, solitary HCC-skull metastasis without known active primary HCC is an unusual presentation warranting further review and consideration. Here, the authors report a unique case of a solitary HCC-skull metastasis in a patient without known active cancer but in long-term remission for HCC. The patient is a 69-year-old male with past HCC who presented with a nontender skull mass. A computed tomography scan showed a heterogeneously enhancing mass centered in the high left parietal bone with intracranial extension. There was a noted mass effect on the left posterior frontoparietal region without worrisome midline shift. Pathology ultimately revealed the mass to be metastatic HCC. To aid in the understanding and clinical management of this rare presentation, we reviewed the literature regarding clinical presentation, radiological features, pathology, and outcome. Ultimately, early detection of the primary source of cancer is pivotal to successful treatment and prognosis, and skull lesions such as these must include HCC in the differential diagnosis.


The clinical significance of redundant nerve roots of the cauda equina in lumbar spinal stenosis patients: A systematic literature review and meta-analysis.
Decompression surgery for lumbar spinal stenosis (LSS) is the most performed spine surgery procedure in patients older than 65 years. Around 40% of LSS patients scheduled for decompression surgery have evidence of redundant nerve roots (RNR) of the cauda equina on their magnetic resonance images (MRI). Little is known about the clinical significance of RNR in LSS patients. The objective was to assess the effects of RNR on clinical scores and recovery in older adults diagnosed with LSS. A systematic literature search was performed in April 2018 on PubMed, Web of Science, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL). Prospective and retrospective cohort studies undertaken to assess differences in clinical outcomes in patients diagnosed with LSS with versus without evidence of RNR on their MRIs were selected. Two authors independently selected studies, abstracted data and assessed risk of bias. We calculated weighted mean differences (WMD) for continuous variables and odds ratio (OR) for variables reported in frequencies. Seven studies comprising a total of 1046 LSS patients were included in the meta-analysis. LSS patients with evidence of RNR (RNR+) were older, WMD 5.7 95% CI [2.2-9.2], p = 0.001, had smaller cross sectional area (CSA) of the stenotic level, WMD -12.2 95% CI [-17.7 to -6.7], p < 0.0001 and longer symptom onset duration, WMD 13.2 95% CI [-0.2-26.7], p = 0.05. The pooled preoperative clinical score in the RNR + group was worse but the difference was not statistically significant, WMD -3.8 95% CI [-7.9 to 0.2], p = 0.07. After decompression surgery RNR + patients had worse clinical scores, -4.7 95% CI [-7.3 to -2.1], p = 0.0004 and lower recovery rates, -9.8 95% CI [-14.8 to -4.7], p = 0.0001. There is limited quality evidence that RNR + patients are older, have a longer symptom history and present higher degrees of lumbar stenosis as given by the narrow CSA in comparison to RNR- patients. After decompression surgery RNR + patients have worse clinical scores and lower recovery rates. In view of these results RNR can be seen as a negative prognostic factor in LSS patients.


Prognostic value of KRAS G12C mutation in lung adenocarcinoma stratified by stages and radiological features.
The role of KRAS G12C is of particular interest given the promising clinical activity of KRAS G12C-specific inhibitors. This study comprehensively investigated the clinicopathological characteristics and prognostic value of KRAS G12C mutation in patients with surgically resected lung adenocarcinoma. Data were collected on 3828 patients with completely resected primary lung adenocarcinomas who underwent KRAS mutation analysis between 2008 and 2020. The association between KRAS G12C and clinicopathologic characteristics, molecular profiles, recurrence patterns, and postoperative outcome were explored. Two hundred seventy-five patients (7.2%) were confirmed to harbor a KRAS mutation, of whom 83 (30.2%) had the G12C subtype. KRAS G12C was more frequent in men, former/current smokers, radiologic solid nodules, invasive mucinous adenocarcinoma, and solid predominant tumors. KRAS G12C tumors had more lymphovascular invasion and higher programmed death-ligand 1 expression than KRAS wild-type tumors. TP53 (36.8%), STK11 (26.3%), and RET (18.4%) mutations were the 3 most frequent in the KRAS G12C group. Logistic regression analysis showed patients with KRAS G12C mutation were prone to experience early recurrence and locoregional recurrence. KRAS G12C mutation was found to be significantly associated with poor survival after propensity score matching. Stratified analysis showed that the KRAS G12C was an independent prognostic factor in stage I tumors and part-solid lesions, respectively. The KRAS G12C mutation had a significant prognostic value in stage I lung adenocarcinomas as well as in part-solid tumors. Furthermore, it exhibited a potentially aggressive phenotype associated with early and locoregional recurrence. These findings might be relevant as better KRAS treatments are developed for clinical application.


School building energy efficiency and NO2 related risk of childhood asthma in England and Wales: Modelling study.
Climate change legislation will require dramatic increases in the energy efficiency of school buildings across the UK by 2050, which has the potential to affect air quality in schools. We assessed how different strategies for improving the energy efficiency of school buildings in England and Wales may affect asthma incidence and associated healthcare utilization costs in the future. Indoor concentrations of traffic-related NO2 were modelled inside school buildings representing 13 climate regions in England and Wales using a building physics school stock model. We used a health impact assessment model to quantify the resulting burden of childhood asthma incidence by combining regional health and population data with exposure-response functions from a recent high-quality systematic review/meta-analysis. We compared the effects of four energy efficiency interventions consisting of combinations of retrofit and operational strategies aiming to improve indoor air quality and thermal comfort on asthma incidence and associated hospitalization costs. The highest childhood asthma incidence was found in the Thames Valley region (including London), in particular in older school buildings, while the lowest concentrations and health burdens were in the newest schools in Wales. Interventions consisting of only operational improvements or combinations of retrofit and operational strategies resulted in reductions in childhood asthma incidence (547 and 676 per annum regional average, respectively) and hospital utilization costs (£52,050 and £64,310 per annum regional average, respectively. Interventions that improved energy efficiency without operational measures resulted in higher childhood asthma incidence and hospital costs. The effect of school energy efficiency retrofit on NO2 exposure and asthma incidence in schoolchildren depends critically on the use of appropriate building operation strategies. The findings from this study make several contributions to fill the knowledge gap about the impact of retrofitting schools on exposure to air pollutants and their effects on children's health.


Curvature increases permeability of the plasma membrane for ions, water and the anti-cancer drugs cisplatin and gemcitabine.
In this work the permeability of a model asymmetric plasma membrane, for ions, water and the anti-cancer drugs cisplatin and gemcitabine is studied by means of all-atom molecular dynamics simulations. It is shown for the first time that permeability of the highly curved membrane increases from one to three orders of magnitude upon membrane bending depending on the compound and the sign of curvature. Our results suggest that the membrane curvature could be an important factor of drug translocation through the membrane.


In vacuo X-ray data collection from graphene-wrapped protein crystals.
The measurement of diffraction data from macromolecular crystal samples held in vacuo holds the promise of a very low X-ray background and zero absorption of incident and scattered beams, leading to better data and the potential for accessing very long X-ray wavelengths (>3 Å) for native sulfur phasing. Maintaining the hydration of protein crystals under vacuum is achieved by the use of liquid jets, as with serial data collection at free-electron lasers, or is side-stepped by cryocooling the samples, as implemented at new synchrotron beamlines. Graphene has been shown to protect crystals from dehydration by creating an extremely thin layer that is impermeable to any exchanges with the environment. Furthermore, owing to its hydrophobicity, most of the aqueous solution surrounding the crystal is excluded during sample preparation, thus eliminating most of the background caused by liquid. Here, it is shown that high-quality data can be recorded at room temperature from graphene-wrapped protein crystals in a rough vacuum. Furthermore, it was observed that graphene protects crystals exposed to different relative humidities and a chemically harsh environment.


Autoimmune hemolytic anemia and giant cell hepatitis: Report of three infants.
Giant cell hepatitis associated with direct Coombs' test-positive hemolytic anemia is a rare condition of childhood and the pathogenesis remains unclear. An autoimmune activation and loss of self-tolerance in these patients may be the underlying pathology related to the response of some of the patients to immunosuppressive treatment. Herein, we report the clinical presentation and course of three consecutive patients with this rare condition. We conclude that serum ferritin at diagnosis may be used for prediction of the outcome.


Association between blood pressure and the risk of chronic kidney disease in treatment-naïve hypertensive patients.
Although hypertension is a well-known risk factor for chronic kidney disease (CKD), the blood pressure (BP) at which antihypertensive interventions should be initiated remains to be determined. Therefore, we investigated the association between BP and CKD in treatment-naïve individuals. This prospective cohort study considered 7,343 individuals in the Korean Genome and Epidemiology Study who were not taking antihypertensive medications. Subjects were categorized into six groups according to their systolic BP (SBP) and five groups according to their diastolic BP (DBP). The primary outcome was incident CKD, which was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2 or the development of proteinuria. The secondary outcome was incident cardiovascular disease (CVD). In the time-varying Cox models, the hazard ratios (95% confidence interval [CI]) for CKD were 1.39 (1.10-1.77) with SBP 130-139 mmHg, 1.79 (1.40-2.28) with SBP 140-159 mmHg, and 3.22 (2.35-4.40) with SBP ≥ 160 mmHg, compared with SBP 100-119 mmHg. In addition, the hazard ratios (95% CI) for CKD were 1.88 (1.48-2.37) with DBP 90-99 mmHg and 4.30 (3.20-5.76) with DBP ≥ 100 mmHg, compared with DBP 70-79 mmHg. A significantly increased CVD risk was also observed in subjects with SBP ≥ 130 mmHg or DBP ≥ 90 mmHg. Our findings indicate that SBP ≥ 130 mmHg and DBP ≥ 90 mmHg are associated with an increased risk of CKD. Therefore, BP-lowering strategies should be considered starting at those thresholds to prevent CKD development.


BRCA, the oviduct, and the space and time continuum of pelvic serous carcinogenesis.
In recent years, the distal oviduct has emerged as a critical organ in the pathogenesis of pelvic ("ovarian") serous cancer. Studies have uncovered early serous tubal intraepithelial carcinomas in approximately 8% of asymptomatic women with germline BRCA1 or BRCA2 mutations, linked serous tubal intraepithelial carcinomas to one half of serous cancers irrespective of genetic risk, and described a precursor lesion in the distal tube with early alterations in p53 function (the p53 signature). This work has established a linear serous carcinogenic sequence in a single focus within the fimbria. In addition, a more broadly distributed array of gene alterations has been discovered in the oviduct, manifested as secretory (or stem) cell outgrowths that are increased in frequency as a function of older age and serous cancer status. These "surrogate precursors" expand the existing model beyond the fimbria, implying that the molecular events leading to serous cancer are distributed over space and time. The potential promise of these discoveries is "targeted prevention" by discovering of multiple pathways integral to carcinogenesis and successfully preventing malignancy by interrupting one or a few of these pathways.


Lateralized rewarding brain stimulation affects forepaw preference in rats.
Rats trained to reach for food pellets into a narrow tubular feeder consistently prefer to perform this stereotype instrumental movement with either the left or right forepaw. In 16 rats with established handedness electrodes were implanted into both lateral hypothalami. The animals were rewarded by intracranial self stimulation (ICSS, 300 msec, 50 Hz, 20-60 microA) for reaching into a modified feeder for a plastic ball operandum, the movement of which between the bottom and entrance of the feeder was monitored by mechanical contacts. The rats readily continued to reach when ICSS was delivered immediately after the photoelectrically detected reach or after the displacement of the operandum. Most rats learned in a single session to modify the movement when ICSS delivery was made contingent upon holding the operandum between the bottom and entrance of the feeder for 256 or 512 msec. The efficiency of reaching (ratio of successful reaches to all reaches) decreased with increasing holding time; only a few animals were able to master a 1024 msec delay. Reaching was supported by ICSS of either lateral hypothalamus. Whereas in 8 rats the strongly expressed forepaw preference was not changed by lateralized ICSS, in 8 latently ambidextrous animals stimulation of the lateral hypothalamus ipsilateral to the preferred forepaw increased reaching with the normally non-preferred forepaw from 15% to 60%. Stimulation of the lateral hypothalamus contralateral to the preferred forepaw did not change the preference. The preference shift was equally well expressed in simple and difficult versions of the task. It is concluded that lateralization of motivational influences can be reflected in the asymmetry of the neural mechanisms processing the lateralized sensory signals and/or elaborating the lateralized motor output.


Microbial transformation of dehydropinguisenol by Aspergillus sp.
Two metabolites were obtained by microbial transformation of a furanosesquiterpene alcohol, dehydropinguisenol, using Aspergillus niger and Aspergillus cellulosae. Their structures were established as 10-oxo-lejeuneapinguisenol and lejeuneapinguisenol on the basis of their spectroscopic data. The latter compound was obtained after 4 and 9 days of incubation with A. cellulosae at 30 degrees C and 25 degrees C, respectively. Aspergillus niger produced both metabolites after 3 and 5 days incubation at 30 degrees C, respectively. A possible pathway for the formation of these compounds is discussed here together with their antimicrobial activity against A. niger and A. cellulosae.


Characterization of the expression products of recombinant human choriogonadotropin and subunits.
Human choriogonadotropin (hCG) is a placental glycoprotein hormone composed of a 92-amino acid alpha subunit noncovalently linked to a 145-amino acid beta subunit. We report here the expression of biologically active hCG in mouse C127 cells transfected with expression vectors containing the DNA coding for both subunits. In addition, the same cell line was used to express the alpha subunit alone. The expression products were purified by affinity chromatography using specific monoclonal antibodies to hCG or its subunits. The system secreting biologically active hCG also produced a 10-fold or greater molar excess of free beta subunit. The dimeric hormone, as well as the excess beta subunit, resembles the standard urinary hCG and beta subunit by chemical and biological criteria. In contrast, when the vector encoding for the alpha subunit was expressed alone, the alpha subunit had a higher molecular weight than both standard alpha and the alpha found in the expressed dimeric hormone. The molecular weight difference between expressed alpha subunit and standard alpha was found to reside in the alpha peptide consisting of residues 52-91 which contained all of the carbohydrate of the alpha subunit. The N-asparagine-linked carbohydrate moieties in the recombinant alpha were found to be triantennary in contrast to biantennary in urinary alpha, and this hyperglycosylation was responsible for the higher molecular weight of the alpha subunit when it was expressed alone. We found no evidence of O-threonine glycosylation at position alpha 39 reported to be present in free forms of the alpha subunit; however, the companion paper (Corless, C.L., Bielinska, M., Ramabhadran, T. V., Daniels-McQueen, S. Otani, T., Reitz, B. A., Tiemeier, D. C., and Boime, I. (1987) J. Biol Chem. 262, 14197-14203) finds a small quantity of O-glycosylation. Since the excess beta subunit appears to be of normal size and contains the expected complement of sugars, only free alpha subunit seems to be a potential substrate for addition of extra sugar moieties. No large beta subunit forms have been found by others, while large alpha subunits have been described both clinically and in tissue culture systems. These observations imply that the conformation of the free alpha subunit, in the regions of the glycosylation recognition sites, allows easier access for glycosyltransferases than those same sites in the beta subunit. When alpha is combined with beta, the local structures around the alpha glycosylation sites are apparently altered so as to make the synthesis of triantennary chains less favorable.


A perspective on the changing landscape of HTS.
Recently, there has been a change in the types of drug target entering early drug discovery portfolios. A significant increase in the number of challenging targets, or which would have historically been classed as intractable, has been observed. Such targets often have shallow or non-existent ligand-binding sites, can have disordered structures or domains or can be involved in protein-protein or protein-DNA interactions. The nature of the screens required to identify useful hits has, by necessity, also changed. The range of drug modalities explored has also increased and the chemistry required to design and optimise these molecules has adapted. In this review, we discuss this changing landscape and provide insights into the future requirements for small-molecule hit and lead generation.


Early and 1-year survival rates in acute myocardial infarction complicated by cardiogenic shock: a retrospective study comparing coronary angioplasty with medical treatment.
Cardiogenic shock remains a frequently lethal complication of acute myocardial infarction. Early revascularization of the infarct-related artery by coronary angioplasty has been suggested to significantly improve patient survival. In-hospital and 1-year survival was assessed in 50 patients hospitalized for acute myocardial infarction complicated by cardiogenic shock. All patients received medical treatment and intraaortic balloon pump support. Thirty-three patients underwent coronary angioplasty (PTCA group), while 17 patients remained on conventional therapy (no PTCA group). The two groups were comparable for all baseline characteristics. Survival was significantly better in the PTCA group than in the no PTCA group: 64% versus 24% in-hospital survival (p = 0.007) and 52% versus 12% at 1 year (p = 0.006). When angioplasty was successful in achieving reperfusion, survival was further enhanced: in-hospital survival rate was 76% versus 25% in patients with unsuccessful angioplasty and 60% versus 25% at 1 year.


Evaluation of application protocol of the 4% hydrogen peroxide for at-home bleaching: A randomized clinical trial.
Few studies evaluated low concentrations of hydrogen peroxide protocols. The aim of this paper was evaluated two application protocols using 4% hydrogen peroxide in at-home bleaching. Eighty-six patients with upper canines' shade A2 or darker were randomly allocated under two experimental conditions: two daily applications of 1 h each or a 2-h single application. Color change was evaluated using Vita Classical, Vita Bleachedguide, and digital spectrophotometer weekly and 1 month after the bleaching procedure through one-way ANOVA. The risk and intensity of tooth sensitivity (TS) was assessed through visual and numeric rating scale and measured by Fisher's exact test, Mann-Whitney test and one-way ANOVA respectively. After 3 weeks, the mean difference for the ΔSGU Vita Classical (1.0; 95% CI -0.1 to 2.0), ΔEab (0.7; 95% CI -1.4 to 2.8), ΔE00 (0.1; 95% CI -1.4 to 1.6) and Wi (1.8; 95% CI -1.9 to 5.5) presented no difference (p > 0.08). The relative risk for TS was 0.91 (0.72 to 1.14) without significant difference neither in the risk (p = 0.6) nor in the TS intensity for both pain scales (p > 0.65). The application protocols evaluated (two daily applications of 1 h each or a 2-h single application) for at-home bleaching with 4% hydrogen peroxide did not showed differences in color change and tooth sensitivity. Higher amount of active hydrogen peroxide in two daily applications for at-home bleaching neither accelerate bleaching nor increase the risk or intensity of tooth sensibility.


Hughes flap in the management of lower lid retraction.
We present a retrospective case series on the use of Hughes flap in managing acquired cicatricial lower lid retraction. This was a multicentre, retrospective case series. Data was collected from medical records across different sites within Australia (Adelaide, Melbourne, and Sydney) and New Zealand (Hamilton). Fourteen patients were identified. The aetiology of cicatricial lower lid retraction included previous lid lesion excision and reconstruction, eyelid trauma, orbital fracture repair, orbital radiotherapy, and lateral canthal dystopia from previous lid surgeries. 4/14 (29%) cases had undergone other surgery to correct the retraction prior to the Hughes flap. Pre-operative lagophthalmos due to lower lid retraction was noted in 11/14 (79%) cases with a median 2 mm (range: 1-5 mm). Exposure keratopathy was present in 7/14 (50%) cases. There were no peri-operative complications during Hughes flap reconstruction. One patient had post-operative upper eyelid retraction that did not require any further intervention. One patient had persistent lagophthalmos and exposure keratopathy that is being managed conservatively. One patient had wound dehiscence and further lid retraction following flap division, which required further surgery. Median length of follow-up was 15 months (range: 0.5-84 months). At final review, improvement or resolution of symptoms was seen in 13/14 (93%) cases. A Hughes flap is an effective surgical technique for the management of cicatricial lower lid retraction.


[Database establishment of the whole rDNA ITS region of Dendrobium species of "fengdou" and authentication by analysis of their sequences].
To establish the whole rDNA ITS region sequence database of various Dendrobium species of "Fengdou" and to authenticate exactly the inspected species of "Fengdou". The rDNA ITS regions of various Dendrobium species of "Fengdou" were amplified and sequenced. The database of their rDNA ITS regions was established in order to authenticate the inspected species by means of the softwares of CLUSTRAL and MEGA which were used to analyze the rDNA ITS region. A database of the rDNA ITS sequences of 21 species of Dendrobium has been established. The notable and stable differences of the interspecies of the rDNA ITS regions have been demonstrated. The numbers of transitions and transversions among 21 species are 11-122. The variable sites are 341 while the informative sites are 195. The ITS sequence differences between the outgroup species (Pholidota yunnanensis) and species of "Fengdou" are obvious. The numbers of transitions and transversions are 131-161. The population differences of the rDNA ITS region of various species of "Fengdou" are very small (0-6). On the basis of the database of various Dendrobium species of "Fengdou" and two genetics software, the botanical origin of the inspected species of "Fengdou" has been authenticated successfully by sequencing the rDNA ITS regions.


Analysis of primary metabolites of Morchella fruit bodies and mycelium based on widely targeted metabolomics.
As a medicinal and edible homologous fungi, Morchella is rich in multiple metabolites. The metabolite is a kind of essential substance with active components. In this study, Morchella fruit bodies and mycelium were selected to identify their metabolite components. The primary metabolites of the two experimental groups were analyzed using a method of widely targeted metabolome based on UPLC-ESI-MS/MS. A total of 354 different metabolites were characterized, including 188 upregulated ones and 166 downregulated ones in the fruit bodies. Further, the main 20 metabolic pathways of the metabolites were analyzed. The first 9 ones are tyrosine metabolites, thyroid hormone biosynthetic pathway, phenylalanine metabolites, linoleic metabolites synthetic pathway, glycerophosphate metabolic pathway, choline in tumors, methyl butyl metabolites, arginine synthetic pathway, arginine and proline metabolites. This study provides theoretical basis for the analysis of metabolic pathway of Morchella fruit bodies and mycelium that serve for further research of their medicinal mechanism and effective components.


A novel, sensitive method for determining benzo[a]pyrene-diones using high-performance liquid chromatography with post-column zinc reduction.
A novel and sensitive high-performance liquid chromatography (HPLC) method was developed to analyze dione metabolites of benzo[a]pyrene (BaP). Because BaP-diones do not fluoresce, detection of low concentrations is difficult to achieve when analyzing these chemicals with a simple HPLC system. We developed a method to increase the detection sensitivities for BaP-diones using reduction by zinc after the chromatographic separation. A post-column zinc reducer was used to convert BaP-diones, in-line, to their corresponding fluorescent BaP-hydroquinones, which can be measured by fluorescence detection with high sensitivity. With 20-muL injections, the limits of detection for the BaP-diones tested (BaP-1,6-dione, BaP-3,6-dione, and BaP-6,12-dione) were all below 1.0 nM. In addition to the high detection sensitivity, this HPLC method provides a wide linear dynamic range for BaP-dione detection (1.0-220 nM). We also studied the extraction recovery of BaP-diones from recombinant human cytochrome P450 and epoxide hydrolase. To demonstrate the application of this method, the kinetics of BaP-dione formation was studied by incubating BaP with these recombinant enzymes. The present method enhances the detection sensitivity for BaP-diones by more than two orders of magnitude compared with traditional ultraviolet detection. Moreover, the method avoids the time-consuming derivatization or reduction steps required by other methods.


Early respiratory dysfunction as a biomarker for epileptic encephalopathy.
West syndrome is an epileptic encephalopathy starting in infancy with almost continuous interictal epileptic activity, so-called hypsarrhythmia pattern, and therefore is an interesting model for investigating the effect of interictal epileptic activity on autonomic function. It is known that autonomic dysfunction contributes to morbidity and mortality in epilepsy. Our aim is to investigate the effect of interictal epileptic activity in West syndrome on respiratory control. Interictal single-lead ECG signals were extracted from 24-h video-EEG recordings in 10 children suffering from West syndrome and 14 control subjects. RR interval time series were calculated, and respiration was derived from the ECG signal. ECG-derived respiration (EDR) signals were computed and time and frequency domain parameters were extracted to characterize the respiration pattern. In time domain, the standard deviation of the EDR signal is significantly lower in patients with West syndrome compared to control subjects. This finding is an indication of a less variable respiratory rate. In frequency domain, we analyzed the mean power spectrum for the EDR. In patients with West syndrome, there is more activity at the lower frequencies considered to be a risk factor for apneas. Second, there is an attenuated peak at the higher frequency band where normal respiratory rate is to be found, indicating an abnormal breathing pattern. Our results show that there is a clear dysfunction in autonomic respiratory control in patients with West syndrome, in between the typical ictal epileptic spasms, compared to control subjects. Respiration is more fixed and contains a higher risk of apneas.


Bedside cerebrospinal fluid glucose analysis.
We studied the reliability and accuracy of a two-minute reagent strip (Chemstrip bG) and hand-held autoanalyzer (Accu-Chek IIR) for determining cerebrospinal fluid glucose. We found that both bedside methods were highly reliable (r = 0.93, Chemstrip bG: r = 0.95, Accu-Chek II) and were very accurate (89.7% and 96.6% accurate at +/- 15 and 20 mg/dL, respectively, for the Chemstrip bG: 91.7% and 95.8% accurate at +/- 15 and 20 mg/dL, respectively, for the Accu-Chek II) over a wide range of glucose values in 237 determinations. There was no significant difference between the two bedside methods. We conclude that these two methods of bedside glucose estimation are both highly reliable and accurate and could be used to quickly determine patients' cerebrospinal fluid glucose values.


Radical second resection provides survival benefit for patients with T2 gallbladder carcinoma first discovered after laparoscopic cholecystectomy.
Port site recurrence or peritoneal seeding is a fatal complication following laparoscopic cholecystectomy for gallbladder carcinoma. The aims of this retrospective analysis were to determine the association of gallbladder perforation during laparoscopic cholecystectomy with port site/peritoneal recurrence and to determine the role of radical second resection in the management of gallbladder carcinoma first diagnosed after laparoscopic cholecystectomy. A total of 28 patients undergoing laparoscopic cholecystectomy for gallbladder carcinoma were analyzed, of whom 10 had a radical second resection. Five patients had recurrences; port site/peritoneum recurrence in 3 and distant metastasis in 2. The incidence of port site/peritoneal recurrence was higher in patients with gallbladder perforation (3/7, 43%) than in those without (0/21, 0%) (p = 0.011). The outcome after laparoscopic cholecystectomy was worse in 7 patients with gallbladder perforation (cumulative 5-year survival of 43%) than in those without (cumulative 5-year survival of 100%) (p <0.001). Among 13 patients with a pT2 tumor, the outcome after radical second resection (cumulative 5-year survival of 100%) was better than that after laparoscopic cholecystectomy alone (cumulative 5-year survival of 50%) (p = 0.039), although there was no survival benefit of radical second resection in the 15 patients with a pT1 tumor (p = 0.65). In conclusion, gallbladder perforation during laparoscopic cholecystectomy is associated with port site/peritoneal recurrence and worse patient survival. Radical second resection may be beneficial for patients with pT2 gallbladder carcinoma first discovered after laparoscopic cholecystectomy.


Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent.
Bibenzyls, a kind of important plant polyphenols, have attracted growing attention for their broad and remarkable pharmacological activities. However, due to the low abundance in nature, uncontrollable and environmentally unfriendly chemical synthesis processes, these compounds are not readily accessible. Herein, one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes. Three types of efficiently post-modifying modular strains were engineered by employing methyltransferases, prenyltransferase, and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules. Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes. Especially, a prenylated bibenzyl derivative (12) was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke. RNA-seq, quantitative RT-PCR, and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor, mitochondria associated 3 (Aifm3), suggesting that Aifm3 might be a new target in ischemic stroke therapy. This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery.


[Not Available].
In 1997, large areas in South Poland were affected by a flood of the River Oder. As a immediate measure to support shelterless people living in these areas, simple pavillons were built, which two years later had to be evacuated because of high contamination with moulds. The rate of mould contamination on the walls in interior microclimate and the occurrence of OTA was estimated in two of these pavillions. The air-flow and the moisture were regulated in the experimental rooms where wallpaper was used as the research material. The gypsum cardboards on the walls were also observed. It was found that the moulds were of different species and the number of them was constantly changing irrespective of the accepted configuration of the research position. In every single wallpaper sample OTA was detected. The greatest amount of OTA was found in the pavillions with humidified air. The test of gipsum cardboard walls in pavilions chosen at random, showed an enormous amount of moulds. However, the OTA was not detected.


Mitochondrial respiration is decreased in visceral but not subcutaneous adipose tissue in obese individuals with fatty liver disease.
Adipose tissue dysfunction is involved in the development of insulin resistance and is responsible for excessive lipid delivery to other organs such as the liver. We tested the hypothesis that impaired mitochondrial function is a common feature of subcutaneous (SAT) and visceral adipose tissue (VAT), but may differently contribute to adipose tissue insulin resistance (IR) in obesity, non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). In this cross-sectional study, we analyzed tissue-specific insulin sensitivity using stable isotope dilution and hyperinsulinemic-normoglycemic clamp tests. We also assessed mitochondrial respiration, mRNA and protein expression, and tissue morphology in biopsies of SAT and VAT from obese humans without NAFL, with NAFL or with NASH (n = 22/group). Compared to individuals without liver disease, persons with NAFL and NASH had about 30% (p = 0.010) and 33% (p = 0.002) lower maximal mitochondrial respiration, respectively, in VAT, but not in SAT. The lower maximal mitochondrial respiration of VAT was associated with lower adipose tissue insulin sensitivity (β = 0.985, p = 0.041) and with increased VAT protein expression of tumor necrosis factor A across all groups (β = -0.085, p = 0.040). VAT from individuals with NASH was characterized by lower expression of oxidative phosphorylation complex IV (p = 0.042) and higher mRNA expression of the macrophage marker CD68 (p = 0.002) than VAT from participants without NAFL. Humans with non-alcoholic fatty liver disease have distinct abnormalities of VAT energy metabolism, which correlate with adipose tissue dysfunction and may favor progression of NAFL to NASH. Adipose tissue (commonly called body fat) can be found under the skin (subcutaneous) or around internal organs (visceral). Dysfunction of adipose tissue can cause insulin resistance and lead to excess delivery of fat to other organs such as the liver. Herein, we show that dysfunction specifically in visceral adipose tissue was associated with fatty liver disease. NCT01477957.


Immediate effects of electroacupuncture in oculomotor nerve palsy following brainstem infarction: A case report.
Research has demonstrated that electroacupuncture (EA) stimulation of paralyzed muscles significantly improves nerve regeneration and functional recovery. An 81-year-old man with no history of diabetes mellitus or hypertension presented with a history of brainstem infarction. Initially, the patient had medial rectus palsy in the left eye and diplopia to the right in both eyes, which almost returned to normal after six sessions of EA. The CARE guidelines informed the case study report. The patient was diagnosed with oculomotor nerve palsy (ONP) and photographed to document ONP recovery after treatment. The selected acupuncture points and surgical methods are listed in the table. Pharmacological treatment of oculomotor palsy is not ideal, and its long-term use has side effects. Although acupuncture is a promising treatment for ONP, existing treatments involve many acupuncture points and long cycles, resulting in poor patient compliance. We chose an innovative modality, electrical stimulation of paralyzed muscles, which may be an effective and safe complementary alternative therapy for ONP.


Atlanto-occipital instability as a result of pituitary adenoma: case report with successful management by cervico-occipital fusion.
A 48-year-old woman with an extensive pituitary adenoma developed atlanto-occipital instability secondary to erosion of the base of the skull by the tumor. The pathophysiology, diagnosis and surgical treatment are described.


[Role of intra-operative echography and computed tomography with multiple detectors in the surgery of hepatic metastases: a prospective study].
To study the performance of the intraoperative ecography in the diagnosis of new liver metastases in the era of computerized tomography (CT) with multidetectors and its impact on the surgical operation. Between February 2005 and April 2006 patients with resectable liver metastases where studied prospectively in a multidisciplinary meeting (surgeons, radiologist, oncologist). The preoperative CT findings were compared with the intraoperative findings and ultrasound study and the results of the surgical operation. Forty-five candidates for curative surgery had a total of 171 hepatic lesions. CT correctly detected 115 lesions with a sensitivity of 67%, and a positive predictive value of 97%, with a false negative rate of 33% and false positive rate of 2%. In 5 patients intraoperative findings were the cause of changing the surgical procedure, three patients were unresectable (rate of resectability of 93%) and two patients needed a larger hepatic resection. CT with multidetectors and multidisciplinary meetings are the most important factors in the decision making of surgery of liver metastases with a high resectability rate. Intraoperative ecography is useful for the detection of 10% more liver metastases, but rarely involves a change in the surgical procedure.


Nuclear trafficking of the HIV-1 pre-integration complex depends on the ADAM10 intracellular domain.
Previously, we showed that ADAM10 is necessary for HIV-1 replication in primary human macrophages and immortalized cell lines. Silencing ADAM10 expression interrupted the HIV-1 life cycle prior to nuclear translocation of viral cDNA. Furthermore, our data indicated that HIV-1 replication depends on the expression of ADAM15 and γ-secretase, which proteolytically processes ADAM10. Silencing ADAM15 or γ-secretase expression inhibits HIV-1 replication between reverse transcription and nuclear entry. Here, we show that ADAM10 expression also supports replication in CD4(+) T lymphocytes. The intracellular domain (ICD) of ADAM10 associates with the HIV-1 pre-integration complex (PIC) in the cytoplasm and immunoprecipitates and co-localizes with HIV-1 integrase, a key component of PIC. Taken together, our data support a model whereby ADAM15/γ-secretase processing of ADAM10 releases the ICD, which then incorporates into HIV-1 PIC to facilitate nuclear trafficking. Thus, these studies suggest ADAM10 as a novel therapeutic target for inhibiting HIV-1 prior to nuclear entry.


Multiple Optical Elastography Techniques Reveal the Regulation of Corneal Stiffness by Collagen XII.
Collagen XII plays a role in regulating the structure and mechanical properties of the cornea. In this work, several optical elastography techniques were used to investigate the effect of collagen XII deficiency on the stiffness of the murine cornea. A three-prong optical elastography approach was used to investigate the mechanical properties of the cornea. Brillouin microscopy, air-coupled ultrasonic optical coherence elastography (OCE) and heartbeat OCE were used to assess the mechanical properties of wild type (WT) and collagen XII-deficient (Col12a1-/-) murine corneas. The Brillouin frequency shift, elastic wave speed, and compressive strain were all measured as a function of intraocular pressure (IOP). All three optical elastography modalities measured a significantly decreased stiffness in the Col12a1-/- compared to the WT (P < 0.01 for all three modalities). The optical coherence elastography techniques showed that mean stiffness increased as a function of IOP; however, Brillouin microscopy showed no discernable trend in Brillouin frequency shift as a function of IOP. Our approach suggests that the absence of collagen XII significantly softens the cornea. Although both optical coherence elastography techniques showed an expected increase in corneal stiffness as a function of IOP, Brillouin microscopy did not show such a relationship, suggesting that the Brillouin longitudinal modulus may not be affected by changes in IOP. Future work will focus on multimodal biomechanical models, evaluating the effects of other collagen types on corneal stiffness, and in vivo measurements.


The role of mitochondrial Ca(2+) and NAD(P)H in the control of aldosterone secretion.
The mineralocorticoid hormone aldosterone is synthesized in the zona glomerulosa of the adrenal cortex. Glomerulosa cells respond to the physiological stimuli, elevated extracellular [K(+)] and angiotensin II, with an intracellular Ca(2+) signal. Cytosolic Ca(2+) facilitates the transport of the steroid-precursor cholesterol to mitochondria and, after a few hours, it also induces the transcription of aldosterone synthase. Therefore, the cytosolic Ca(2+) signal is regarded as the most important short and long-term mediator of aldosterone secretion. However, cytosolic Ca(2+) is also taken up by mitochondria and, in turn, the mitochondrial Ca(2+) response activates mitochondrial dehydrogenases resulting in stimulation of respiration and increase in reduced pyridine nucleotides. Since both cholesterol side-chain cleavage and all of the hydroxylation steps of steroid synthesis require NADPH as a cofactor, the importance of cytosolic Ca(2+) - mitochondrial Ca(2+) coupling and of appropriate NADPH supply in respect to hormone production can be assumed. However, the importance of the mitochondrial factors has been neglected so far. Here, after summarizing earlier findings we provide new results obtained through modifying mitochondrial Ca(2+) uptake by knocking down p38 MAPK or OPA1 and overexpressing S100G, supporting the notion that mitochondrial Ca(2+) and reduced pyridine nucleotides are facilitating factors for both basal and stimulated steroid production.


A new meta-module design for efficient reconfiguration of modular robots.
We propose a new meta-module design for two important classes of modular robots. The new meta-modules are three-dimensional, robust and compact, improving on the previously proposed ones. One of them applies to so-called edge-hinged modular robot units, such as M-TRAN, SuperBot, SMORES, UBot, PolyBot and CKBot, while the other one applies to so-called central-point-hinged modular robot units, which include Molecubes and Roombots. The new meta-modules use the rotational degrees of freedom of these two types of robot units in order to expand and contract, as to double or halve their length in each of the two directions of its three dimensions, therefore simulating the capabilities of Crystalline and Telecube robots. Furthermore, in the edge-hinged case we prove that the novel meta-module can also perform the scrunch, relax and transfer moves that are necessary in any tunneling-based reconfiguration algorithm for expanding/contracting modular robots such as Crystalline and Telecube. This implies that the use of meta-meta-modules is unnecessary, and that currently existing efficient reconfiguration algorithms can be applied to a much larger set of modular robots than initially intended. We also prove that the size of the new meta-modules is optimal and cannot be further reduced. The online version supplementary material available at 10.1007/s10514-021-09977-6.


Lewis acid-catalyzed biphasic 2-methyltetrahydrofuran/H2O pretreatment of lignocelluloses to enhance cellulose enzymatic hydrolysis and lignin valorization.
Lewis acid-catalyzed pretreatment in a biphasic system consisting of bio-based solvent 2-methyltetrahydrofuran (2-MeTHF) and water for a highly integrated one-pot catalytic transformation of lignocelluloses have been achieved. The aim of this work was to study the effects of different Lewis acid catalysts and pretreatment temperatures on the structural characteristics of precipitated lignin and enzymatic hydrolysis of the pretreated substrates, as well as the quantitative analysis of precipitates, solid residues, soluble carbohydrates and inhibitors. After the AlCl3-catalyzed biphasic 2-MeTHF/H2O pretreatment at 180 °C, its maximum cellulose conversion rate was enhanced by 7.4-fold as compared to the raw material. The precipitated lignin exhibited the representative structure, relatively low molecular weight and high purity for preparing value-added aromatic chemicals or renewable polymers. Overall, AlCl3-catalyzed biphasic 2-MeTHF/H2O pretreatment may offer a promising approach for enhancing enzymatic hydrolysis and obtaining valorized lignin by-product.


Novel synthesis of nitro-quinoxalinone derivatives as aldose reductase inhibitors.
A novel, non-acid series of nitroquinoxalinone derivatives was synthesized and tested for their inhibitory activity against aldose reductase as targeting enzyme. All active compounds displayed an 8-nitro group, and showed significant activity in IC50 values ranging from 1.54 to 18.17 μM. Among them 6,7-dichloro-5,8-dinitro-3-phenoxyquinoxalin-2(1H)-one (7e), exhibited the strongest aldose reductase activity with an IC50 value of 1.54 μM and a good SAR (structure-activity relationship) profile.


The prostatic specific antigen era is alive and well: prostatic specific antigen and biochemical progression following radical prostatectomy.
Prostate specific antigen (PSA) has been shown to predict the presence of prostate cancer on biopsy, pathological stage, and biochemical progression following primary therapy. A recent study found only a weak association between PSA and tumor volume in the radical prostatectomy (RP) specimen and concluded that the PSA era is over. We examined the association between PSA and clinical progression in men undergoing RP. The study population consisted of 2,312 men treated with RP between 1992 and 2004 by a single surgeon. We evaluated the association between preoperative PSA and biochemical progression on multivariate analysis. Men with higher preoperative PSA concentrations had higher grade cancers in the biopsy and RP specimen, and more adverse pathological features. After adjusting for the clinical covariates of age, race, grade, stage, and year of surgery, preoperative PSA was significantly associated with the risk of biochemical progression. When only men with PSA less than 10 ng/ml were examined, PSA remained a significant predictor of biochemical progression on multivariate analysis (RR 1.30, 95% CI 1.18 to 1.44, p <0.001). For each 2-point increase in PSA, the risk of biochemical progression increased approximately 2-fold. Preoperative PSA was significantly associated with high grade disease and adverse pathological findings. After adjusting for clinical covariates, PSA was significantly associated with the risk of biochemical progression, even in men with PSA less than 10 ng/ml. Despite multiple limitations, PSA remains the best prostate cancer tumor marker available.


A pilot study using proximity extension assay of cerebrospinal fluid and its extracellular vesicles identifies novel amyotrophic lateral sclerosis biomarker candidates.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder which is characterized by progressive degeneration of the motor system. Typically, the disease starts with focal weakness which spreads to involve most muscles and leads to death from respiratory failure within five years of diagnosis. Due to the heterogenic nature of the disease, diagnostics is complex, and it generally takes twelve months from symptom-onset to diagnosis. The discovery of novel biomarkers could lead to accelerated diagnosis, earlier start of treatment, improved patient-segmentation, and treatment follow-up as well as an increased insight into the pathology. Here, we analyzed cerebrospinal fluid (CSF) and CSF-derived extracellular vesicles (CSF-EVs) from ALS-patients and matched controls (n = 9 each) using the ultra-sensitive proximity extension assay (PEA), cardiovascular III-panel. On average, 84 and 61 proteins could be detected in CSF and CSF-EVs respectively. In CSF, three proteins were significantly upregulated in ALS-patients (Junctional Adhesion Molecule A Protein, Tumor necrosis factor receptor 2 and Chitinase 1) while myoglobin was down-regulated. In CSF-EVs, no significantly differentially expressed proteins were identified, but there was a trend for downregulation of Perlecan. To our knowledge, only CHIT1 has been previously described as a CSF-based biomarker candidate for ALS. By combining the four differentially expressed markers in CSF and support vector machine algorithm, all ALS patients and 8 of 9 controls were correctly classified. In conclusion, we here demonstrate the feasibility of using PEA of CSF and CSF-EVs for biomarker discovery and propose three de novo biomarker candidates for ALS, however, further studies are necessary to demonstrate clinical usability.


Progastrin and its glycine-extended posttranslational processing intermediates in human gastrointestinal tissues.
We examined the posttranslational modification of gastrin in human gastrointestinal and Zollinger-Ellison tumor tissues using antibodies specific for progastrin and its glycine-extended processing intermediates. Gel filtration of antral and duodenal extracts on Sephadex G-50 revealed multiple molecular forms of immunoreactive glycine-extended processing intermediates corresponding to known molecular forms of gastrin and cholecystokinin. Immunoaffinity chromatography studies of antral mucosal and gastrinoma extracts identified a molecular form of glycine-extended processing intermediates that was characterized by an amino terminus identical to that of gastrin heptadecapeptide. Large differences in the relative contents of precursors and products of gastrin synthesis were found in gastrinoma tissue as compared to gastrointestinal mucosal extracts. These studies suggest the potential importance of glycine-extended peptides as intermediates in the posttranslational processing of gastrin and cholecystokinin in humans and indicate that gastrin processing mechanisms may be altered in Zollinger-Ellison tumors.


Obestatin: its physicochemical characteristics and physiological functions.
Obestatin, a novel 23 amino acid amidated peptide encoded by the same gene with ghrelin, was initially reported to reduce food intake, body weight gain, gastric emptying and suppress intestinal motility through an interaction with the orphan receptor GPR39. However, recently reports have shown that above findings had been questioned by several groups. Further studies explained that obestatin was involved in inhibiting thirst and anxiety, improving memory, regulating sleep, affecting cell proliferation, and increasing the secretion of pancreatic juice enzymes. We also identified that obestatin could stimulate piglet liver and adipose cell proliferation, and inhibit the secretion of IGF-I. According to the controversy over the effects and the cognate ligand of obestatin, here we provide the latest review on the structure, distribution and physiological functions of obestatin.


Comparative study of the effect of baicalin and its natural analogs on neurons with oxygen and glucose deprivation involving innate immune reaction of TLR2/TNFα.
This work is to study the baicalin and its three analogs, baicalin, wogonoside, and wogonin, on the protective effect of neuron from oxygen-glucose deprivation (OGD) and toll-like receptor 2 (TLR2) expression in OGD damage. The results showed that baicalin and its three analogs did protect neurons from OGD damage and downregulated protein level of TLR2. D-Glucopyranosiduronic acid on site 7 in the structure played a core of cytotoxicity of these flavonoid analogs. The methoxyl group on carbon 8 of the structure had the relation with TLR2 protein expression, as well as the anti-inflammation. In addition, we detected caspase3 and antioxidation capability, to investigate the effect of four analogs on cell apoptosis and total antioxidation competence in OGD model.


N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: randomized, double-blind, placebo-controlled trial.
N-acetylcysteine (NAC) has been proposed as a potential therapy for obsessive-compulsive disorder (OCD) as it may regulate the exchange of glutamate and prevent its pre-oxidant effects. The aim of the present double-blind, placebo-controlled trial was to assess the efficacy and tolerability of NAC augmentation in moderate-to-severe (OCD) treatment. In this randomized, double-blind, two-centre, placebo-controlled, 10-week trial, patients with moderate-to-severe OCD were enrolled. Patients were randomized into two parallel groups to receive fluvoxamine (200 mg daily) plus placebo or fluvoxamine (200 mg daily) plus NAC (2000 mg daily). A total of 44 patients (22 in each group) were visited to evaluate response to therapy using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) at baseline, and at weeks 4, 8 and 10. Side effects were recorded using predesigned checklists upon each visit. Repeated-measures ANOVA showed a significant effect for time × treatment interaction (Greenhouse-Geisser corrected: F = 5·14, d.f. = 1·64, P = 0·012) in the Y-BOCS total score and a significant effect for time × treatment interaction (Greenhouse-Geisser corrected: F = 5·44, d.f. = 1·54, P = 0·011) in the Y-BOCS obsession subscale between the two groups. Our results showed that NAC might be effective as an augmentative agent in the treatment of moderate-to-severe OCD. Iranian Registry of Clinical Trials (www.irct.ir): IRCT201405271556N60.


Conversion, shrinkage, water sorption, flexural strength and modulus of re-mineralizing dental composites.
Cure, volumetric changes and mechanical properties were assessed for new dental composites containing chlorhexidine (CHX) and reactive calcium phosphate-containing (CaP) to reduce recurrent caries. 20wt.% of light curable urethane dimethacrylate based liquid was mixed with 80wt.% glass filler containing 10wt.% CHX and 0-40wt.% CaP. Conversion versus depth with 20 or 40s light exposure was assessed by FTIR. Solidification depth and polymerization shrinkage were determined using ISO 4049 and 17304, respectively. Subsequent volume expansion and biaxial flexural strength and modulus change upon water immersion were determined over 4 weeks. Hydroxyapatite precipitation in simulated body fluid was assessed at 1 week. Conversion decreased linearly with both depth and CaP content. Average solidification depths were 4.5, 3.9, 3.3, 2.9 and 5.0 with 0, 10, 20, and 40% CaP and a commercial composite, Z250, respectively. Conversions at these depths were 53±2% for experimental materials but with Z250 only 32%. With Z250 more than 50% conversion was achieved only below 1.1mm. Shrinkage was 3% and 2.5% for experimental materials and Z250, respectively. Early water sorption increased linearly, whilst strength and modulus decreased exponentially to final values when plotted versus square root of time. Maximum volumetric expansion increased linearly with CaP rise and balanced shrinkage at 10-20wt.% CaP. Strength and modulus for Z250 decreased from 191 to 158MPa and 3.2 to 2.5GPa. Experimental composites initial strength and modulus decreased linearly from 169 to 139MPa and 5.8 to 3.8GPa with increasing CaP. Extrapolated final values decreased from 156 to 84MPa and 4.1 to 1.7GPa. All materials containing CaP promoted hydroxyapatite precipitation. The lower surface of composite restorations should both be solid and have greater than 50% conversion. The results, therefore, suggest the experimental composite may be placed in much thicker layers than Z250 and have reduced unbounded cytotoxic monomer. Experimental materials with 10-20wt.% additionally have volumetric expansion to compensate shrinkage, antibacterial and re-mineralizing components and competitive mechanical properties.


Uncertainty risks and strategic reaction of restaurant firms amid COVID-19: Evidence from China.
To contain the pandemic of coronavirus (COVID-19), social distancing, self-isolation and travel restrictions have been imposed globally. To shed light on how COVID-19 is affecting restaurant industry, this study aims to explore the factors that affect restaurant firms' financial turnaround for their sustainability after the business shutdowns amid the COVID-19 pandemic. By utilizing a total of 86,507 small- and medium-sized restaurant firms' sales data collected from nine cities in Mainland China, the exploratory approach of this study successfully determines positive impacts of three aspects of operational characteristics (i.e., delivery, discounts, and service type) and brand effects as uncertainty minimizing factors amid distinctive business shutdowns and restrictions. This is the first empirical study in the management realm on the impacts of COVID-19 on restaurant industry. This paper strengthens the extant literature by highlighting the impact of COVID-19 on the restaurant industry after the business restrictions are lifted.


Low-dose non-enhanced CT versus full-dose contrast-enhanced CT in integrated PET/CT scans for diagnosing ovarian cancer recurrence.
To evaluate low-dose non-enhanced CT (ldCT) and full-dose contrast-enhanced CT (ceCT) in integrated 18F-fluorodeoxyglucose (FDG)-PET/CT studies for restaging of ovarian cancer. One hundred and twenty women who had undergone treatment for ovarian cancer underwent a conventional PET/CT scans with ldCT, and then ceCT. Two observers interpreted and decided in consensus on the PET/ldCT and PET/ceCT images by a 3-point scale (N: negative, E: equivocal, P: positive) per patient and lesion site. Final diagnoses were obtained by histopathological examinations, or clinical follow-up for at least 6 months. Patient-based analysis showed that the sensitivity, specificity, and accuracy of PET/ceCT was 86.9% (40/46), 95.9% (71/74), and 92.5% (111/120), respectively, whereas those of PET/ldCT were 78.3% (36/46), 95.0% (70/74), and 88.3% (106/120), respectively. All sensitivity, specificity, and accuracy significantly differed between two methods (McNemar test, p<0.0005, p=0.023, and p<0.0001, respectively). The scales of detecting 104 recurrent lesion sites were N:14, E:6, P:84 for PET/ceCT, and N:15, E:17, P:72 for PET/ldCT, respectively. Eleven equivocal and one negative regions by PET/ldCT were correctly interpreted as positive by PET/ceCT. PET/ceCT is a more accurate imaging modality with higher confidence for assessing ovarian cancer recurrence than PET/ldCT.


Exploratory and confirmatory factor analyses of the Brief Symptom Inventory among substance abusers.
The Brief Symptom Inventory (BSI) is a multidimensional measure of psychological and somatic distress that is used to obtain detailed symptom profiles. The BSI has been questioned regarding its ability to differentiate among its proposed nine dimensions, and the factor structure underlying the BSI has not been confirmed with substance abusers. Exploratory factor analyses were completed on substance abusers (ntotal = 453; nwomen = 121; nmen = 332); nine factors were not identified. Five models were then submitted to confirmatory factor analyses using an independent sample of substance abusers (ntotal = 456; nwomen = 127; nmen = 329). A one-factor model (i.e., global psychological distress) best represented the data. Implications for using the BSI in research and counseling are discussed.


Osteonectin--a differentiation marker of bone cells.
Bone matrix consists of type-I collagen and non-collagenous proteins. The latter represent only 10% of its total protein content. Since type-I collagen is also present in various other connective tissue sites (e.g., skin) it cannot be considered as bone specific. Among the non-collagenous components osteonectin--a 32 kilodalton (KD) glycoprotein linking mineral to collagen fibrils--is thought to be bone specific due to its biochemical properties. In the present study various skeletal and non-skeletal tissues were investigated for the presence of osteonectin by means of immunocytochemical methods. Two polyclonal antibodies against human and bovine osteonectin were applied. Immunocytochemically, osteonectin could be demonstrated in active osteoblasts and osteoprogenitor cells as well as in young osteocytes, while aged, quiescent osteocytes did not contain the protein, suggesting that the protein is a marker of the osteoblastic functional differentiation of bone cells. Osteonectin was absent in all non-skeletal tissues with the exception of chondrocytes in so-called mineralizing chondroid bone.


A precise and time-saving method of setting up an indirectly bonded retainer.
A lingual retainer characterized by precise fit and minimum tissue damage is presented. Experience based on the use of 94 retainers is reported and the reasons for failure discussed.


The Epidemiology of Respiratory Syncytial Virus in New York City during the Coronavirus Disease-2019 Pandemic Compared with Previous Years.
Fewer respiratory syncytial virus infections were observed in 2020-2021 with interseasonal resurgence. Children were more likely to have severe disease with less known risk factors in comparison with controls from 2018-2019. The overall codetection rates were similar, but with higher parainfluenza, rhinovirus/enterovirus, and lower influenza proportions compared with previous seasons.


Late effects of cancer in children, teenagers and young adults: Population-based study on the burden of 183 conditions, in-patient and critical care admissions and years of life lost.
Children, teenagers and young adults who survived cancer are prone to developing late effects. The burden of late effects across a large number of conditions, in-patient hospitalisation and critical care admissions have not been described using a population-based dataset. We aim to systematically quantify the cumulative burden of late effects across all cancer subtypes, treatment modalities and chemotherapy drug classes. We employed primary care records linked to hospitals, the death registry and cancer registry from 1998-2020. CTYA survivors were 25 years or younger at the time of cancer diagnosis had survived ≥5 years post-diagnosis. Year-of-birth and sex-matched community controls were used for comparison. We considered nine treatment types, nine chemotherapy classes and 183 physical and mental health late effects. Cumulative burden was estimated using mean cumulative count, which considers recurring events. Multivariable logistic regression was used to investigate the association between treatment exposures and late effects. Excess years of life lost (YLL) attributable to late effects were estimated. Among 4,063 patients diagnosed with cancer, 3,466 survived ≥ 5 years (85%); 13,517 matched controls were identified. The cumulative burden of late effects at age 35 was the highest in survivors of leukaemia (23.52 per individual [95% CI:19.85-29.33]) and lowest in survivors of germ cell tumours (CI:6.04 [5.32-6.91]). In controls, the cumulative burden was 3.99 (CI:3.93-4.08) at age 35 years. When survivors reach age 45, the cumulative burden for immunological conditions and infections was the highest (3.27 [CI:3.01-3.58]), followed by cardiovascular conditions (3.08 [CI:1.98-3.29]). Survivors who received chemotherapy and radiotherapy had the highest disease burden compared to those who received surgery only. These patients also had the highest burden of hospitalisation (by age 45: 10.43 [CI:8.27-11.95]). Survivors who received antimetabolite chemotherapy had the highest disease and hospitalisation burden, while the lowest burden is observed in those receiving antitumour antibiotics. Regression analyses revealed that survivors who received only surgery had lower odds of developing cardiovascular (adjusted odds ratio 0.73 [CI:0.56-0.94]), haematological (aOR 0.51 [CI:0.37-0.70]), immunology and infection (aOR 0.84 [CI:0.71-0.99]) and renal (aOR 0.51 [CI:0.39-0.66]) late effects. By contrast, the opposite trend was observed in survivors who received chemo-radiotherapy. High antimetabolite chemotherapy cumulative dose was associated with increased risks of subsequent cancer (aOR 2.32 [CI:1.06-4.84]), metastatic cancer (aOR 4.44 [CI:1.29-11.66]) and renal (aOR 3.48 [CI:1.36-7.86]) conditions. Patients who received radiation dose of ≥50 Gy experienced higher risks of developing metastatic cancer (aOR 5.51 [CI:2.21-11.86]), cancer (aOR 3.77 [CI:2.22-6.34]), haematological (aOR 3.43 [CI:1.54-6.83]) and neurological (aOR 3.24 [CI:1.78-5.66]) conditions. Similar trends were observed in survivors who received more than three teletherapy fields. Cumulative burden analyses on 183 conditions separately revealed varying dominance of different late effects across cancer types, socioeconomic deprivation and treatment modalities. Late effects are associated with excess YLL (i.e., the difference in YLL between survivors with or without late effects), which was the most pronounced among survivors with haematological comorbidities. To our knowledge, this is the first study to dissect and quantify the importance of late morbidities on subsequent survival using linked electronic health records from multiple settings. The burden of late effects is heterogeneous, as is the risk of premature mortality associated with late effects. We provide an extensive knowledgebase to help inform treatment decisions at the point of diagnosis, future interventional trials and late-effects screening centred on the holistic needs of this vulnerable population.


Development of the Communication and Acceptance Scale (CAS) for group aural rehabilitation.
The aim of the current study was to develop a reliable instrument for the Active Communication Education (ACE) programme evaluating changes in communication strategies and the emotional consequences, knowledge and acceptance of hearing loss and to examine its reliability and face, content and construct validity. Semistructured interviews and questionnaires were conducted with participants and clinicians engaged in the ACE intervention. The psychometric properties were evaluated in two phases for two samples of adults with hearing loss who participated in the ACE programme, including 61 and 41 participants, respectively. The final Communication and Acceptance Scale (CAS) contained 18 items, and the reliability of the overall scale (Cronbach's alpha 0.86) and the test-retest reliability (r = 0.89, p < 0.001) were good. The construct validity, evaluated with principal component analysis, suggested a five-factor solution explaining 72% of the variance. The questionnaire revealed statistically significant short- and long-term effects of the ACE programme. Both participants and clinicians found the questionnaire relevant, useful and easy to administer. The CAS questionnaire was found to be valid and reliable, but because of the low sample size, further analysis with a larger population is needed.


Effect of occlusal coverage depths on the precision of 3D-printed orthognathic surgical splints.
Precise orthognathic surgical splints are important in surgical-orthodontic treatment. This study aimed to propose a standardized protocol for three-dimensional (3D)-printed splints and assess the precision of splints with different occlusal coverage on the dentition (occlusal coverage depth, OCD), thus optimizing the design of 3D-printed splints to minimize the seemingly unavoidable systematic errors. Resin models in optimal occlusion from 19 patients were selected and scanned. Intermediate splints (ISs) and final splints (FSs) with 2-mm, 3-mm, 4-mm, and 5-mm OCDs were fabricated and grouped as IS-2, IS-3, IS-4, IS-5, FS-2, FS-3, FS-4, and FS-5, respectively. The dentitions were occluded with each splint and scanned as a whole to compare with the original occlusion. Translational and rotational deviations of the lower dentition and translational deviations of the landmarks were measured. For vertical translation, the lower dentitions translated inferiorly to the upper dentition in most of the splints, and the translation increased as OCD got larger. Vertical translations of the dentitions in 89.47% of IS-2, 68.42% of IS-3, 42.11% of IS-4, 10.53% of IS-5, 94.74% of FS-2, 63.16% of FS-3, 26.32% of FS-4, and 21.05% of FS-5 splints were below 1 mm, respectively. For pitch rotation, the lower dentitions rotated inferiorly and posteriorly in most groups, and the rotation increased as OCD got larger. Pitch rotations of the dentitions in 100% of IS-2, 89.47% of IS-3, 57.89% of IS-4, 52.63% of IS-5, 100.00% of FS-2, 78.95% of FS-3, 52.63% of FS-4, and 47.37% of FS-5 splints were below 2°, respectively. On the other hand, the transversal and sagittal translations, roll and yaw rotations of most groups were clinically acceptable (translation < 1 mm and rotation < 2°). The deviations of ISs and FSs showed no statistical significance at all levels of coverage (P > 0.05). A protocol was proposed to generate 3D-printed ISs and FSs with normalized basal planes and standardized OCDs. Deviations of the ISs and FSs were more evident in the vertical dimension and pitch rotation and had a tendency to increase as the OCD got larger. ISs and FSs with both 2-mm and 3-mm OCD are recommendable regarding the precision relative to clinical acceptability. However, considering the fabrication, structural stability, and clinical application, ISs and FSs with 3-mm OCD are recommended for accurate fitting.


Expression of bcl-2 oncoprotein in Indian oral squamous cell carcinomas.
Thirty-nine oral squamous cell carcinomas were assessed for bcl-2 protein expression by immunostaining of tumour sections. Twenty-three per cent of these tumours showed strong nuclear staining for bcl-2 protein. Tumours of the cheek and tongue together accounted for 77% of overexpression of this protein. When bcl-2 expression was compared with p53 expression, they were found to be non-overlapping. These results suggest that overexpression of either of these genes may substitute each other in the development of oral carcinomas of Indians.


A Dielectric Elastomer Actuator That Can Self-Heal Integrally.
Dielectric actuators are prone to be worn or partially damaged when operating at high electric fields. The introduction of self-healing features into dielectric actuators is favorable for extending its life span and security. Although many attempts have been made to produce self-healing dielectric actuators, most of them focus on the healing of either the electrodes or the dielectric layers. A dielectric actuator that exhibits integral self-healing is still unprecedented. Meanwhile, realizing integral self-healing in dielectric actuator is highly challenging because both the electrode and the dielectric layer need to be healed while the interface between the electrode and the dielectric layer should remain unaffected during the healing process. In this paper, we synthesized self-healing polydimethylsiloxane (PDMS) polymers containing different amounts of polyaniline (PANI) (denoted as PDMS-PANIn, where n represents the weight percentage of PANI) as the dielectric layer and electrode, respectively. PDMS-PANI2.5 polymer exhibits good dielectric properties (ε = 11.11 at 50 Hz) and was used as the dielectric layer, while PDMS-PANI20 polymer having a high conductivity of 4.5 × 10-5 S/cm was used as the electrode. As both of them have excellent self-healing ability and are compatible and diffusible to each other, the entire actuator device can still cause actuated strain after cutting and healing at room temperature for 48 h. Our strategy for realizing integral self-healing of actuator is also applicable to other electronic devices.


Immunocytochemical investigation of alpha-fetoprotein-positive cells in hepatocarcinogenesis and hepatomas induced by 3'-ME-DAB.
AFP-positive cells during 3'-Me-DAB hepatocarcinogenesis and in hepatomas induced by 3'-Me-DAB were observed by the light microscope immunoperoxidase method, and the location of AFP-immunoreaction products in hepatocytes was determined by the electron microscope immunoperoxidase method. Simultaneously serum concentrations of AFP were measured by radioimmunoassay. Serum concentrations of AFP during hepatocarcinogenesis showed a biphasic pattern, and proliferation of cholangiolar cells in the periportal areas was associated with the first peak of serum AFP in the early stage of hepatocarcinogenesis. AFP-containing cells in the late stage were distributed in clusters in the peripheral areas of hyperplastic nodules. The clusters were composed of two different types of AFP-positive cells, one atypical in shape and structure and the other preserving the structure of hepatic cords. In neoplasms, a heterogeneous AFP immunoreaction was recognized in hepatoma cells. In non-neoplastic nodules, cholangiofibrosis surrounded by AFP-positive cholangiolar cells developed. Ultrastructural immunoperoxidase studies revealed immunoreaction products of AFP on the membrane of r-ER, outer nuclear membrane, s-ER and Golgi complex in hepatocytes of hyperplastic nodules as well as of hepatocellular carcinoma cells. It is suggested that cholangiolar cells detected in hepatocarcinogenesis may form proliferating bile ductules, and the appearance of a cluster in association with AFP in hyperplastic nodules supports the hypothesis that some hyperplastic nodules with clusters of AFP-positive cells are important cell populations which may develop into hepatocellular carcinoma.