Diabetes mellitus and accompanying hyperlipidemia are independent risk factors for adhesive capsulitis: a nationwide population-based cohort study (version 2).
Previous case-control studies of Caucasian ethnicity have reported the association of adhesive capsulitis (AC) with diabetes mellitus (DM). To further investigate the risk of AC in subjects with DM in an Asian population, we performed the present cohort study featured the analyses of a randomly selected sub-dataset of one million individuals insured by the Taiwan National Health Insurance for the period spanning 1996-2008. The study and comparison cohorts consisted of 5,109 newly diagnosed diabetic patients and 20,473 randomly selected non-diabetic subjects aged ≥ 20 years in the year 2000. Both cohorts were followed up until December 2008 to measure AC incidence. We found that the incidence density of AC in the DM cohort was 3.08 times that of the comparison cohort (146.9 vs. 47.7 per 10,000 person-years), and rate ratios varied from 1.23 to 4.98 by categorized sociodemographic factors and comorbidity. The hazard ratio (HR) of AC for DM subjects remained significantly higher than that for non-DM subjects (p < 0.001) in all models. The HR increased in older age-groups (p < 0.001) and females (p < 0.001). Hyperlipidemia consistently increases the risk of AC in both univariate (HR = 2.67, 95% confidence interval (CI) 2.36-4.06) and multivariate analyses (HR = 1.29, 95% CI 1.11-1.49). In this eight-year study period, we found that DM and accompanying hyperlipidemia were independent risk factors for AC. The risks are higher for older-aged women. Findings in the present study help to identify high-risk patient groups to exercise early prevention of AC and enhance comprehensive care quality of DM subjects.


Cluster analysis in kinetic modelling of the brain: a noninvasive alternative to arterial sampling.
In emission tomography, quantification of brain tracer uptake, metabolism or binding requires knowledge of the cerebral input function. Traditionally, this is achieved with arterial blood sampling. We propose a noninvasive alternative via the use of a blood vessel time-activity curve (TAC) extracted directly from dynamic positron emission tomography (PET) scans by cluster analysis. Five healthy subjects were injected with the 5HT(2A)-receptor ligand [(18)F]-altanserin and blood samples were subsequently taken from the radial artery and cubital vein. Eight regions-of-interest (ROI) TACs were extracted from the PET data set. Hierarchical K-means cluster analysis was performed on the PET time series to extract a cerebral vasculature ROI. The number of clusters was varied from K = 1 to 10 for the second of the two-stage method. Determination of the correct number of clusters was performed by the 'within-variance' measure and by 3D visual inspection of the homogeneity of the determined clusters. The cluster-determined input curve was then used in Logan plot analysis and compared with the arterial and venous blood samples, and additionally with one of the currently used alternatives to arterial blood sampling, the Simplified Reference Tissue Model (SRTM) and Logan analysis with cerebellar TAC as an input. There was a good agreement (P < 0.05) between the values of Distribution Volume (DV) obtained from the K-means-clustered input function and those from the arterial blood samples. This work acts as a proof-of-principle that the use of cluster analysis on a PET data set could obviate the requirement for arterial cannulation when determining the input function for kinetic modelling of ligand binding, and that this may be a superior approach as compared to the other noninvasive alternatives.


A retrospective and prospective look at medical education in the United States: trends shaping anatomical sciences education.
During the last decade of the 20th century and the first decade of the 21st century, curricular reform has been a popular theme. In fact, reform on the current scale has not occurred since the early 1900s, when Abraham Flexner released his landmark report 'Medical Education in the United States and Canada'. His report, suggesting major changes in how physicians were educated, became the norm and few changes occurred until the last quarter of the 20th century. During this period increased demands on medical school curriculums due to the explosion of knowledge in biomedical sciences and the pressure to add additional clinical experiences increased the momentum for curriculum reform. In 1984 an Association of American Medical Colleges (AAMC) report, 'Physicians for the Twenty-First Century: The Report of the Panel on the General Professional Education of the Physician (GPEP) and College Preparation for Medicine', discussed many items related to reforming medical education including the value of integration, increased use of active learning formats, more self-directed learning, improved communication skills and increased problem-solving activities. This was followed by a report released in 1993 entitled 'Educating Medical Students: Assessing Change in Medical Education - The Road to Implementation' (ACME-TRI), which identified educational problems by surveying medical school deans, suggested ways to deal with these issues and presented a plan of action. Recently, the Carnegie Foundation for the Advancement of Teaching released 'Education Physicians: A Call for Reform of Medical School and Residency' with additional suggestions. At this point the question that might be asked is - Where is all this going and how is it going to affect anatomy education?


Effects of various amino acids as organic nitrogen sources on the growth and biochemical composition of Chlorella pyrenoidosa.
This study investigated the effects of eighteen l-amino acids on the growth and biochemical composition of Chlorella pyrenoidosa. Under the nitrate deficiency condition, ten l-amino acids were found to exert stronger stimulative effects on the algal growth than the other amino acids. After 10-day culture, addition of 0.5gL(-1) the above mentioned ten amino acids significantly increased the cellular protein contents by 441.3-110.8%, respectively, and significantly decreased the carbohydrate contents by 60.7-16.2%, respectively. Under the normal nitrate condition, the cellular biochemical composition was not significantly affected by addition of serine, leucine, proline, aspartic acid, asparagine, and glycine, whereas addition of aspartic acid and arginine increased the algal biomass by 110.2% and 62.8% compared with the control. Finally, the significance of this work in the biotechnological application of culturing C. pyrenoidosa in organic wastewater rich in amino acids was further discussed.


Stability of acetal and non acetal-type analogs of artemisinin in simulated stomach acid.
A series of non acetal-type analogs of artemisinin containing C-C bond at position-12 have been found to be 15-22 times more stable than acetal(C-O)-type prodrugs of artemisinin in simulated stomach acid.


CD44 regulates vascular endothelial barrier integrity via a PECAM-1 dependent mechanism.
Vascular integrity is a critical parameter in normal growth and development. Loss of appropriate vascular barrier function is present in various immune- and injury-mediated pathological conditions. CD44 is an adhesion molecule expressed by multiple cell types, including endothelial cells (EC). The goal of the present study was to examine how loss of CD44 affected vascular permeability. Using C57BL/6 WT and CD44-KO mice, we found no significant permeability to Evan's Blue in either strain at baseline. However, there was significantly increased histamine-induced permeability in CD44-deficient mice compared to WT counterparts. Similar results were observed in vitro, where CD44-deficient endothelial monolayers were also impermeable to 40kD-FITC dextran in the absence of vasoactive challenge, but exhibited enhanced and prolonged permeability following histamine. However, CD44-KO monolayers have reduced baseline barrier strength by electrical resistance, which correlated with increased permeability, at baseline, to smaller molecular weight 4-kD FITC-dextran, suggesting weakly formed endothelial junctions. The CD44-KO EC displayed several characteristics consistent with impaired barrier function/dysfunctional EC junctions, including differential expression, phosphorylation, and localization of endothelial junction proteins, increased matrix metalloprotease expression, and altered cellular morphology. Reduced platelet endothelial cell adhesion molecule-1 (PECAM-1) expression by CD44-KO EC in vivo and in vitro was also observed. Reconstitution of murine CD44 or PECAM-1 restored these defects to near WT status, suggesting CD44 regulates vascular permeability and integrity through a PECAM-1 dependent mechanism.


Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis.
Ferroptosis, a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. In this study, we found that activating mutation of phosphatidylinositol 3-kinase (PI3K) or loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function, highly frequent events in human cancer, confers ferroptosis resistance in cancer cells, and that inhibition of the PI3K-AKT-mTOR signaling axis sensitizes cancer cells to ferroptosis induction. Mechanistically, this resistance requires sustained activation of mTORC1 and the mechanistic target of rapamycin (mTOR)C1-dependent induction of sterol regulatory element-binding protein 1 (SREBP1), a central transcription factor regulating lipid metabolism. Furthermore, stearoyl-CoA desaturase-1 (SCD1), a transcriptional target of SREBP1, mediates the ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids. Genetic or pharmacologic ablation of SREBP1 or SCD1 sensitized ferroptosis in cancer cells with PI3K-AKT-mTOR pathway mutation. Conversely, ectopic expression of SREPB1 or SCD1 restored ferroptosis resistance in these cells, even when mTORC1 was inhibited. In xenograft mouse models for PI3K-mutated breast cancer and PTEN-defective prostate cancer, the combination of mTORC1 inhibition with ferroptosis induction resulted in near-complete tumor regression. In conclusion, hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with ferroptosis induction shows therapeutic promise in preclinical models.


Embryonic developmental process and clinical anatomy of the preperitoneal fascia and its clinical significance.
Many researchers have different views on the origin and anatomy of the preperitoneal fascia. The purpose of this study is to review studies on the anatomy related to the preperitoneal fascia and to investigate the origin, structure, and clinical significance of the preperitoneal fascia in conjunction with previous anatomical findings of the genitourinary fascia, using the embryogenesis of the genitourinary system as a guide. Publications on the preperitoneal and genitourinary fascia are reviewed, with emphasis on the anatomy of the preperitoneal fascia and its relationship to the embryonic development of the genitourinary organs. We also describe previous anatomical studies of the genitourinary fascia in the inguinal region through the fixation of formalin-fixed cadavers. Published literature on the origin, structure, and distribution of the preperitoneal fascia is sometimes inconsistent. However, studies on the urogenital fascia provide more than sufficient evidence that the formation of the preperitoneal fascia is closely related to the embryonic development of the urogenital fascia and its tegument. Combined with previous anatomical studies of the genitourinary fascia in the inguinal region of formalin-fixed cadavers showed that there is a complete fascial system. This fascial system moves from the retroperitoneum to the anterior peritoneum as the preperitoneal fascia. We can assume that the preperitoneal fascia (PPF) is continuous with the retroperitoneal renal fascia, ureter and its accessory vessels, lymphatic vessels, peritoneum of the bladder, internal spermatic fascia, and other peritoneal and pelvic urogenital organ surfaces, which means that the urogenital fascia (UGF) is a complete fascial system, which migrates into PPF in the preperitoneal space and the internal spermatic fascia in the inguinal canal.


Early control of a community measles outbreak.
Door-to-door immunizations and a community canvass for susceptibles were marshalled to quell a rubeola outbreak in Norfolk, one of 25 outbreaks reported in Virginia from January through August 1977.


Inflammation Mediates Exercise Effects on Fatigue in Patients with Breast Cancer.
The randomized controlled OptiTrain trial showed beneficial effects on fatigue after a 16-wk exercise intervention in patients with breast cancer undergoing adjuvant chemotherapy. We hypothesize that exercise alters systemic inflammation and that this partially mediates the beneficial effects of exercise on fatigue. Two hundred and forty women scheduled for chemotherapy were randomized to 16 wk of resistance and high-intensity interval training (RT-HIIT), moderate-intensity aerobic and high-intensity interval training (AT-HIIT), or usual care (UC). In the current mechanistic analyses, we included all participants with >60% attendance and a random selection of controls (RT-HIIT = 30, AT-HIIT = 27, UC = 29). Fatigue (Piper Fatigue Scale) and 92 markers (e.g., interleukin-6 [IL-6] and tumor necrosis factor α [TNF-α]) were assessed at baseline and postintervention. Mediation analyses were conducted to explore whether changes in inflammation markers mediated the effect of exercise on fatigue. Overall, chemotherapy led to an increase in inflammation. The increases in IL-6 (pleiotropic cytokine) and CD8a (T-cell surface glycoprotein) were however significantly less pronounced after RT-HIIT compared with UC (-0.47, 95% confidence interval = -0.87 to -0.07, and -0.28, 95% confidence interval = -0.57 to 0.004, respectively). Changes in IL-6 and CD8a significantly mediated the exercise effects on both general and physical fatigue by 32.0% and 27.7%, and 31.2% and 26.4%, respectively. No significant between-group differences in inflammatory markers at 16 wk were found between AT-HIIT and UC. This study is the first showing that supervised RT-HIIT partially counteracted the increase in inflammation during chemotherapy, i.e., IL-6 and soluble CD8a, which resulted in lower fatigue levels postintervention. Exercise, including both resistance and high-intensity aerobic training, might be put forward as an effective treatment to reduce chemotherapy-induced inflammation and subsequent fatigue.


Augmented Reality in Orthopedic Practice and Education.
Augmented reality (AR) technology enhances a user's perception through the superimposition of digital information on physical images while still allowing for interaction with the physical world. The tracking, data processing, and display technology of traditional computer-assisted surgery (CAS) navigation have the potential to be consolidated to an AR headset equipped with high-fidelity cameras, microcomputers, and optical see-through lenses that create digital holographic images. This article evaluates AR applications specific to total knee arthroplasty, total hip arthroplasty, and the opportunities for AR to enhance arthroplasty education and professional development.


Phosphorylation of SAMHD1 by cyclin A2/CDK1 regulates its restriction activity toward HIV-1.
SAMHD1 restricts HIV-1 replication in myeloid and quiescent CD4(+) T cells. Here, we show that SAMHD1 restriction activity is regulated by phosphorylation. SAMHD1 interacts with cyclin A2/cdk1 only in cycling cells. Cyclin A2/CDK1 phosphorylates SAMHD1 at the Threonine 592 residue both in vitro and in vivo. Phosphorylation of SAMHD1 Thr592 correlates with loss of its ability to restrict HIV-1. Indeed, while PMA treatment of proliferating THP1 cells results in reduced Thr592 phosphorylation, activation of resting peripheral blood mononuclear cells (PBMCs) and purified quiescent CD4(+) T cells results in increased phosphorylation of SAMHD1 Thr592. Interestingly, we found that treatment of cells by type 1 interferon reduced Thr592 phosphorylation, reinforcing the link between the phosphorylation of SAMHD1 and its antiviral activity. Unlike wild-type SAMHD1, a phosphorylation-defective mutant was able to restrict HIV-1 replication in both PMA-treated and untreated cells. Our results uncover the phosphorylation of SAMHD1 at Thr592 by cyclin A2/CDK1 as a key regulatory mechanism of its antiviral activity.


Generalization of the geometric description of a light beam in radiometry and photometry.
Radiometric and photometric quantities rely on a geometric description of the beam subtended by a source and a receptor. In this paper, a generalization of this description is proposed as the product of the apparent size of the source times the receptor angular extent, whatever the natures of these elements: point, line, surface, or volume. The obtained flux density per geometric extent expressions are then applied to the determination of the irradiances induced in the near field and far field by a rectilinear source represented as a point source, a line source, and a surface source.


Phytoseiid mites (Acari: Mesostigmata) from Araucaria Forest of the State of Rio Grande do Sul, Brazil, with new records and descriptions of four new species.
This paper reports on the Phytoseiidae from an Araucaria forest in the State of Rio Grande do Sul, describing four new species, namely Transeius kroeffis n. sp., Typhlodromalus araucariae n. sp., Typhlodromips pompeui n. sp. and Typhlodromips salvadorii n. sp.. Iphiseiodes moraesi Ferla & Silva, Neoseiulus tunus (DeLeon), Typhlodromips japi Lofego, Demite & Feres, Typhlodromips pallinii Gonçalves, Silva & Ferla, Typhloseiopsis dorsoreticulatus Lofego, Demite & Feres are reported for the first time from this type of habitat in Rio Grande do Sul state, Brazil.


Structure-activity relationship studies of carboxamido-biaryl ethers as opioid receptor antagonists (OpRAs). Part 1.
A structurally unique and new class of opioid receptor antagonists (OpRAs) that bear no structural resemblance with morphine or endogenous opioid peptides has been discovered. A series of carboxamido-biaryl ethers were identified as potent receptor antagonists against mu, kappa and delta opioid receptors. The structure-activity relationship indicated para-substituted aryloxyaryl primary carboxamide bearing an amine tether on the distal phenyl ring was optimal for potent in vitro functional antagonism against three opioid receptor subtypes.


The History and Prospects of Rabbit Sperm Sexing.
Sperm sex selection is a longstanding challenge in the field of animal reproduction. The cuniculture industry, in particular producers of males or females for breeding purposes, would greatly benefit from the pre-selection of the offspring's sex. This review article overviews the current and future developments in rabbit sperm sexing technologies, as well as the implications of implementing these methodologies in cuniculture. The first attempts of sperm sexing were performed in rabbits; however, a both efficient and cost-effective methodology was not yet developed for this species. Those included sperm sexing according to differences in sperm density, surface electric charge, pH susceptibility, antisera reaction, and flow cytometry. Separation by flow cytometry has proven to be efficient in rabbits, yielding fractions with approximately 81% and 86% purity for X- and Y-sperm, respectively. However, it is not cost-effective for cuniculture and decreases sperm quality. The advantages, limitations, and practical considerations of each method are presented, highlighting their applicability and efficiency. Furthermore, herein we explore the potential of immunological-based techniques that overcome some of the limitations of earlier methods, as well as recent advancements in sperm sexing technologies in other animal models, which could be applied to rabbits. Finally, the challenges associated with the development and widespread implementation of rabbit sperm sexing technologies are addressed. By understanding the advantages and limitations of existing and emerging methods, researchers can direct their efforts towards the most promising directions, ultimately contributing to a more efficient, profitable, and sustainable cuniculture.


Renal transplantation for Wilms tumor: report of 20 cases.
Renal transplantation as part of the treatment for Wilms tumor was done on 20 patients. In 80 per cent the neoplasms were bilateral. Transplantation is indicated in individuals whose renal function is severely impaired or absent because of the malignancy, treatment or both. Patients who received homografts less than a year after treatment of the tumors had a 47 per cent incidence of recurrence or metastases compared to a zero incidence of these problems in those whose transplants were delayed for longer periods. Survival for 2 years or more was obtained in 75 per cent of the recipients with unilateral neoplasms and in 38 per cent of the patients with bilateral tumors.


Factors affecting improved glycaemic control in youth using insulin pumps.
The purpose of this study was to evaluate factors associated with insulin pump therapy resulting in lower HbA(1c) levels in young people with Type 1 diabetes mellitus. Insulin pumps were downloaded from 150 youth (81 male), ages 5-20 years. Consecutive insulin pump downloads, 3 months apart, were available for 85 (43 male) of the 150 youth and changes in pump use were correlated with changes (≥0.5%, ≥ 6 mmol/mol) in HbA(1c) levels. Using cross-sectional data, lower HbA(1c) values correlated with use of more frequent daily insulin boluses (r=-0.46, P<0.0001) and more frequent blood glucose checks/day (r=-0.35, P<0.0001). Young people with HbA(1c) levels <7.5% (58 mmol/mol) vs. values of 7.5-9.0% (58-75 mmol/mol) or ≥ 9.0% (75 mmol/mol) tested blood glucose more frequently/day (P<0.0001), bolused more frequently/day (P<0.0001), reported more grams of carbohydrates eaten/day (P<0.05) and had a higher per cent bolus insulin/day (P<0.05) compared with the ≥9.0% of youth. Using longitudinal data, 48 of 85 patients had a change in HbA(1c) level of ≥0.5% (6 mmol/mol) between downloads (24 improved). Increased bolus insulin (OR=1.15, P=0.03) and time of temporary basal rate use (OR=1.017, P=0.01) predicted ≥0.5% (6 mmol/mol) decrease in HbA(1c) in logistic regression. This study emphasizes the importance of blood glucose testing, of bolus insulin administration and of an increase in the time of temporary basal rate use in relation to improving glycaemic control.


T-cell counts in peripheral blood at leukapheresis predict responses to subsequent CAR-T cell therapy.
Prediction of responses to chimeric antigen receptor (CAR)-T cell therapies is essential to maximize their therapeutic efficacy for diffuse large B-cell lymphoma (DLBCL). While several tumor-intrinsic risk factors of resistance and/or early relapse have been identified, clinically useful markers that determine potential activity of CAR-T cells have not been fully investigated. T-cell property at the time of leukapheresis may serve as such a marker. Therefore, we evaluated the clinical impact of CD3+ cell count in peripheral blood at leukapheresis on clinical outcomes of CAR-T cell therapy. In total, 44 patients with relapsed or refractory (r/r) DLBCL who received tisagenlecleucel at Kyoto University Hospital were included. According to CD3+ cell counts, patients were categorized into CD3LOW and CD3HIGH groups with a threshold of 553/μL, based on receiver operating characteristic curve analysis. 1-year progression-free survival was significantly higher in the CD3HIGH group than the CD3LOW group (68.3% vs. 17.3%; adjusted hazard ratio [aHR], 0.37; p = 0.042). Overall survival was also superior in the CD3HIGH group (aHR, 0.24; p = 0.043). Moreover, higher CD3+ cell counts at leukapheresis were associated with significantly higher lymphocyte counts in peripheral blood at day 7 after CAR-T cell infusion (median 860 vs. 420/μL, P = 0.021), suggesting more extensive expansion of infused CAR-T cells in vivo. In conclusion, we demonstrated that the CD3+ cell count at leukapheresis predicts both expansion of CAR-T cells after infusion and outcomes of CAR-T cell therapy, and are useful for building comprehensive therapeutic strategies at the time of leukapheresis.


A scoping review of complication prediction models in spinal surgery: An analysis of model development, validation and impact.
Predictive analytics are being used increasingly in the field of spinal surgery with the development of models to predict post-surgical complications. Predictive models should be valid, generalizable, and clinically useful. The purpose of this review was to identify existing post-surgical complication prediction models for spinal surgery and to determine if these models are being adequately investigated with internal/external validation, model updating and model impact studies. This was a scoping review of studies pertaining to models for the prediction of post-surgical complication after spinal surgery published over 10 years (2010-2020). Qualitative data was extracted from the studies to include study classification, adherence to Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines and risk of bias (ROB) assessment using the Prediction model study Risk Of Bias Assessment Tool (PROBAST). Model evaluation was determined using area under the curve (AUC) when available. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement was used as a basis for the search methodology in four different databases. Thirty studies were included in the scoping review and 80% (24/30) included model development with or without internal validation. Twenty percent (6/30) were exclusively external validation studies and only one study included an impact analysis in addition to model development and internal validation. Two studies referenced the TRIPOD guidelines and there was a high ROB in 100% of the studies using the PROBAST tool. The majority of post-surgical complication prediction models in spinal surgery have not undergone standardized model development and internal validation or adequate external validation and impact evaluation. As such there is uncertainty as to their validity, generalizability, and clinical utility. Future efforts should be made to use existing tools to ensure standardization in development and rigorous evaluation of prediction models in spinal surgery.


Clinical decisions made by nurses in intensive care--results of a telephone survey.
A telephone survey of 89 GICUs in England was performed, using stratified quota sampling. 75 (84%) units reported changes in practice over the past 3 years. The reported changes were not only task orientated but also encompassed increased autonomy, organisational changes and increased workload. The absence of significant relationships between the activities suggests that nursing practice development is dependent on patient need and/or local factors. The lack of pattern suggests that it may be inappropriate to compare units for the purpose of nurse staffing.


Maximal performance of intact N-glycopeptide enrichment using sequential HILIC and MAX columns.
Low abundance and heterogeneity of N-glycosylation at the peptide level poses a great challenge to the structural and functional analysis of glycosylation in the field of glycobiology. Solving this conundrum requires a sufficient and specific method for intact N-glycopeptide enrichment. Using the C18 or HLB desalting column followed by the mixed-mode strong anion exchange (MAX) or hydrophilic interaction chromatography (HILIC) glycopeptide enrichment column are commonly applied approaches for sample preparation of intact N-glycopeptides from complex samples. Herein, we compared the effects of different combinations of two desalting columns and two enrichment columns using equal amounts of mouse brain tissues from the same source. The results revealed the C18 column was a bit superior to the HLB column, and the MAX and HILIC columns were complementary on intact N-glycopeptides enrichment. Additionally, the results also demonstrated that enriching glycopeptides using a HILIC column followed by a MAX column from the flow-through solution got a better enrichment performance than the reversed order. Based on these results, the sequential enrichment of glycopeptides using HILIC and then MAX columns could maximize the enrichment performance of intact N-glycopeptides, and therefore is an option for in-depth analysis of site-specific glycoproteome.


An Unexpected Foreign Body (a Thermometer) in the Bladder: A Case Report.
Foreign bodies in the bladder are rarely observed because of difficult access. These patients usually have a mental disorder, a background of intense sexual perversion, or inquisitiveness. A 48-year-old, deaf, and mentally retarded woman was referred to the nephrology clinic for severe anemia and impaired renal function. Imaging tests showed a mercury thermometer positioned in the bladder and a stone, 5 cm in diameter, around it. This had caused bilateral ureteral obstruction. The patient underwent an open cysteotomy. Obstructive uropathy is one of the causes of kidney failure; therefore, foreign bodies should be included in the differential diagnosis.


Allelopathic effects of diatom filtrates on the toxic benthic dinoflagellate Ostreopsis cf. ovata.
Ostreopsis blooms regularly occur in many Mediterranean coastal areas in late summer-autumn. In the northern Adriatic Sea, Ostreopsis blooms affect diatom-dominated microphytobenthic communities. In this study, the effects of the filtrates of some diatom species, both benthic (Tabularia affinis, Proschkinia complanatoides and Navicula sp.) and planktonic (Thalassiosira sp. and Skeletonema marinoi) on cell morphology, cytological features and growth of O. cf. ovata were investigated. Our results showed a marked decrease of O. cf. ovata growth when cells were exposed to all diatom filtrates tested. The highest inhibitions were observed for exposures to P. complanatoides and Navicula sp. filtrates (92.5% and 80%, respectively) and increased with the age of diatom culture. Moreover, a clear DNA degradation and abnormal forms of O. cf. ovata cells (83.8% of the total) were found at the highest concentrations using Navicula sp. filtrate after 10 days of the inoculum.


Immunotherapy in Gastro-Oesophageal Cancer: Current Practice and the Future of Personalised Therapy.
Initial studies of immune checkpoint inhibitors in biomarker unselected gastro-oesophageal cancer yielded limited improvement in survival. However, emerging data from recent clinical trials suggest immunotherapies may offer a meaningful clinical benefit within selected populations. Gastro-oesophageal cancer is a heterogeneous disease with respect to histopathological and molecular features; hypermutation and the biology of immune checkpoint pathways are key to appropriate selection of populations most likely to benefit from immune checkpoint inhibitors. Programmed death-ligand 1 expression, typically measured using the combined positive score, is an important biomarker in determining which patients may benefit from immunotherapy agents. However, combined positive score thresholds are not standardised across trials and the benefit in programmed death-ligand 1-negative cohorts is uncertain. Data suggest that patients with tumours with microsatellite instability, high tumour mutational burden and Epstein-Barr Virus positivity are more likely to benefit from immunotherapy, which may be of importance within programmed death-ligand 1-negative populations. Here, we describe the current evidence base for the use of checkpoint inhibitors in the treatment of advanced gastro-oesophageal cancer and adjuvant treatment of high-risk oesophageal cancer, as well as the ongoing studies of immunotherapy in the treatment of patients with gastro-oesophageal cancers across an increasing range of clinical settings.


Advanced transgenic approaches to understand alcohol-related phenotypes in animals.
During the past two decades, the use of genetically manipulated animal models in alcohol research has greatly improved the understanding of the mechanisms underlying alcohol addiction. In this chapter, we present an overview of the progress made in this field by summarizing findings obtained from studies of mice harboring global and conditional mutations in genes that influence alcohol-related phenotypes. The first part reviews behavioral paradigms for modeling the different phases of the alcohol addiction cycle and other alcohol-induced behavioral phenotypes in mice. The second part reviews the current data available using genetic models targeting the main neurotransmitter and neuropeptide systems involved in the reinforcement and stress pathways, focusing on the phenotypes modeling the alcohol addiction cycle. Finally, the third part will discuss the current findings and future directions, and proposes advanced transgenic mouse models for their potential use in alcohol research.


Tumor microenvironment-responsive Ag2S-PAsp(DOX)-cRGD nanoparticles-mediated photochemotherapy enhances the immune response to tumor therapy.
Chemotherapy drugs play important roles in clinical treatment, and most first-line regimens of cancer therapy contain chemotherapy drugs. In particular, some chemotherapeutic drugs can also produce ICD effect and enhance the immune response of the body. However, most chemotherapy drugs do not specifically target tumors or the complex tumor microenvironment, which renders their curative effect insufficient. Therefore, we constructed a tumor microenvironment-responsive drug delivery system (Ag2S-PAsp-cRGD) combined with doxorubicin (DOX) for tumor therapy. Firstly, Ag2S nanoparticles (NPs) were modified with polymer aspartic acid (PAsp) to construct the drug-loading platform. Then, an active targeting ligand (cRGD) was coupled through an amide reaction to enhance the functional targeting ability of the drug delivery system. In vivo imaging of the system showed that the nanoparticles accumulated in the tumor site, which facilitated the delivery of the chemotherapy drug DOX to the targeted tumor site. Furthermore, the photothermal effect of Ag2S NPs can effectively killed tumor cells, and also helped the release of DOX from nanoparticles into tumor tissue, thus enhancing the chemotherapeutic effect. Moreover, combined with the ICD effect jointly induced by photothermal therapy (PTT) and DOX, the treatment further activated the host immune response against tumors by enhancing the presentation of antigens and promoting the differentiation of T cells. This strategy of photo-chemo-immunotherapy showed excellent antitumor effect, not only eliminating the primary tumor but also preventing recurrence and inhibiting metastasis.


Diffusion-weighted MR imaging of focal liver lesions in the left and right lobes: is there a difference in ADC values?
To determine possible differences between the left and right hepatic lobes in apparent diffusion coefficient (ADC) values of benign and malignant focal liver lesions (FLLs) and normal liver parenchyma. Thirty-six patients (16 males, 20 females; mean age 56.8 years) with FLLs of the same etiology in both the left and right hepatic lobes (13 patients with 26 benign FLLs and 23 patients with 46 malignant FLLs) who underwent 1.5T magnetic resonance imaging (MRI) including diffusion-weighted MRI (b values: 0 and 800 seconds/mm) with respiratory gating and without cardiac gating were included in this Health Insurance Portability and Accountability Act-compliant and institutional review board-approved study. ADC values of normal liver parenchyma and FLLs in each hepatic lobe were calculated and compared by using Student's t-test and Wilcoxon signed-rank test, respectively. The mean ADC values of normal liver parenchyma, benign FLLs, and malignant FLLs were significantly higher (P < .001, P = .003, and P = .005, respectively) in the left hepatic lobe (1.74 × 10(-3), 1.81 × 10(-3), and 1.48 × 10(-3) mm²/second, respectively) than in the right hepatic lobe (1.48 × 10(-3), 1.54 × 10(-3), and 1.24 × 10(-3) mm²/second, respectively). ADC values of benign and malignant FLLs calculated from noncardiac-gated DW-MRI are significantly higher in the left hepatic lobe compared with the right hepatic lobe. This may be a limitation for characterization of FLLs based on ADC measurements.


Same people, different group: Social structures are a central component of group concepts.
We examine whether people conceptualize organized groups as having at least two parts: In addition to members (e.g., Alice), they also have social structures (i.e., roles and relations). If groups have members and social structures, then numerically distinct groups can have the same members if they differ in their structures. In Studies 1-4, participants numerically distinguished groups that had the same members when they had different structures. Participants numerically distinguished even when groups had the same function-the same people playing chess together Monday and Tuesday can be numerically distinct groups. In Study 4, we compare clubs to tables, and find that participants numerically distinguish tables by their structures too (i.e., the configuration of their parts) even when they have the same parts (which can be disassembled and then reassembled with ease). In Study 5, we find that participants rate groups as existing in space and time like concrete objects, suggesting that participants represent groups as at least partially concrete, such that groups have at least two parts (their structures and their members). Finally, in Study 6, we show that people will judge the same person as exemplary with respect to one group but condemnable with respect to another-even when those groups have the same members.


Synthesis of acidified magnetic sludge-biochar and its role in ammonium nitrogen removal: Perception on effect and mechanism.
An acidified magnetic sludge-biochar (MSB) was prepared to enhance ammonium nitrogen (AN) removal efficiency in eutrophic water, and MSB was obtained by secondary pyrolysis of sludge biochar powder. A series of MSB were prepared under 300, 400, 500, 600 °C and different valence states of iron ions by impregnation pyrolysis, which is based on the deposition of unstable iron minerals on biochar matrix. Physicochemical properties of pristine biochar and MSB were revealed through characterization analysis, suggesting that MSB prepared by ferric chloride at 400 °C presented the largest adsorption capacity, and the acid-modification enhanced the ammonium adsorption capacity by 10.7%. Electrostatic attraction and ion-exchange processes were identified as the main adsorption mechanisms of MSB on AN. As the most dominant mechanism, ion exchange of AN with functional groups containing -OH and CO on the surface of MSB resulted in the relative content of -OH (61.3%) and CO (11.5%) bonds reduced to 34.2% and 7.0% respectively. The novel magnetic sludge-biochar with acid-modification possessed enhanced electron transfer capacity, revealing a removal pathway of ammonium by nitrification. The findings above demonstrated that MSB is a promising adsorbent for ammonium removal and can be applied to the natural nitrogen-rich water regulation.


Demonstration of superior vena caval obstruction and "hot spot" on liver scan in a case of non-Hodgkin's lymphoma.
A case of total superior vena cava obstruction and "hot spot" in the liver demonstrated by a radiocolloid liver scan in a case of non-Hodgkin's lymphoma of the anterior mediastinum, is presented. The study showed total obstruction of the superior vena cava and the presence of collateral circulation. The patient received radiation therapy, and a subsequent radiocolloid study showed relief of the obstruction and disappearance of the "hot spot."


Chronic lithium chloride treatment has variable effects on motor behaviour and survival of mice transgenic for the Huntington's disease mutation.
Expression of the Huntington's disease (HD) mutation in mice (R6/2 line) causes a progressive neurological phenotype that includes deterioration of motor function resembling that seen in HD. The current study sought to determine whether or not chronic treatment of R6/2 mice with lithium chloride would have an effect on the progression of the phenotype, in light of lithium's reported neuroprotective and anti-depressive properties. Treatment began either before or after the onset of symptoms. Chronic treatment with lithium caused a significant improvement in rotarod performance when treatment was started post- but not pre-symptomatically. There was no overall effect on survival in either group, but further analysis revealed that in the post-symptomatic group, mice could be assigned to one of two distinct groups, depending on the effects of lithium. One subgroup of mice lost weight faster, died earlier and showed rotarod performance similar to the vehicle-treated controls. The other subgroup lost weight at a normal rate, died at a similar age, but showed greatly improved motor performance compared to controls. The improvement in rotarod performance suggests that lithium may improve motor symptoms as well as depression in some HD patients.


Differential effects of ovarian steroids on anxiety versus fear as measured by open field test and fear-potentiated startle.
The ovarian steroids, estrogen (E) and progesterone (P), have been shown to affect anxiety and fear in humans and animals, although with inconsistent results. These ambiguous findings may be due to differential actions of ovarian steroids on anxiety versus fear. To investigate such a role, we used the open field test (OFT) and fear-potentiated startle (FPS). We examined these behaviors between cycling female rats in proestrus (high E and rising P) or diestrus (low E and P), as well as between ovariectomized rats treated for 2 weeks with placebo, E, or E plus P (OVX, OVX/E, OVX/EP, respectively). We found no differences in anxiety-like or fear behaviors in OFT or FPS between proestrus and diestrus rats, perhaps due to the opposing effects of E and P. In contrast, we found that the OVX/E rats spent more time in the center of the OFT compared to the OVX and OVX/EP rats with no difference in overall activity level, suggesting that E reduced anxiety and this was opposed by P. With FPS, the OVX/E rats showed increased startle in the first third of the testing session, followed by a rapid decline in startle magnitude in subsequent trials. The addition of P to E treatment counteracted this effect. In conclusion, E may have differential effects on specific components of anxiety and fear; E may decrease anxiety in a naturalistic environment, but intensify both fear learning and extinction processes. P antagonizes these E effects on anxiety and fear.


Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production.
Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed. In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model. 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production. We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent.


Comparison of valsartan and amlodipine on ambulatory blood pressure variability in hypertensive patients.
We tested the hypothesis that calcium channel blockers (CCBs: amlodipine group, n = 38)) are superior to angiotensin receptor blockers (ARBs: valsartan group, n = 38) against ambulatory blood pressure variability (BPV) in untreated Japanese hypertensive patients. Both drugs significantly reduced ambulatory systolic and diastolic BP values. With regard to BPV, standard deviation (SD) in SBP did not change with the administration of either drug, but the ARB significantly increased SD in awake DBP (12 ± 4-14 ± 4 mmHg). The ARB also significantly increased the coefficients of variation (CVs)in awake and 24-h SBP/DBP (all P < 0.05), but amlodipine did not change the CV. CCB significantly reduced the maximum values of awake SBP (193 ± 24-182 ± 27 mmHg, P = 0.02), sleep SBP (156 ± 18-139 ± 14 mmHg, P < 0 .001), and awake and sleep DBP (P < 0.01 in both cases), but the ARB did not change the maximum BP values. In conclusion, a once-daily morning dose of CCB amlodipine was more effective at controlling ambulatory BPV than ARB valsartan, especially in reducing maximum BP levels.


Construction of a 13-microRNA-based signature and prognostic nomogram for predicting overall survival in patients with hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a common malignancy associated with a poor prognosis due to difficulties in reliably estimating overall survival (OS). MicroRNAs (miRNAs) play critical roles in HCC initiation, progression, and metastasis and are highly correlated with patient prognosis. Thus, miRNA-based risk signatures and nomograms are urgently required for predicting OS in patients with HCC. We constructed a 13-miRNA-based signature and prognostic nomogram using 408 HCC samples and 58 normal tissues with miRNA sequencing data and clinical data from 323 patients downloaded from The Cancer Genome Atlas. A total of 195 patients were assigned as the internal validation cohort for verification and testing. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis was applied to investigate pathway enrichment for the signature. We identified and validated a 13-miRNA risk signature highly associating with the OS of HCC patients. The signature showed good performances by calculating C-index, area under the curve, and calibration curves. After verification and testing using an internal validation cohort, the results yielded a miRNA-based signature and a prognostic nomogram with reliable predictive accuracy. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis indicated that various genes and multiple pathways were closely related to the mechanisms of HCC proliferation and metastasis. We successfully identified a 13-miRNA-based signature and prognostic nomogram that are capable of predicting OS in patients with HCC.


Protein family clustering for structural genomics.
A major goal of structural genomics is the provision of a structural template for a large fraction of protein domains. The magnitude of this task depends on the number and nature of protein sequence families. With a large number of bacterial genomes now fully sequenced, it is possible to obtain improved estimates of the number and diversity of families in that kingdom. We have used an automated clustering procedure to group all sequences in a set of genomes into protein families. Bench-marking shows the clustering method is sensitive at detecting remote family members, and has a low level of false positives. This comprehensive protein family set has been used to address the following questions. (1) What is the structure coverage for currently known families? (2) How will the number of known apparent families grow as more genomes are sequenced? (3) What is a practical strategy for maximizing structure coverage in future? Our study indicates that approximately 20% of known families with three or more members currently have a representative structure. The study indicates also that the number of apparent protein families will be considerably larger than previously thought: We estimate that, by the criteria of this work, there will be about 250,000 protein families when 1000 microbial genomes have been sequenced. However, the vast majority of these families will be small, and it will be possible to obtain structural templates for 70-80% of protein domains with an achievable number of representative structures, by systematically sampling the larger families.


A method for studying insoluble immune complexes.
Two variants of a method for determining the average composition of insoluble immune complex particles (IICP) are described. The first variant is based on measuring the specific turbidity (the turbidity per unit mass concentration of the dispersed substance) and the average size of IICP determined from dynamic light scattering (DLS). In the second variant, the slope of the logarithmic turbidity spectrum (wavelength exponent) is used instead of DLS particle size. Both variants allow the average biopolymer volume fraction to be determined in terms of the average refractive index of IICP. The method is exemplified by two experimental antigen+antibody systems: (i) lipopolysaccharide-protein complex (LPPC) of Azospirillum brasilense Sp245+rabbit anti-LPPC; and (ii) human IgG (hIgG)+sheep anti-hIgG. We have found that IICP can be modeled by incompact porous particles that contain about 30% of biopolymer substance and 70% of buffer.


Kainate-induced retina amacrine-like cell damage is mediated by AMPA receptors.
We investigated the effect of domoate, kainate and AMPA on 45Ca2+ uptake and on metabolic activity of cultured chick amacrine-like cells, as measured by reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Domoate and kainate stimulated 45Ca2+ uptake and decreased MTT reduction, in a LY 303070-sensitive manner. AMPA caused a small increase on 45Ca2+ uptake, but it was without effect on MTT reduction. AMPA reduced both the 45Ca2+ entry and neurotoxicity induced by kainate, and cyclothiazide enhanced both the 45Ca2+ entry and neurotoxicity induced by AMPA. The results indicate that the AMPA receptors are the non-NMDA glutamate receptors involved in excitotoxicity.


Two USA Ehrlichia spp. cause febrile illness in goats.
Ehrlichia spp. are not currently recognized as a cause of illness in goats in the USA, but three Ehrlichia are enzootic in lone star ticks (Amblyomma americanum) in the eastern USA, and related bacteria in other countries cause illness in goats. We exposed naïve goats to Ehrlichia-infected Amblyomma and demonstrated that infection and clinical illness can be caused by two USA species, E. ewingii and the recently discovered Panola Mountain Ehrlichia sp. Clinical features in all five goats are described; ehrlichioses were associated with pyrexia, serous nasal discharge, inappetance, lethargy, decreased alkaline phosphatase, and, in most cases, neutropenia. Goats remained chronically infected for several months following exposure to ehrlichiae and transmitted the pathogens to uninfected ticks. In the eastern USA, undifferentiated febrile illness in goats might be caused by previously unrecognized ehrlichial infections, and pastures housing-infected goats could become infested with a large number of infected ticks.


The trend of caesarean birth rate changes in China after 'universal two-child policy' era: a population-based study in 2013-2018.
The universal two-child policy in China which was announced in October 2015 might affect the caesarean birth rate. Few studies reported the caesarean birth rate affected by the policy especially after the universal two-child policy period. This study aimed to demonstrate the caesarean birth rate changes before and after the universal two-child policy and further elaborate the underlying influencing factors. This nationwide, retrospective, population-based study was based on National Free Pre-Pregnancy Check-ups Project (NFPCP). Couples planning to conceive in next 6 months were encouraged to participate in NFPCP. Baseline information was collected using a standardized questionnaire with a face-to-face interview, and medical examinations were conducted. Two rounds of follow-up interviews were then conducted by trained nurses to update pregnancy status and outcomes. NFPCP participants who completed deliveries before December 31, 2018, were included in the current study. We used marginal effect of year to examine the trend of caesarean birth rate over time and interrupted time series (ITS) analysis to determine impacts of the universal two-child policy on the trend of caesarean birth rate. A total of 9,398,045 participants were included in the final analysis. High-risk factors to increase caesarean birth rate were identified. In the current study, the standardized caesarean birth rate declined from 34.1% in 2013 to 31.8% in 2015 and increased to 35.6% in 2018. ITS analysis showed the caesarean birth rate decreased by 0.1% (95% CI 0.1-0.1) per month before the release of universal two-child policy, 1.3% (95% CI 0.6-2.1%) absolute drop during the policy release month, and increased by 0.2% (95% CI 0.1-0.2%) per month after the policy implementation. For the period after the policy release, the increasing trends were observed in rural participants and urban primiparas. The prevalence of caesarean birth rates within China varied regionally. The decreasing trend of caesarean birth rate was reported after immediate release of the universal two-child policy. An increasing trend of caesarean birth rate was observed 2-3 years after the policy. It reminds us that the caesarean birth rate control is a long-lasting process and all the strategies need to be continually reinforced.


Violations of Health as a Human Right and Moral Distress: Considerations for Social Work Practice and Education.
Healthcare professionals may experience moral distress when navigating difficult positions in which acting or providing for their patient's best interest may not be possible due to barriers outside of their control. This phenomenon has primarily been investigated within nursing and other clinical disciplines; however, experiences of moral distress have also been noted in the social work profession. Healthcare professionals, including social workers, may experience moral distress when witnessing violations of their patients' human rights. This article discusses research reporting on experiences of moral distress within the social work profession, a reality social work students may also face during their field placements. Understanding the causes and effects of moral distress within the social work profession is important when preparing social work students as they transition into the workforce. Future research investigating moral distress should include the perspectives of social work field students, as their experiences are understudied. This phenomenon is especially important to investigate, as the current COVID-19 pandemic is expected to exacerbate health challenges.


Indoor exposure to environmental tobacco smoke and dampness: respiratory symptoms in Sardinian children--DRIAS study.
Indoor exposures at home, environmental tobacco smoke (ETS) and mould/dampness adversely affect respiratory health of children. Disturbi Respiratori nell'Infanzia e Ambiente in Sardegna (DRIAS) (Respiratory Symptoms in children and the Environment in Sardegna, Italy) aims at relating the prevalence of respiratory and allergic symptoms to indoor exposures in Sardinian children. DRIAS, a cross-sectional investigation of respiratory symptoms/diseases, used a modified version of ISAAC questionnaire, included 4122 children attending 29 primary schools in the school year 2004-2005. If both parents smoke the prevalence for current wheeze and current asthma is almost doubled in comparison with never smokers, for persistent cough and phlegm a role is suggested when only mother smokes. Among mothers smoking in pregnancy, the prevalence of current wheeze and current asthma is increased. Exposure to ETS and family atopy have a joint effect resulting in an almost tripling of prevalence for current wheeze and more than four times for current asthma. Exposure to "dampness" (mould or dampness) both during the first year of life and currently is associated with increased prevalence of current wheeze, persistent cough or phlegm and current rhino-conjunctivitis; if exposure is only during the first year of life a doubling or more of prevalence is observed for current wheeze, current asthma, and persistent cough or phlegm. DRIAS results add evidence to the causal role of childhood exposure to ETS in the development of respiratory symptoms (cough, phlegm, and wheezing) and asthma. The joint effect of ETS and family atopy is corroborated. The results strengthen the evidence for a causal association between "dampness" and respiratory health, pointing to its possible independent role in causing asthma, a long-lasting exposure entails a doubled prevalence for both asthmatic and bronchitis symptoms.


Relative nutritional quality of C3 and C4 grasses for a graminivorous lepidopteran, Paratrytone melane (Hesperiidae).
We tested the hypothesis that C4 grasses are inferior to C3 grasses as host plants for herbivorous insects by measuring the relative performance of larvae of a graminivorous lepidopteran, Paratrytone melane (Hesperiidae), fed C3 and C4 grasses. Relative growth rates and final weights were higher in larvae fed a C3 grass in Experiment I. However, in two additional experiments, relative growth rates and final weights were not significantly different in larvae fed C3 and C4 grasses. We examined two factors which are believed to cause C4 grasses to be of lower nutritional value than C3 grasses: foliar nutrient levels and nutrient digestibility. In general, foliar nutrient levels were higher in C3 grasses. In Experiment I, protein and soluble carbohydrates were digested from a C3 and a C4 grass with equivalent efficiencies. Therefore, differences in larval performance are best explained by higher nutrient levels in the C3 grass in this experiment. In Experiment II, soluble carbohydrates were digested with similar efficiencies from C3 and C4 grasses but protein was digested with greater efficiency from the C3 grasses. We conclude (1) that the bundle sheath anatomy of C4 grasses is not a barrier to soluble carbohydrate digestion and does not have a nutritionally significant effect on protein digestion and (2) that P. melane may consume C4 grasses at compensatory rates.


Rapid quantification of the heteroplasmy of mutant mitochondrial DNAs in Leber's hereditary optic neuropathy using the Invader technology.
To quantify the degree of heteroplasmy of a mitochondrial DNA (mtDNA) mutation in Leber's hereditary optic neuropathy (LHON) a biplex Invader assay was applied. To determine the optimum condition for the Invader assay, mtDNAs were assayed in various amounts of total DNA in 1-4-h incubations at 63 degrees C. To evaluate the suitability of the Invader assay to detect the three mutations, G3460A, G11778A, and T14484C, 10 ng of DNAs from 224 patients with bilateral optic atrophy was assayed. To quantify mtDNA heteroplasmy, a standard curve of known mixture ratios of mutation against calculation by the Invader assay was constructed. Seventy-two of the 224 patients had one of the three mutations, which corresponded with the mutation detected earlier by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. The percentages of mutant mtDNAs were calculated by the Invader assay in five heteroplasmic families, including 30 individuals with the G11778A mutation. The results were compared with those calculated earlier by labeled polymerase chain reaction followed by single-strand conformation polymorphism (PCR-SSCP) analysis. In 1-8 ng of DNA, the fluorescence intensity increased near linearly during a 4-h assay. With more than 16 ng of DNA, the intensities were saturated even at the 2-h assay. A linear relationship was observed between the results obtained from separate mixtures and from the Invader assay analysis. Because two fluorescent intensities are not always the same, one of the two intensities was modified to adjust to that of the other. Complete concordance was observed between PCR-RFLP analysis and Invader assay genotyping for the 224 patients. Results of percentage of heteroplasmy in five LHON families obtained by the Invader assay were consistent with those by the PCR-SSCP analysis. Invader assay is a simple, rapid, and reliable method of genotyping mtDNA mutations as well as quantifying heteroplasmy simultaneously under optimum conditions.


A case-control study of male colorectal cancer in Aichi Prefecture, Japan: with special reference to occupational activity level, drinking habits and family history.
The relationships of occupational activity level, drinking habits and family history of cancer to the risk of male colorectal cancer by subsites were investigated in a case-control study involving 1,716 cases with colon cancer, 1,611 cases with rectal cancer and 16,600 controls with other sites of cancer identified from the Aichi Cancer Registry, Japan 1979-1987. An occupation with a low activity level was associated with an increased risk of colorectal cancer; the age-adjusted relative risk (RR) compared to the high activity level group was 1.92 (95% confidence interval (CI): 1.38-2.67) for proximal colon cancer, 1.52 (95% CI: 1.19-1.94) for distal colon cancer and 1.38 (95% CI: 1.17-1.62) for rectal cancer. Beer drinkers showed an increased risk of colorectal cancer; the age-adjusted RR was 1.49 (95% CI: 1.13-1.95) for proximal colon cancer, 1.65 (95% CI: 1.34-2.04) for distal colon cancer and 1.88 (95% CI: 1.62-2.18) for rectal cancer. The RR for family history of colorectal cancer was 3.40 (95% CI: 2.19-5.29) for proximal colon cancer, 2.54 (95% CI: 1.73-3.75) for distal colon cancer and 1.78 (95% CI: 1.28-2.49) for rectal cancer. Multivariate analysis controlled for age, residence, marital status and smoking in addition to occupational activity level, beer drinking and family history of colorectal cancer did not materially change the RRs. When these three variables were combined, the RR was 15.72 (95% CI: 5.40-45.78) for proximal colon cancer, 10.55 (95% CI: 4.24-26.27) for distal colon cancer and 6.69 (95% CI: 3.12-14.36) for rectal cancer.


[Atherosclerosis--development and mortality in advanced age in the People's Republic of Bulgaria].
This report is based on a 9-year thorough epidemiological study of the lethality of atherosclerosis among people older than 45 years in Bulgaria.


Altered mechanism of glucagon-mediated hepatic glycogenolysis during long-term starvation in the rat.
The effect of long-term starvation on glucagon-mediated hepatic glycogenolysis was investigated in the rat in vivo. Following glucagon (50 microgram/kg i.v.) fed rats showed rapid phosphorylase activation but no change in synthase-I activities. In contrast, rats fasted 72 hr (long-term fasting) showed rapid synthase inactivation but no significant phosphorylase activation. Rats fasted 24 hr (short-term fasting) demonstrated coordinated inactivation of synthase and activation of phosphorylase. Hepatic cyclic AMP responses were greater in fasted rats. Hepatic glycogen concentrations in rats fasted 72 hr were approximately 30% of fed levels. After glucagon, comparable decrements in hepatic glycogen and increments in plasma glucose concentrations were seen in fed and 72-hr groups. The diminished responsiveness of the hepatic phosphorylase system in rats fasted 72 hr was not attributable to altered cyclic AMP-dependent protein kinase or phosphorylase kinase activities. However, the diminished responsiveness could be ascribed to diminished total phosphorylase with nearly complete activation in the basal state. In fed and fasted rats, synthase decrements after glucagon correlated closely with basal levels of synthase-I. Thus, it is proposed that the enzymatic mechanism of glucagon-mediated hepatic glycogenolysis differs in fed and fasted rats. It is also proposed that partial hepatic glycogen reaccumulation during long-term fasting could be physiologically important for glucose homeostasis.


Mathematical modelling of growth of Escherichia coli at subinhibitory levels of chloramphenicol or tetracyclines.
A mathematical model is suggested to describe the subinhibitory effects of chloramphenicol upon growth of Escherichia coli. It represents a generalization of Monod's equation. Our model was constructed entirely on the basis of biochemical factors, such as the reversibility of the interaction between the drug and its ribosomal target or intracellular uptake. The subinhibitory effects of chloramphenicol were satisfactorily described by this law within the range of 0.4-2.4 micrograms/ml. After simplifying the equation, this model was extrapolated to provide an accurate description of the mode of action of other bacteriostatic antibiotics which also inhibit the 50-S ribosomal subunit (tetracycline and doxycycline). The expanded model seems to accurately typify the effect of these antibiotics, whereas bactericidal aminoglycosides follow a completely different growth law.


Generalized use of a handheld prompting system.
This study determined the effectiveness of a commercially produced handheld computer, as a prompting system in facilitating the generalization and increasing the probability of long-term maintenance of vocational skills by adolescents with moderate intellectual disabilities. Four students successfully used the system in learning a task and then generalized the use of the prompting system to complete increasingly more complex tasks. Task performance was maintained at a 100% level for up to 9 weeks.


Current concepts and novel applications of LH activity in ovarian stimulation.
Luteinizing hormone (LH) is a crucial physiological regulator of the human menstrual cycle. LH activity is also contained in many medications used to treat anovulation and to stimulate multiple folliculogenesis for assisted reproduction techniques. However, LH activity had previously been regarded as just a contaminant of follicle-stimulating hormone (FSH)-containing products and deemed potentially detrimental for reproductive function. Novel experimental and clinical evidence now suggests that the administration of pharmacological amounts of LH activity, instead of being harmful, is therapeutically advantageous, particularly in the support and modulation of ovarian folliculogenesis. The aim of this article is to provide an overview of the effects of LH activity administration in ovarian stimulation and to outline novel unconventional gonadotropin regimens that might improve the efficacy, safety and convenience of ovulation induction.


Roles of FGFR3 during morphogenesis of Meckel's cartilage and mandibular bones.
To address the functions of FGFR2 and FGFR3 signaling during mandibular skeletogenesis, we over-expressed in the developing chick mandible, replication-competent retroviruses carrying truncated FGFR2c or FGFR3c that function as dominant negative receptors (RCAS-dnFGFR2 and RCAS-dnFGFR3). Injection of RCAS-dnFGFR3 between HH15 and 20 led to reduced proliferation, increased apoptosis, and decreased differentiation of chondroblasts in Meckel's cartilage. These changes resulted in the formation of a hypoplastic mandibular process and truncated Meckel's cartilage. This treatment also affected the proliferation and survival of osteoprogenitor cells in osteogenic condensations, leading to the absence of five mandibular bones on the injected side. Injection of RCAS-dnFGFR2 between HH15 and 20 or RCAS-dnFGFR3 at HH26 did not affect the morphogenesis of Meckel's cartilage but resulted in truncations of the mandibular bones. RCAS-dnFGFR3 affected the proliferation and survival of the cells within the periosteum and osteoblasts. Together these results demonstrate that FGFR3 signaling is required for the elongation of Meckel's cartilage and FGFR2 and FGFR3 have roles during intramembranous ossification of mandibular bones.


Synthetic bacterial lipopeptide analogs: structural requirements for adjuvanticity.
Modern vaccines aim at conferring immune protection, independently of the nature of the etiological agent causing the disease. These new therapeutics are based on highly purified antigenic moieties that offer potential advantages over traditional vaccines, including a high degree of safety and the capacity of eliciting highly specific immune responses. In spite of these advantages however, subunit vaccines tend to be poorly immunogenic in vivo, and require the coadministration of adjuvants that indirectly enhance cellular immunity. Thus, recombinant vaccines development is dependent on the design of new molecules, non-immunogenic per se, but endowed with immune modulatory properties. Synthetic analogs of bacterial lipoproteins were described more than a decade ago, but their capacity to act as adjuvants has been only recently dissected. These low molecular weight non-immunogenic molecules can be reproducibly synthetized, are safe, and of easy handling and administration. Furthermore, new experimental data from our laboratory reveal their powerful adjuvant effect on human HLA-I/II restricted T cell responses and identify the molecular and cellular requirements for optimal adjuvanticity.


Regional changes in monoamines and metabolites following defensive aggression in the rat.
Pharmacological studies have demonstrated that shock-induced defensive fighting is modulated by manipulations of the serotonergic, noradrenergic and dopaminergic neurotransmitter systems. In the present study, regional changes in 5- hydroxytryptamine , norepinephrine, dopamine and their metabolites 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylethylene glycol and 3,4-dihydroxyphenylacetic acid were measured following shock-induced fighting using high performance liquid chromatography coupled with electrochemical detection. Fighting produced reductions in the serotonergic, noradrenergic and dopaminergic systems and elevations in the noradrenergic and dopaminergic systems within the brain stem, hypothalamus, hippocampus, caudate and amygdala relative to shocked or non-shocked controls. These data demonstrate that the activities of these neurotransmitters are involved in defensive aggression in rats. The changes in catecholamines may indicate adaptive responses to stress, while the changes in serotonin may indicate a permissive function for serotonin depletion in defensive fighting.


Direct and indirect impacts of synthetic biology on biodiversity conservation.
The world's biodiversity is in crisis. Synthetic biology has the potential to transform biodiversity conservation, both directly and indirectly, in ways that are negative and positive. However, applying these biotechnology tools to environmental questions is fraught with uncertainty and could harm cultures, rights, livelihoods, and nature. Decisions about whether or not to use synthetic biology for conservation should be understood alongside the reality of ongoing biodiversity loss. In 2022, the 196 Parties to the United Nations Convention on Biological Diversity are negotiating the post-2020 Global Biodiversity Framework that will guide action by governments and other stakeholders for the next decade to conserve the worlds' biodiversity. To date, synthetic biologists, conservationists, and policy makers have operated in isolation. At this critical time, this review brings these diverse perspectives together and emerges out of the need for a balanced and inclusive examination of the potential application of these technologies to biodiversity conservation.


In-line solid-phase extraction-capillary electrophoresis coupled with mass spectrometry for determination of drugs of abuse in human urine.
In-line solid-phase extraction-capillary electrophoresis coupled with mass spectrometric detection (SPE-CE-MS) has been used for determination of 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), codeine (COD), hydrocodeine (HCOD), and 6-acetylmorphine (6AM) in urine. The preconcentration system consists of a small capillary filled with Oasis HLB sorbent and inserted into the inlet section of the electrophoresis capillary. The SPE-CE-MS experimental conditions were optimized as follows: the sample (adjusted to pH 6.0) was loaded at 930 mbar for 60 min, elution was performed with methanol at 50 mbar for 35 s, 60 mmol L(-1) ammonium acetate at pH 3.8 was used as running buffer, the separation voltage was 30 kV, and the sheath liquid at a flow rate of 5.0 μL min(-1) was isopropanol-water 50:50 (v/v) containing 0.5% acetic acid. Analysis of urine samples spiked with the four drugs and diluted 1:1 (v/v) was studied in the linear range 0.08-10 ng mL(-1). Detection limits (LODs) (S/N = 3) were between 0.013 and 0.210 ng mL(-1). Repeatability (expressed as relative standard deviation) was below 7.2%. The method developed enables simple and effective determination of these drugs of abuse in urine samples at the levels encountered in toxicology and doping.


Esophageal body and upper esophageal sphincter motor responses to esophageal provocation during maturation in preterm newborns.
We studied the maturation of esophageal body and upper esophageal sphincter (UES) motor responses that protect against reflux in newborns. The responses of esophageal body and UES on midesophageal provocation were quantified using a micromanometric water perfusion system and a specially designed catheter with a UES sleeve and 5 side-hole recording sites. Eighteen healthy premature infants were studied twice, at 33.4 weeks' and 35.7 weeks' mean postmenstrual ages (PMAs). Mean threshold volumes and the distribution of responses including secondary peristalsis, UES pressure increase, and primary peristalsis were similar for air and liquids. Secondary peristalsis and UES pressure increases were volume dependent for both studies, but their characteristics changed as PMA increased in that (1) completely propagated secondary peristalsis with liquids increased; (2) proximal esophageal contraction duration was shorter for air and liquids; and (3) propagating velocity for liquids was faster. Esophageal and UES motor responses to abrupt midesophageal provocation are present as early as 33 weeks' PMA, and the response-characteristics improve during development. Reflexes that may facilitate esophageal clearance include (1) secondary peristalsis; (2) esophago-UES-contractile reflex; and (3) esophago-deglutition response.


Yale-Brown Obsessive Compulsive Scale and US National Institute of Mental Health Global Obsessive Compulsive Scale in Turkish: reliability and validity.
Fifteen patients with DSM-III-R diagnosis of obsessive-compulsive disorder (OCD) were rated according to the Turkish version of the Yale Brown Obsessive Compulsive Scale (Y-BOCS) and the US National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH-GOCS) by 7 raters independently from audiotaped interviews. Patients also completed the Maudsley Obsessive Compulsive Inventory (MOCI). Interrater reliability of Y-BOCS and NIMH-GOCS were very good as well as correlations between these two scales. The correlations of MOCI with Y-BOCS and NIMH-GOCS were not significant. We found Y-BOCS and NIMH-GOCS to be reliable and valid instruments in assessing the severity of OCD. These findings suggest that MOCI may not be a suitable instrument for assessing the severity of OCD.


PTSD: diagnosis, evolution, and treatment of combat-related psychological/psychiatric injury.
The long Iraq and Afghanistan conflicts have thrust Combat Related Post-Traumatic Stress Disorder (CR-PTSD) into the public consciousness and promoted national dialogue on the incidence and results of war related psychological trauma. In the first of a two part series we outline our contemporary understanding of CR-PTSD, the evolution of the diagnosis throughout the history of modern warfare, its impact on the mind and body, and its treatment. PTSD has become the mental health issue of our time.


New dominant syndrome of microcephaly, facial abnormalities, micromelia, and mental retardation.
We report on three brothers, aged 6, 3, and 2 years, with a hitherto undescribed combination of microcephaly, facial abnormalities, micromelia, and mild mental retardation. Their facial abnormalities included a forehead with bitemporal constriction, upslanting palpebral fissures, synophrys, a short nose with anteverted nostrils, a short columella, a cupid bow-shaped, thin vermilion border of the upper lip, and micrognathia. Their mother had similar clinical manifestations, but was of normal intelligence. The disease was apparently transmitted in a dominant fashion.


Calculated Decisions: Pain assessment in advanced dementia (PAINAD) scale
The PAINAD scale is used to assess pain in patients with dementia.


Analysis of type II polyketide beta-ketoacyl synthase specificity in Streptomyces coelicolor A3(2) by trans complementation of actinorhodin synthase mutants.
Complementation of defined actinorhodin beta-ketoacyl synthase (KS) mutants by various other KS genes suggested that the ORF1-encoded KS may be relatively generalized in function, whereas the ORF2-encoded KS component may provide specificity in polyketide chain construction. Evidence for differential temporal-spatial expression of the actinorhodin and spore pigment KSs in Streptomyces coelicolor was obtained.


G proteins in cellular control.
In the past year, cDNA cloning has revealed substantial diversity in G protein alpha, beta and gamma subunits. The number of cellular functions recognized to be controlled by G proteins is also increasing. Most G proteins are associated with the cytoplasmic surface of the plasma membrane, and molecular mechanisms for membrane association of certain G protein subunits have been defined recently. Mutations in G protein subunits, both artificially induced and naturally occurring, have provided important insights into G protein structure and function.


Simultaneous determination of citalopram, fluoxetine, paroxetine and their metabolites in plasma by temperature-programmed packed capillary liquid chromatography with on-column focusing of large injection volumes.
A miniaturized temperature-programmed packed capillary liquid chromatographic method with on-column large volume injection and UV detection for the simultaneous determination of the three selective serotonin reuptake inhibitors citalopram, fluoxetine, paroxetine and their metabolites in plasma is presented. An established reversed-phase C8 solid-phase extraction method was employed, and the separation was carried out on a 3.5-microm Kromasil C18 0.32x300 mm column with temperature-programming from 35 (3 min) to 100 degrees C (10 min) at 1.3 degrees C/min. The mobile phase consisted of acetonitrile-45 mM ammonium formate (pH 4.00) (25:75, v/v). The non-eluting sample focusing solvent composition acetonitrile-45 mM ammonium formate (pH 4.00) (3:97, v/v) allowed injection of 10 microl or more of the plasma extracts. The method was validated for the concentration range 0.05-5.0 microM, and the calibration curves were linear with coefficients of correlation >0.993. The limits of quantification for the antidepressants and their metabolites ranged from 0.05 to 0.26 microM. The within and between assay precision of relative peak height were in the range 2-22 and 2-15% relative standard deviation, respectively. The within and between assay recoveries were in the 61-99 and 54-92% range for the antidepressants, respectively, and between 52-102 and 51-102% for the metabolites.


Obesity and future prostate cancer risk among men after an initial benign biopsy of the prostate.
In general population studies, obesity has been associated with risk of high-grade prostate cancer, but little is known about obesity and future prostate cancer risk among men with an initial benign biopsy of the prostate; a high-risk population. Within a cohort of 6,692 men followed up after a biopsy or transurethral resection of the prostate (TURP) with benign findings, a nested case-control study was conducted of 494 prostate cancer cases and controls matched on age, race, follow-up duration, biopsy versus TURP and date of procedure. Body mass index at the time of the initial procedure was abstracted from medical records, and initial biopsy specimens were reviewed for the presence of prostatic intraepithelial neoplasia (PIN). Obesity was associated with the presence of PIN in the initial benign specimen [OR = 2.15; 95% confidence interval (CI) 1.13-4.11]. After adjustment for the matching variables, family history of prostate cancer, prostate-specific antigen (PSA) levels at the initial procedure, the number of PSA tests and digital rectal examinations during follow-up, obesity (OR = 1.57; 95% CI, 1.07-2.30) at the time of the initial procedure was associated with prostate cancer incidence during follow-up. Risk associated with obesity was confined to cases with follow-up less than 1,538 days, the median duration of follow-up among cases (OR = 1.95; 95% CI, 1.09-3.48). Obesity is associated with the presence of PIN in benign specimens and with future prostate cancer risk after an initial benign finding. Obesity may be a factor to consider when planning clinical follow-up after a benign biopsy.


Green synthesis of microalgae-based carbon dots for decoration of TiO2 nanoparticles in enhancement of organic dye photodegradation.
TiO2 is a well-known semiconductor used widely in the photocatalyst field, but its photocatalytic applications are hampered by a fast electron-hole recombination rate and low visible light absorption due to a wide-band-gap energy. Herein, we present a simple, low cost, and green approach to obtain carbon dots from microalgae, namely microalgae-based carbon dots (MCDs), using an unprecedented microwave-assisted treatment. The MCDs were successfully decorated on the surface of TiO2 nanoparticles. The as-prepared composite exhibited a superior photodegradation of methylene blue, compared with pristine TiO2 (83% and 27%, respectively) under visible light irradiation. The MCDs in TiO2-MCDs serve as electron reservoirs to trap photoinduced electrons and as photosensitizers for the improvement of visible light absorption; both factors play an important role in the improvement of the TiO2 photocatalytic activity. Furthermore, the as-prepared composite photocatalyst also exhibits high photostability and recyclability during the photodegradation of methylene blue. Therefore, this work provides an original approach to the development of environmentally friendly and highly effective photocatalysts for the treatment of various organic pollutants, which can go a long way toward ensuring a safe and sustainable environment.


Enhanced accumulation of reduced glutathione by Scopoletin improves survivability of dopaminergic neurons in Parkinson's model.
Parkinson's disease (PD) is a neuromotor disorder, primarily manifested by motor anomalies due to progressive loss of dopaminergic neurons. Although alterations in genetic factors have been linked with its etiology, exponential accumulation of environmental entities such as reactive oxygen species (ROS) initiate a cyclic chain reaction resulting in accumulation of cellular inclusions, dysfunctional mitochondria, and overwhelming of antioxidant machinery, thus accelerating disease pathogenesis. Involvement of oxidative stress in PD is further substantiated through ROS induced Parkinsonian models and elevated oxidative markers in clinical PD samples; thereby, making modulation of neuronal oxidative load as one of the major approaches in management of PD. Here we have found a potent antioxidant moiety Scopoletin (Sp), a common derivative in most of the nootropic herbs, with robust neuroprotective ability. Sp increased cellular resistance to ROS through efficient recycling of GSH to prevent oxidative damage. The Sp treated cells showed higher loads of reduced glutathione making them resistant to perturbation of antioxidant machinery or neurotoxin MPP+. Sp could restore the redox balance, mitochondrial function, and prevented oxidative damage, leading to recovery of dopaminergic neural networks and motion abilities in Drosophila genetic model of PD. Our data also suggest that Sp, in combination increases the therapeutic potency of L-DOPA by mitigating its chronic toxicity. Together, we highlight the possible ability of Sp in preventing oxidative stress mediated loss of dopaminergic neurons and at the same time enhance the efficacy of dopamine recharging regimens.


Coloured cornea replacements with anti-infective properties: expanding the safe use of silver nanoparticles in regenerative medicine.
Despite the broad anti-microbial and anti-inflammatory properties of silver nanoparticles (AgNPs), their use in bioengineered corneal replacements or bandage contact lenses has been hindered due to their intense yellow coloration. In this communication, we report the development of a new strategy to pre-stabilize and incorporate AgNPs with different colours into collagen matrices for fabrication of corneal implants and lenses, and assessed their in vitro and in vivo activity.


Female condom color and scent preference in Durban, South Africa.
To assess preferences for female condom (FC) colors and scents. Women aged 18-40 years were randomized to one of three FCs (FC2, Cupid1, Cupid2) two of which offered a choice of color and scent (red/strawberry, purple/vanilla, natural/unscented). Women could choose any variety within condom types while participating in an FC contraceptive efficacy study in South Africa. One hundred and thirty-three women were allocated to each FC type. Strawberry was the most popular variety for both FC2 and Cupid1 (60.9%, 78.3% respectively). Some women chose more than one variety but few chose the natural. Data support a clear preference for colored and scented FCs. These data can inform FC programme managers to predict demand for different varieties of FC and can adjust supply of FCs accordingly.


SHP2 Contributes to Resistance of KRAS p.G12C-Driven Lung Cancer Cells to MRTX849 by Regulating β-catenin/c-MYC Axis.
SHP2 has been promulgated to be involved in chemoresistance in a variety of cancers. However, its relationship with MRTX849-resistance in KRAS G12C mutant lung cancer has not been revealed. Lung cancer cell lines resistant to MRTX849 were first constructed by repeated dosing over 10 months, and the parental and drug-resistant strains were evaluated for SHP2 expression at different time points (2, 4, 6, 8, 10 months). We further analyzed whether SHP2 knockdown affects the sensitivity of MRTX849-resistant cells to MRTX849, and overexpression of SHP2 in the parental cell line to assess its effect on MRTX849 resistance, mainly by CCK-8, clonogenic assay, TUNEL staining and Western blotting to assess cell viability, proliferation, apoptosis, as well as β-catenin/c-MYC pathway protein expression. SHP2 expression remained largely unchanged in the parental cell line, whereas they were gradually upregulated in a time-dependent manner in the resistant cell line. SHP2 knockdown enhanced the sensitivity of MRTX849-resistant cell lines to MRTX849 and encouraged the killing of lung cancer cells by MRTX849, as indicated by a more significant decrease in cell viability and proliferation after knockdown of SHP2 in the presence of MRTX849 compared with MRTX849 untreated, while apoptosis was more significantly enhanced. Additionally, SHP2 overexpression enhanced the resistance of MRTX849 to lung cancer cells. Eventually, we confirmed that the MRTX849-resistance effect of SHP2 on lung cancer cells was through the activation of the β-catenin/c-MYC pathway. SHP2 contributes to resistance of KRAS G12C-driven lung cancer cells to MRTX849 by regulating β-catenin/c-MYC axis.


Chromosomes and causation of human cancer and leukemia: XXXVI. The 14q+ anomaly in an American Burkitt lymphoma and its value in the definition of lymphoproliferative disorders.
A case of a 10-year-old boy with American Burkitt lymphoma is presented in whom a 14q+ due to t(8;14)(q23;q32) was shown to exist in the ascitic lymphoma cells. This appears to be the first demonstration of such a translocation in uncultured material. In addition, another translocation involving the X chromosome, hitherto not observed in Burkitt tumors, was demonstrated. The karyotypic findings have been related to the cytogenetic experience in Burkitt and other lymphomas, with emphasis being put on the importance of the 14q+ anomaly in lymphoproliferative diseases.


Shelf life extension of minced squab using poly-lactic acid films containing Cinnamomum verum essential oil.
The effects of poly-lactic acid films containing different concentrations of Cinnamomum verum essential oil (CVEO) on microbial, chemical and sensory criteria of minced squab were assessed during the storage at 4 °C for 12 days. The counts of total aerobic bacteria, psychrotrophic bacteria, lactic acid bacteria, pseudomonads and Enterobacteriacea of wrapped samples with PLA films containing 0.6 and 0.9 % CVEO never reached 7 log CFU/g during the storage. Counts of E. coli and L. monocytogenes spiked to the PLA-wrapped with 0.6 or 0.9 CVEO squab samples were an order and 2 orders of magnitude lower, respectively, after the storage comparing to control. Also, samples wrapped with PLA films containing different concentrations of CVEO had lower total volatile base nitrogen, and thiobarbituric acid reactive substances values vs. control. Finally, applying of PLA films containing different concentration of CVEO, led to minor changes in sensory characteristics (P > 0.05).


Co-adsorption of Cations as the Cause of the Apparent pH Dependence of Hydrogen Adsorption on a Stepped Platinum Single-Crystal Electrode.
The successful deployment of advanced energy-conversion systems depends critically on our understanding of the fundamental interactions of the key adsorbed intermediates (hydrogen *H and hydroxyl *OH) at electrified metal-aqueous electrolyte interfaces. The effect of alkali metal cations (Li+ , Na+ , K+ , Cs+ ) on the non-Nernstian pH shift of the step-related voltammetric peak of the Pt(553) electrode is investigated over a wide pH window (1 to 13) by means of experimental and computational methods. The co-adsorbed alkali cations along the step weaken the OH adsorption at the step sites, causing a positive shift of the potential of the step-related peak on Pt(553). Density functional calculations explain the observations on the identity and concentration of alkali cations on the non-Nernstian pH shift, and demonstrate that cation-hydroxyl co-adsorption causes the apparent pH dependence of "hydrogen" adsorption in the step sites of platinum electrodes.


Examining a community model of epilepsy care for people with learning disabilities.
To assess the use of specialised medical epilepsy services by people with learning disabilities (LD) and epilepsy in a community healthcare setting, to compare medical epilepsy care in this group to current management guidelines, and to contrast important outcomes with those achieved in different healthcare settings. Postal survey with a carer completed questionnaire addressed to all adults with epilepsy registered on an LD register in Sheffield, UK (n=442). An analysis based on 225 returned questionnaires revealed that 22.7% of individuals with LD and epilepsy had been free of seizures for over 1 year. 95.1% were taking antiepileptic drugs (AEDs), 46.2% had had an EEG, and 41.3% a brain scan. 53.3% of diagnoses had been made by epilepsy experts, 38.7% of individuals with LD and epilepsy were under specialist review. Although patients with more severe epilepsy were more likely to be under specialist care, 60.6% of patients with ongoing seizures, 57.9% with major seizures and 68.7% of individuals taken to hospital with prolonged had no access to specialist advice. The proportion of people with LD who achieved seizure-control in the described population was lower than in all previously reported studies of LD patient groups. The poor outcome in terms of seizure-control, the lack of access to the epilepsy specialist service, and the apparent under-utilisation of investigations indicate that there are grounds for serious concern about this community model of medical epilepsy care for people with LD.


Quantification analysis of translation initiation signal in vertebrate mRNAs: effect of nucleotides at positions +4(-)+6 upon efficiency of translation initiation.
Concerning the translation initiation signal in vertebrate mRNAs, a consensus, sequence, (GCC)GCC(A or G) CCATGG, has been proposed, but actual initiation sequences differ from it in a greater or lesser degree. Kozak monitored selection by ribosomes of the first versus second ATG codons as a function of mutations introduced at positions +4, and +6 of the first ATG codon. Codons possessing G at +4 strongly enhanced selection of the first ATG codon. However, ATG codon recognition was unaffected by most mutations in positions and +6. These data were well understood by our quantification analysis.


Identification of an interactome network between lncRNAs and miRNAs in thyroid cancer reveals SPTY2D1-AS1 as a new tumor suppressor.
Thyroid cancer is the most common primary endocrine malignancy in adults and its incidence is rapidly increasing. Long non-coding RNAs (lncRNAs), generally defined as RNA molecules longer than 200 nucleotides with no protein-encoding capacity, are highly tissue-specific molecules that serve important roles in gene regulation through a variety of different mechanisms, including acting as competing endogenous RNAs (ceRNAs) that 'sponge' microRNAs (miRNAs). In the present study, using an integrated approach through RNA-sequencing of paired thyroid tumor and non-tumor samples, we have identified an interactome network between lncRNAs and miRNAs and examined the functional consequences in vitro and in vivo of one of such interactions. We have identified a likely operative post-transcriptional regulatory network in which the downregulated lncRNA, SPTY2D1-AS1, is predicted to target the most abundant and upregulated miRNAs in thyroid cancer, particularly miR-221, a well-known oncomiRNA in cancer. Indeed, SPTY2D1-AS1 functions as a potent tumor suppressor in vitro and in vivo, it is downregulated in the most advanced stages of human thyroid cancer, and it seems to block the processing of the primary form of miR-221. Overall, our results link SPTY2D1-AS1 to thyroid cancer progression and highlight the potential use of this lncRNA as a therapeutic target of thyroid cancer.


Adenomatoid tumor of testicular tunica albuginea mimicking testicular carcinoma.
Adenomatoid tumors are an uncommon neoplasm of the paratesticular tissues, with the majority of the reported cases involving the epididymis. A case is reported of an adenomatoid tumor of the testicular tunica albuginea that masqueraded as testicular carcinoma.


Complement in graft versus host disease: IL Depletion of complement components during a systemic graft versus host reaction in the rat (38499).
Serum complement (C) and C components were examined during a systemic graft versus host (GVH) reaction in the rat. In our series of experiments (Lewis times Brown Norway) F-1 hybrid rats (60-80g) were given 200 times 10-6 or 400 times 10-6 Lewis spleen cells intravenously. Clinical GVH disease appeared 5-7 days after cell injection. Five of six rats in the experimental groups had a fall in levels of serum C2 (20-76%) and C4 (75-98%). Only one of six rats in the control group had a significant fall in C components. In a subsequent experiment (Fisher 344 times Brown Norway) F-1hybrid rats (60g) were given 400 times 10-6 Fischer 344 spleen cells or 200 times 10-6 Fischer 344 Ficoll-Hypaque separated spleen lymphocytes. Clincal GVH disease in this instance appeared on day 10. As in the previous experiments C2 and C4 fell markedly, 20-60% and 60-8-%, respectively, from baseline titers. The control groups did not have a significant fall in C2 or C4. Further examination showed reduction in C3, C5, C6,AND C8 suggesting a sequential activation of the C system via the classical pathway. We have postulated that the cells undergoing blast transformation may be activating the C system through membrane changes during the GVH reaction. Furthermore, the deficiency of C AND C components during GVH disease may contribute to the increased susceptibility of the host to infection and sepsis.


The effect of a supplement which is nutrient dense compared to standard concentration on the total nutritional intake of anorectic patients.
A randomised, double-blind trial was conducted to compare the intake of a standard (4.2kJ/ml) and a nutrient dense (6.3kJ/ml) commericial liquid supplement, and to assess their effect on total nutrient intake. Both products were offered as a supplement to the regular hospital diet to 34 elderly in-patients with poor appetite and intake. Only 24 of these patients completed the entire supplementation period of 10 days. Median (interquartile range) volumes of intake were 300 (200-400) ml of the standard product and 400 (250-500) ml of the nutrient dense product (NS). Neither product decreased energy intake from the hospital diet. In fact, patients on the standard product increased slightly their intake from the hospital diet. This was enough to outweigh the increased contribution to total energy intake provided by the nutrient dense product. Both products received high palatability ratings, but high ratings did not imply high volume intake or good compliance.


[Desensitization for 4 successive years using calcium phosphate-adsorbed pollen extracts: study of sera with RAST and PRIST immunoimprints].
The clinical study for four years running of desensitization treatment to adsorbed pollen calcium phosphate, prepared "at request" by Institut Pasteur, shows that these preparations produced particularly good results. The population of allergic subjects is divided into two categories as from first year of treatment: good responders and non responders. A study on the serums of these patients, in view of a different "immuno-imprint" in these two groups, has not yet been conclusive, whereas we were expecting much from this prognosis test, which would have given us better treatment information.