Time course and extent of angiotensin II antagonism after irbesartan, losartan, and valsartan in humans assessed by angiotensin II dose response and radioligand receptor assay.
To compare the angiotensin II antagonistic properties of the usual recommended oral starting doses of various angiotensin II receptor antagonists-150 mg irbesartan, 80 mg valsartan, and 50 mg losartan-in humans. Eighteen healthy men were enrolled in a double-blind, randomized crossover study. Angiotensin II dose-effect curves of diastolic blood pressure and radioreceptor assay were performed before and up to 47 hours after single and multiple doses of the antagonists. The rightward shift of the angiotensin II dose-effect curves (dose ratio-1) assessed the antagonistic effects in vivo. The degree of receptor occupancy in plasma was detected by a rat lung radioreceptor assay ex vivo in vitro. All of the drugs clearly showed antagonistic effects to angiotensin II in vivo (dose ratio-1) and in vitro (radioreceptor assay). Within the given doses the dose ratio-1 for irbesartan was greater than for valsartan and losartan after single and repetitive dosing, reaching statistical significance at various time points up to 36 hours versus valsartan and up to 47 hours versus losartan. The apparent half-lives of the decay of the effects were approximately 8 hours for valsartan and losartan, whereas 15 to 18 hours were obtained with irbesartan. These findings were supported by the radioreceptor assay data: the percentage of receptor occupancy for irbesartan was significantly greater than for valsartan and losartan up to 47 hours. Angiotensin II antagonistic effects of irbesartan, valsartan, and losartan were compared. Irbesartan showed the slowest decay and longest duration of its antagonistic effects. With the recommended initial doses used in this study, the following rank order of antagonistic intensity was obtained: irbesartan > valsartan > losartan. The findings of this study, specifically the longer-lasting effects of irbesartan, may have clinical implications.


Energy requirements of infants and children.
The energy requirements of infants and children are defined as the amount of food energy needed to balance total energy expenditure (TEE) at a desirable level of physical activity, and to support optimal growth and development. New TEE data from doubly labeled water and heart rate monitoring are available to derive the energy requirements. Compared with the 1985 FAO/WHO/UNU recommendations, the 2004 FAO/WHO/UNU and 2002 IOM recommendations are approximately 12-20% lower during infancy. The 2004 FAO/WHO/UNU recommendations are on average 18% lower for boys and 20% lower for girls <7 years of age, and 12% lower for boys and 5% lower for girls 7-11 years of age. From 12 to 18 years of age, the requirements are 12% higher for boys and girls. The 2002 IOM recommendations are 8% lower for children <7 years of age, 2% lower for children 7-11 years of age, and 8% higher for children 12-18 years of age. Although the basic principles underlying energy requirements have not changed, the recommendations for energy intake have been decreased in infancy and early childhood, and increased in adolescence based on newly available TEE data.


[Corneal epithelial cells and human conjunctival cell line (Chang) produce an interleukin 3-like factor].
Tissue mast cells play a central role in the pathogenesis of allergic eye diseases. In the study reported here the authors investigated whether human corneal epithelial cells and a human epitheloid conjunctival cell line (Chang) can produce an interleukin 3 (IL 3)-like mast cell-activating factor. The activity was detected at a m.w. of 15 and 30 kD, the isoelectric points were located at a pH of 7.85, 7.15 and 6.75. The authors believe that this cytokine, which is produced by epithelial cells of the cornea and conjunctiva, might play an important role in the pathogenesis of allergic ocular diseases.


Should knee-length replace thigh-length graduated compression stockings in the prevention of deep-vein thrombosis?
To compare knee-length with thigh-length graduated compression stockings for correct application and rate of compliance when they are prescribed for the prevention of deep-vein thrombosis in surgical patients. Patients who were prescribed graduated compression stockings were prospectively studied in three surgical units at Groote Schuur Hospital from February to June 1997. Knee-length stockings were prescribed in the colorectal unit, while the thigh-length variety were prescribed in the hepatobiliary and trauma units. Patients were observed for the correct application and size of stockings, and the presence of compression bands. A total of 72 patients were studied. One patient in the knee-length group and 7 patients in the thigh-length group were not wearing their stockings. Twenty-one of 30 patients (70%) in the knee-length group and 15 of 42 (35.7%) in the thigh-length group had correctly applied stockings (P = 0.009). Knee-length are more likely to be correctly applied than thigh-length stockings. Knee-length should replace thigh-length stockings in general surgical patients.


Sexual victimization history, depression, and task physiology as predictors of sexual revictimization: results from a 6-month prospective pilot study.
The current study examined depression and physiological reactivity to a sexual threat task as longitudinal predictors of sexual revictimization in women with sexual victimization histories. The sample included 14 young adult women (M(age) = 19.15) who reported child sexual abuse. Heart rate and root mean square of the successive differences were measured at baseline and during the presentation of sexual victimization-related words during an Emotional Stroop task. Results indicated that women who reported a greater history of childhood sexual abuse and adult sexual victimization were at increased risk for sexual revictimization 6 months after initial data collection. Furthermore, even after accounting for their childhood and adult sexual victimization histories and depression symptoms, women who exhibited reduced, or blunted, physiological activity during the sexual victimization stimuli of the Stroop task were more likely to report sexual revictimization during the 6-month follow-up. The findings suggest that sexual victimization survivors may benefit from interventions that address physiological blunting and the recognition of sexual threat cues in their environment.


Evaluation of the 2016-2020 regional tuberculosis response framework, WHO Western Pacific Region.
To assess the implementation of the Regional framework for action on implementation of the End TB Strategy in the Western Pacific, 2016-2020 in countries and areas in the World Health Organization Western Pacific Region. We used a mixed methods approach to assess the framework's measurable and perceived impact. We conducted an analysis of national tuberculosis strategic plans, a cross-sectional survey of senior staff of tuberculosis programmes, key informant interviews and some country case studies. Of the 37 countries and areas of the Western Pacific Region, 14 had a national tuberculosis strategic plan, including all countries and areas with a high incidence of tuberculosis. Most senior tuberculosis programme staff who responded to the survey (16/23) found the regional framework useful when developing their national targets and grant applications. Programmatic challenges identified included financing, human resources, public-private mix, active case finding, and paediatric and drug-resistant tuberculosis. Most of the 17 key informants thought that the regional framework's categorization of actions (for all settings, for specific settings and for pre-elimination settings) was useful, but that the added value of the regional framework over other relevant documents was not obvious because of overlap in content. The regional framework influenced national level tuberculosis control planning and implementation in a positive way. A future regional framework should provide a longer-term strategic horizon and specifically address emerging trends and persistent problems faced by countries or areas of the region.


Studies on Tn951 (lac+) expression in Agrobacterium.
None of the Agrobacterium tumefaciens and A. rubi strains tested produces detectable amounts of beta-galactosidase although they are capable of utilizing lactose as sole source of carbon. This opportunity was taken to investigate the expression of lac transposon Tn951 (Cornelis et al. 1978) in Agrobacterium with the ultimate goal of using this system to investigate alien gene expression. When the transposon was introduced with the help of a broad-host range plasmid, RP1, the transconjugants produced significant quantities of beta-galactosidase which was inducible by isopropyl-beta-D-thiogalactopyranoside. Tn951 was capable of restoring the Lac+ phenotype to an A. tumefaciens mutant not capable of using lactose. Cellobiose, a known inducer of aldohexopyranoside: cytochrome c oxidoreductase (which regulates the characteristic 3-ketolactose production in Agrobacterium; van Beeumen and De Ley (1968), had no effect on beta-galactosidase activity.


Basic Characteristics of Oligodendrogliomas at the Shohada-e Tajrish Hospital (2008 to 2014).
Gliomas are the most prevalent subgroup of primary brain tumors with a relatively high mortality. However, oligodendrogliomas have a better prognosis compared to other subtypes due to their sensitivity to chemotherapy. Considering the low incidence and the resulting lack of information about oligodendrogliomas, particularly in Iran, this study aimed at assessing their basic characteristics. In this descriptive retrospective study, patients with definite diagnosis of oligodendroglioma were identified by reviewing the archives of pathology reports at the department of pathology of Shohada-e Tajrish Hospital during years 2008 to 2014. Age, gender, location, and the grade of the tumor were extracted and entered to the SPSS statistical software for analysis. A total of 182 patients, including 115 males (63.2%) and 67 females (36.8%), were included with a mean age of 38.5±13.36 years. Frontal lobe was involved in 53 patients (29.1%), parietal lobe in 31 (17.0%), temporal lobe in 22 (12.1%), frontoparietal area in 15 (8.2%), parieto-occipital area in 11 (6.0%), temporoparietal and frontotemporal areas each in 9 subjects (4.9%), occipital lobe in 5 (2.7%), and the brainstem in 4 (2.2%). Furthermore, 108 cases (59.3%) had grade-2 and the remaining74 patients (40.7%) had grade-3 anaplastic oligodendrogliomas. The mean age of subjects with brainstem oligodendrogliomas was significantly lower than the other patients (p=0.025). Oligodendrogliomas commonly effects the frontal lobe, followed by the parietal and temporal lobes. The mean age of subjects with brainstem lesions was significantly lower than other patients. Age, gender or location of the tumor did not independently predict a higher grade lesion.


The role of stoichiometric analysis in studies of metabolism: an example.
Stoichiometric analysis uses matrix algebra to deduce the constraints implicit in metabolic networks. When applied to simple networks, it can often give the impression of being an unnecessarily complicated way of arriving at information that is obvious from inspection, for example, that the sum of the concentrations of the adenine nucleotides is constant. Applied to a more complicated example, that of glycolysis in Trypanosoma brucei, it yields information that is far from obvious and may have importance for developing therapeutic ways of eliminating this parasite. Even in simplified form, the network contains nine reactions or transport steps involving 11 metabolites. This immediately shows that there must be at least two stoichiometric constraints, and indeed two can be recognized by inspection: conservation of adenine nucleotides and conservation of the two forms of NAD. There is, however, a third, which involves eight different phosphorylated intermediates in non-obvious combinations and is very difficult to recognize by inspection. It is also difficult to recognize by inspection that no fourth stoichiometric constraint exists. Gaussian elimination provides a systematic way of analysing a network in such a way that all the stoichiometric relationships that it contains emerge automatically.


CLAVATA2 forms a distinct CLE-binding receptor complex regulating Arabidopsis stem cell specification.
CLAVATA1 (CLV1), CLV2, CLV3, CORYNE (CRN), BAM1 and BAM2 are key regulators that function at the shoot apical meristem (SAM) of plants to promote differentiation by limiting the size of the organizing center that maintains stem cell identity in neighboring cells. Previous results have indicated that the extracellular domain of the receptor kinase CLV1 binds to the CLV3-derived CLE ligand. The biochemical role of the receptor-like protein CLV2 has remained largely unknown. Although genetic analysis suggested that CLV2, together with the membrane kinase CRN, acts in parallel with CLV1, recent studies using transient expression indicated that CLV2 and CRN from a complex with CLV1. Here, we report detection of distinct CLV2-CRN heteromultimeric and CLV1-BAM multimeric complexes in transient expression in tobacco and in Arabidopsis meristems. Weaker interactions between the two complexes were detectable in transient expression. We also find that CLV2 alone generates a membrane-localized CLE binding activity independent of CLV1. CLV2, CLV1 and the CLV1 homologs BAM1 and BAM2 all bind to the CLV3-derived CLE peptide with similar kinetics, but BAM receptors show a broader range of interactions with different CLE peptides. Finally, we show that BAM and CLV1 overexpression can compensate for the loss of CLV2 function in vivo. These results suggest two parallel ligand-binding receptor complexes controlling stem cell specification in Arabidopsis.


The effect of different flushing methods in a short peripheral catheter.
To develop a rabbit model of a short peripheral catheter (SPC) and to observe the effects of different flushing methods on blood vessels. Thirty rabbits were randomly divided into three groups (A, B, and C), with ten rabbits per group. In group A, we used pulsed flush; in group B, we used uniform flush; and no treatment was used in group C. We observed that a uniform flush reduced blockage, phlebitis, and exudation compared to a pulsed flush by visual observation. The histopathological examination found that the morphological changes in group A were more severe than in group B and C related to loss of venous endothelial cells, inflammatory cell infiltration, edema, epidermal and chondrocyte degeneration, except for the thrombosis on group B that was more serious than in group A, especially in the distal side of puncture points. The distal region of groups A and B had more inflammatory cell infiltration than the proximal region. Thrombosis was more severe in the distal region than in the proximal region in group B. The uniform flush produced less damage to the vascular endothelium and surrounding tissues and was superior to the pulsed flush. However, the uniform flush is prone to thrombosis.


Endometrial carcinoma arising in a bicornuate uterus.
Endometrial carcinomas arising in a bicornuate uterus are rare, only five case of which have been previously reported. We present a case of endometrial cancer arising in a bicornuate uterus, occurring in a 65-year-old woman. Unlike previously reported cases, our case showed mixed endometrial adenocarcinoma and undifferentiated carcinoma in one horn and focal adenocarcinoma in the other. Adequate tissue sampling of both horns is necessary for accurate diagnosis of malignancy in patients with a bicornuate uterus. Physicians should be aware of the possibility of this abnormality in cases when endometrial cancer is suspected but histology fails to confirm.


Prognostic factors in patients with endocrine tumours of the duodenopancreatic area.
The development of endocrine tumours of the duodenopancreatic area (ETDP) is thought to be slow, but their natural history is not well known. The aim of this study was to determine the factors that influence survival of patients with ETDP. Eighty two patients with ETDP (44 non-functioning tumours, 23 gastrinomas, seven calcitonin-secreting tumours, four glucagonomas, three insulinomas, one somatostatinoma) followed from October 1991 to June 1997 were included in the study. The following factors were investigated: primary tumour size, hormonal clinical syndrome, liver metastases, lymph node metastases, extranodular/extrahepatic metastases, progression of liver metastases, local invasion, complete resection of the primary tumour, and degree of tumoral differentiation. The prognostic significance of these factors was investigated by uni- and multi-variate analysis. Twenty eight patients (34%) died within a median of 17 months (range 1-110) from diagnosis. Liver metastases (p = 0.001), lymph node metastases (p = 0.001), progression of liver metastases (p < 0.00001), lack of complete resection of the primary tumour (p = 0.001), extranodular/extrahepatic metastases (p = 0.001), local invasion (p = 0.001), primary tumour size > or = 3 cm (p = 0.001), non-functioning tumours (p = 0.02), and poor tumoral differentiation (p = 0.006) were associated with an unfavourable outcome by univariate analysis. Multivariate analysis identified only liver metastases (risk ratio (RR) = 8.3; p < 0.0001), poor tumoral cell differentiation (RR = 8.1; p = 0.0001), and lack of complete resection of the primary tumour (RR = 4.8; p = 0.0007) as independent risk factors. Five year survival rates were 40 and 100% in patients with and without liver metastases, 85 and 42% in patients with and without complete resection of primary tumour, and 17 and 71% in patients with poor and good tumour cell differentiation respectively. Liver metastases are a major prognostic factor in patients with ETDP. Progression of liver metastases is also an important factor which must be taken into account when deciding on the therapeutic approach. The only other independent prognostic factors are tumoral cell differentiation and complete resection of the primary tumour.


Regression analysis for detecting epileptic seizure with different feature extracting strategies.
Due to the excitability of neurons in the brain, a neurological disorder is produced known as epilepsy. The brain activity of patients suffering from epilepsy is monitored through electroencephalography (EEG). The multivariate nature of features from time domain, frequency domain, complexity and wavelet entropy based, and the statistical features were extracted from healthy and epileptic subjects using the Bonn University database and seizure and non-seizure intervals using the CHB MIT database. The robust machine learning regression methods based on regression, support vector regression (SVR), regression tree (RT), ensemble regression, Gaussian process regression (GPR) were employed for detecting and predicting epileptic seizures. Performance was measured in terms of root mean square error (RMSE), squared error, mean square error (MSE) and mean absolute error (MAE). Moreover, detailed optimization was performed using a RT to predict the selected features from each feature category. A deeper analysis was conducted on features and tree regression methods where optimal RMSE and MSE results were obtained. The best optimal performance was obtained using the ensemble boosted regression tree (BRT) and exponential GPR with an RMSE of 0.47, an MSE (0.22), an R Square (RS) (0.25) and an MAE (0.30) using the Bonn University database and support vector machine (SVM) fine Gaussian with RMSE (0.63634), RS (0.03), MSE (0.40493) and MAE (0.31744); squared exponential GPR and rational quadratic GPR with an RMSE of 0.63841, an RS (0.03), an MSE (0.40757) and an MAE (0.3472) was obtained using the CHB MIT database. A further deeper analysis for the prediction of selected features was performed on an RT to compute the optimal feasible point, observed and estimated function values, function evaluation time, objective function evaluation time and overall elapsed time.


Prediction of Postoperative Creatinine Levels by Artificial Intelligence after Partial Nephrectomy.
Background and Objectives: Multiple factors are associated with postoperative functional outcomes, such as acute kidney injury (AKI), following partial nephrectomy (PN). The pre-, peri-, and postoperative factors are heavily intertwined and change dynamically, making it difficult to predict postoperative renal function. Therefore, we aimed to build an artificial intelligence (AI) model that utilizes perioperative factors to predict residual renal function and incidence of AKI following PN. Methods and Materials: This retrospective study included 785 patients (training set 706, test set 79) from six tertiary referral centers who underwent open or robotic PN. Forty-four perioperative features were used as inputs to train the AI prediction model. XG-Boost and genetic algorithms were used for the final model selection and to determine feature importance. The primary outcome measure was immediate postoperative serum creatinine (Cr) level. The secondary outcome was the incidence of AKI (estimated glomerular filtration rate (eGFR) < 60 mL/h). The average difference between the true and predicted serum Cr levels was considered the mean absolute error (MAE) and was used as a model evaluation parameter. Results: An AI model for predicting immediate postoperative serum Cr levels was selected from 2000 candidates by providing the lowest MAE (0.03 mg/dL). The model-predicted immediate postoperative serum Cr levels correlated closely with the measured values (R2 = 0.9669). The sensitivity and specificity of the model for predicting AKI were 85.5% and 99.7% in the training set, and 100.0% and 100.0% in the test set, respectively. The limitations of this study included its retrospective design. Conclusions: Our AI model successfully predicted accurate serum Cr levels and the likelihood of AKI. The accuracy of our model suggests that personalized guidelines to optimize multidisciplinary plans involving pre- and postoperative care need to be developed.


Retention of the herpes simplex virus type 1 (HSV-1) UL37 protein on single-stranded DNA columns requires the HSV-1 ICP8 protein.
The UL37 and ICP8 proteins present in herpes simplex virus type 1 (HSV-1)-infected-cell extracts produced at 24 h postinfection coeluted from single-stranded-DNA-cellulose columns. Experiments carried out with the UL37 protein expressed by a vaccinia virus recombinant (V37) revealed that the UL37 protein did not exhibit DNA-binding activity in the absence of other HSV proteins. Analysis of extracts derived from cells coinfected with V37 and an ICP8-expressing vaccinia virus recombinant (V8) and analysis of extracts prepared from cells infected with the HSV-1 ICP8 deletion mutants d21 and n10 revealed that the retention of the UL37 protein on single-stranded DNA columns required a DNA-binding-competent ICP8 protein.


Exploratory Approach to Incorporating Carbon Footprint in Health Technology Assessment (HTA) Modelling: Cost-Effectiveness Analysis of Health Interventions in the United Kingdom.
Health interventions contribute to the production of greenhouse gas emissions. Thus, reducing carbon footprint is essential in supporting the UK National Health Service (NHS) pathway to net zero. This study explores the approach in which carbon footprint can be included when applying Health Technology Assessment (HTA) modelling using obesity intervention in the United Kingdom (UK) as a case study. Using decision analytic modelling, we conducted an HTA incorporating the impacts of obesity-related treatment decisions on UK carbon emissions. A cohort Markov model was used to track the emissions of the UK population after receiving one of two obesity treatments: semaglutide and bariatric surgery. This study introduced two new carbon measurement tools that may be useful for future policymaking, incremental carbon footprint effectiveness ratio (ICFER) and incremental carbon footprint cost ratio (ICFCR), which made it possible to assess the emission impacts of proposed health policies. Using the obesity intervention case study, we found that both treatments have an incremental cost-effectiveness ratio (ICER) of < £20,000 per quality-adjusted life-years (QALYs) gained. This is below the UK threshold, indicating that these are cost-effective treatments for obesity, but could increase the NHS carbon footprint. However, it could reduce the overall UK societal carbon footprint by reducing the number of people with obesity. The ICFCR shows a reduction of 1.13-4.51 kgCO2e (kilogram of carbon dioxide equivalent) for every pound spent on obesity treatment. This study illustrates a case study for estimating the effect of health policies on carbon emissions and provides a quantitative measure for obesity-related treatment decisions.


Metabolomics Deciphered Metabolic Reprogramming Required for Biofilm Formation.
Biofilm formation plays a key role in many bacteria causing infections, which mostly accounts for high-frequency infectious recurrence and antibiotics resistance. In this study, we sought to compare modified metabolism of biofilm and planktonic populations with UTI89, a predominant agent of urinary tract infection, by combining mass spectrometry based untargeted and targeted metabolomics methods, as well as cytological visualization, which enable us to identify the driven metabolites and associated metabolic pathways underlying biofilm formation. Surprisingly, our finding revealed distinct differences in both phenotypic morphology and metabolism between two patterns. Furthermore, we identified and characterized 38 differential metabolites and associated three metabolic pathways involving glycerolipid metabolism, amino acid metabolism and carbohydrate metabolism that were altered mostly during biofilm formation. This discovery in metabolic phenotyping permitted biofilm formation shall provide us a novel insight into the dissociation of biofilm, which enable to develop novel biofilm based treatments against pathogen causing infections, with lower antibiotic resistance.


Pancreatic Vasoactive Intestinal Peptide-Producing Tumor as a Rare Cause of Acute Diarrhea and Severe Hypokalemia.
Pancreatic vasoactive intestinal peptide-producing tumor (VIPoma) is a rare functional neuroendocrine tumor most commonly presenting with watery diarrhea and electrolyte abnormalities that include hypokalemia, hypercalcemia and metabolic acidosis. This type of tumor has usually insidious clinical behavior that is characterized by chronic secretory diarrhea, lasting usually from months to years before diagnosis, not responsive to usual medical or dietary treatment approaches. Given the resemblance of VIPoma with other more common causes of chronic watery diarrhea, the final diagnosis is often delayed and the tumors are usually large and metastatic at the time of detection. Our case of pancreatic VIPoma demonstrates an unusual clinical course for this type of tumor with acute refractory diarrhea and rapid deterioration of patient's clinical and biochemical status that required emergent in-hospital diagnosis and treatment. Our patient is a 45-year-old woman who presented with abrupt, watery diarrhea during the past 24 h before admission accompanied with severe hypokalemia as well as hyponatremia, hyperglycemia and hypercalcemia. Despite aggressive management with fluid administration and electrolyte replenishment, no significant improvement in patient's symptoms and electrolyte imbalance was observed. After exclusion of other causes of acute diarrhea from the medical history and the laboratory tests, the clinical suspicion of a functional neuroendocrine tumor was raised. After the establishment of final diagnosis of pancreatic VIPoma with biochemical tests and magnetic resonance imaging (MRI), somatostatin analogues were prescribed and the patient underwent distal pancreatectomy and splenectomy with no signs of lymph node and splenic metastases. Few days after the surgical resection of the tumor, the patient readmitted to our hospital with tarry stools and severe anemia. The abdominal computed tomography (CT) revealed a retroperitoneal cystic lesion. The gastrointestinal bleeding gradually recessed after endoscopic hemostasis of duodenal ulcer lesions whereas the cystic lesion (postoperative lymphocele) was successfully drained under CT-guidance before discharge. After almost 10 years postoperatively, the patient is still asymptomatic with no signs of relapse or metastasis of the disease in the periodic laboratory and imaging follow-up. In conclusion, pancreatic VIPoma can sometimes manifest symptoms of abrupt onset and rapid progression that require high clinical suspicion, appropriate diagnostic workup and aggressive management.


Hydroxychloroquine/chloroquine for the treatment of hospitalized patients with COVID-19: An individual participant data meta-analysis.
Results from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data, including unanalyzed data from trials terminated early, enables more detailed investigation of the efficacy and safety of HCQ/CQ among subgroups of hospitalized patients. We searched ClinicalTrials.gov in May and June 2020 for US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients in which the outcomes defined in this study were recorded or could be extrapolated. The primary outcome was a 7-point ordinal scale measured between day 28 and 35 post enrollment; comparisons used proportional odds ratios. Harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator. The data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions. Eight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We did not find evidence of a difference in COVID-19 ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and found no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively). The findings of this individual participant data meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients.


Comparative evaluation of autocontouring in clinical practice: A practical method using the Turing test.
Automated techniques for estimating the contours of organs and structures in medical images have become more widespread and a variety of measures are available for assessing their quality. Quantitative measures of geometric agreement, for example, overlap with a gold-standard delineation, are popular but may not predict the level of clinical acceptance for the contouring method. Therefore, surrogate measures that relate more directly to the clinical judgment of contours, and to the way they are used in routine workflows, need to be developed. The purpose of this study is to propose a method (inspired by the Turing Test) for providing contour quality measures that directly draw upon practitioners' assessments of manual and automatic contours. This approach assumes that an inability to distinguish automatically produced contours from those of clinical experts would indicate that the contours are of sufficient quality for clinical use. In turn, it is anticipated that such contours would receive less manual editing prior to being accepted for clinical use. In this study, an initial assessment of this approach is performed with radiation oncologists and therapists. Eight clinical observers were presented with thoracic organ-at-risk contours through a web interface and were asked to determine if they were automatically generated or manually delineated. The accuracy of the visual determination was assessed, and the proportion of contours for which the source was misclassified recorded. Contours of six different organs in a clinical workflow were for 20 patient cases. The time required to edit autocontours to a clinically acceptable standard was also measured, as a gold standard of clinical utility. Established quantitative measures of autocontouring performance, such as Dice similarity coefficient with respect to the original clinical contour and the misclassification rate accessed with the proposed framework, were evaluated as surrogates of the editing time measured. The misclassification rates for each organ were: esophagus 30.0%, heart 22.9%, left lung 51.2%, right lung 58.5%, mediastinum envelope 43.9%, and spinal cord 46.8%. The time savings resulting from editing the autocontours compared to the standard clinical workflow were 12%, 25%, 43%, 77%, 46%, and 50%, respectively, for these organs. The median Dice similarity coefficients between the clinical contours and the autocontours were 0.46, 0.90, 0.98, 0.98, 0.94, and 0.86, respectively, for these organs. A better correspondence with time saving was observed for the misclassification rate than the quantitative contour measures explored. From this, we conclude that the inability to accurately judge the source of a contour indicates a reduced need for editing and therefore a greater time saving overall. Hence, task-based assessments of contouring performance may be considered as an additional way of evaluating the clinical utility of autosegmentation methods.


[Infectious diseases among Brazilian preschool children attending daycare centers].
The scope of this article is to analyze the prevalence and factors associated with the development of infectious diseases that affect children in daycare centers, namely respiratory infections, diarrheal disease and parasitic infections. Bibliographic research was conducted in the MEDLINE, LILACS and SciELO databases, and observational studies were included. 129 studies were identified, of which 21 were considered relevant to this study, namely two longitudinal and 19 cross-sectional studies. The systematization of the reviewed studies highlighted: i) the presence of intestinal parasites was the main outcome analyzed, followed by respiratory infections; ii) only one study investigated the occurrence of diarrheal disease; iii) the Giardia lamblia was the most prevalent parasitosis; iv) the variables that were most often associated with the development of intestinal parasitosis were child age, family income and maternal education; v) the attendance at daycare centers was a risk factor for intestinal parasites and respiratory infections. Respiratory and parasitic infections are major problems in institutionalized children in daycare centers. The reduction of such diseases involves a complex web of socio-economic, sanitation and daycare center infrastructure aspects.


A 4-selenocysteine, 2-selenocysteine insertion sequence (SECIS) element methionine sulfoxide reductase from Metridium senile reveals a non-catalytic function of selenocysteines.
Selenocysteine (Sec) residues occur in thiol oxidoreductase families, and functionally characterized selenoenzymes typically have a single Sec residue used directly for redox catalysis. However, how new Sec residues evolve and whether non-catalytic Sec residues exist in proteins is not known. Here, we computationally identified several genes with multiple Sec insertion sequence (SECIS) elements, one of which was a methionine-R-sulfoxide reductase (MsrB) homolog from Metridium senile that has four in-frame UGA codons and two nearly identical SECIS elements. One of the UGA codons corresponded to the conserved catalytic Sec or Cys in MsrBs, whereas the three other UGA codons evolved recently and had no homologs with Sec or Cys in these positions. Metabolic (75)Se labeling showed that all four in-frame UGA codons supported Sec insertion and that both SECIS elements were functional and collaborated in Sec insertion at each UGA codon. Interestingly, recombinant M. senile MsrB bound iron, and further analyses suggested the possibility of binding an iron-sulfur cluster by the protein. These data show that Sec residues may appear transiently in genes containing SECIS elements and be adapted for non-catalytic functions.


Viral hepatitis: past and future of HBV and HDV.
Viral hepatitis is a significant disease afflicting hundreds of millions of people. Hepatitis-causing viruses initiate significant morbidity and mortality by establishing both acute and chronic infections, and several of these viruses are specifically associated with the development of hepatocellular carcinoma (HCC). Consequently, intense research efforts are focused on increasing our understanding of virus biology and on improving antiviral therapy. Even though viral hepatitis can be caused by several viruses from a range of virus families, the discovery of components of the hepatitis B virus (HBV) became a catalyst for the development of diagnostic assays that differentiate between these viruses as well as strategies for novel methods of vaccine development. Improvements in both the treatment and prevention of viral hepatitis are advancing rapidly. However, HBV, along with the associated infection by the hepatitis D virus, is still among the most common pathogens afflicting humans.


Addressing HIV prevention and disease burden among Africans aged over 50 years.
Although sub-Saharan Africans aged 50 years or over constitute about 4.7% of the general population and 5.6% of the total adult population infected with HIV, they remain the forgotten cohort of the AIDS pandemic. Based on a literature review and data from the World Health Organization Demographic Health Surveys, the authors analyse the prevalence of HIV among African men aged 50-59 and provide a brief analysis of risk factors, as well as the influence of demographic, epidemiologic, pathophysiologic and socio-cultural transitions on HIV prevention and disease burden among older Africans. Evidence-based HIV prevention and treatment interventions are urgently required in order to address the wellbeing of HIV-infected, older Africans.


Chronic disaster impact: the long-term psychological and physical health consequences of housing damage due to induced earthquakes.
To evaluate the long-term (psychosomatic) health consequences of man-made earthquakes compared with a non-exposure control group. Exposure was hypothesised to have an increasingly negative impact on health outcomes over time. Large-scale gas extraction in the Netherlands causing earthquakes and considerable damage. A representative sample of inhabitants randomly selected from municipal population records; contacted 5 times during 21 months (T1: N=3934; T5: N=2150; mean age: 56.54; 50% men; at T5, N=846 (39.3%) had no, 459 (21.3%) once and 736 (34.2%) repeated damages). (Psychosomatic) health outcomes: self-rated health and Mental Health Inventory (both: validated; Short Form Health Survey); stress related health symptoms (shortened version of previously validated symptoms list). Independent variable: exposure to the consequences of earthquakes assessed via physical (peak ground acceleration) and personal exposure (damage to housing: none, once, repeated). Exposure to induced earthquakes has negative health consequences especially for those whose homes were damaged repeatedly. Compared with a no-damage control group, repeated damage was associated with lower self-rated health (OR:1.64), mental health (OR:1.83) and more stress-related health symptoms (OR:2.52). Effects increased over time: in terms of relative risk, by T5, those whose homes had repeated damage were respectively 1.60 and 2.11 times more likely to report poor health and negative mental health and 2.84 times more at risk of elevated stress related health symptoms. Results for physical exposure were comparable. This is the first study to provide evidence that induced earthquakes can have negative health consequences for inhabitants over time. It identifies the subpopulation particularly at risk: people with repeated damages who have experienced many earthquakes. Findings can have important implications for the prevention of negative health consequences of induced earthquakes.


Magnetic resonance imaging in the evaluation of congenital heart disease.
Magnetic resonance imaging is a powerful tool for studying patients with congenital heart disease. Its phenomenal contrast resolution, improved spatial resolution, and large field-of-view allow for graphic depiction of a wide array of congenital defects. Although this method was originally handicapped by the time it took to perform an exam and by poor image quality, advances in hardware and software coupled with attention to technique have led to a reliable diagnostic imaging modality. Although the technology is still evolving, it is not unreasonable to hope that the noninvasive imaging modalities of magnetic resonance and echocardiography will ultimately replace angiography in the evaluation of congenital heart disease.


MBGR protocol of orofacial myofunctional evaluation with scores.
The MBGR Protocol with scores was first published in 2009. This protocol was widely administered by speech-language pathologists experienced in orofacial myology in different states from Brazil for four months. From the comments and suggestions of these professionals, the protocol was reviewed and modified. A consistent visual training materials program was prepared, and speech-language pathologists, experienced in orofacial myology from different states of Brazil, Venezuela, Peru, and Colombia were trained with the provided materials. These speech-language pathologists administered the protocol for two years. From the data collected by the speech-language pathologists, modifications were made, and a final version was designed. This final version was administered for two-months by the same speech-language pathologists from Brazil, Venezuela, Peru, and Colombia in order to re-test the final version of MBGR protocol. The aim of this study was to demonstrate the efficiency and effectiveness of the protocol to assess orofacial myofunctional alterations. The final version of the MBGR protocol with scores has proven to be efficient and effective in the identification of individuals experiencing orofacial myofunctional disorders.


Directed evolution and targeted mutagenesis to murinize Listeria monocytogenes internalin A for enhanced infectivity in the murine oral infection model.
Internalin A (InlA) is a critical virulence factor which mediates the initiation of Listeria monocytogenes infection by the oral route in permissive hosts. The interaction of InlA with the host cell ligand E-cadherin efficiently stimulates L. monocytogenes entry into human enterocytes, but has only a limited interaction with murine cells. We have created a surface display library of randomly mutated InlA in a non-invasive heterologous host Lactococcus lactis in order to create and screen novel variants of this invasion factor. After sequential passage through a murine cell line (CT-26), multiple clones with enhanced invasion characteristics were identified. Competitive index experiments were conducted in mice using selected mutations introduced into L. monocytogenes EGD-e background. A novel single amino acid change was identified which enhanced virulence by the oral route in the murine model and will form the basis of further engineering approaches. As a control a previously described EGD-InlA(m) murinized strain was also re-created as part of this study with minor modifications and designated EGD-e InlA(m)*. The strain was created using a procedure that minimizes the likelihood of secondary mutations and incorporates Listeria-optimized codons encoding the altered amino acids. L. monocytogenes EGD-e InlA(m)* yielded consistently higher level murine infections by the oral route when compared to EGD-e, but did not display the two-fold increased invasion into a human cell line that was previously described for the EGD-InlA(m) strain. We have used both site-directed mutagenesis and directed evolution to create variants of InlA which may inform future structure-function analyses of this protein. During the course of the study we engineered a murinized strain of L. monocytogenes EGD-e which shows reproducibly higher infectivity in the intragastric murine infection model than the wild type, but does not display enhanced entry into human cells as previously observed. This murinized L. monocytogenes strain will provide a useful tool for the analysis of the gastrointestinal phase of listeriosis.


Using Response Times for Joint Modeling of Response and Omission Behavior.
For adequate modeling of missing responses, a thorough understanding of the nonresponse mechanisms is vital. As a large number of major testing programs are in the process or already have been moving to computer-based assessment, a rich body of additional data on examinee behavior becomes easily accessible. These additional data may contain valuable information on the processes associated with nonresponse. Bringing together research on item omissions with approaches for modeling response time data, we propose a framework for simultaneously modeling response behavior and omission behavior utilizing timing information for both. As such, the proposed model allows (a) to gain a deeper understanding of response and nonresponse behavior in general and, in particular, of the processes underlying item omissions in LSAs, (b) to model the processes determining the time examinees require to generate a response or to omit an item, and (c) to account for nonignorable item omissions. Parameter recovery of the proposed model is studied within a simulation study. An illustration of the model by means of an application to real data is provided.


Postoperative surveillance and long-term outcome after endovascular aortic aneurysm repair in the Netherlands: study protocol for the retrospective ODYSSEUS study.
Strict imaging surveillance protocols to detect complications following endovascular aneurysm repair (EVAR) are common practice. However, controversy exists as to whether all EVAR patients need intense surveillance. The 2019 European Society for Vascular Surgery guidelines for management of abdominal aortic aneurysm (AAA) suggest that patients may be considered for limited follow-up with imaging if classified as 'low risk' for complications based on their initial postoperative imaging. The current study aims to investigate the intervention-free survival and overall survival stratified for patients with and without yearly imaging surveillance. The Observing a Decade of Yearly Standardised Surveillance in EVAR patients with Ultrasound or CT Scan study comprises a national multicentre retrospective cohort study in 17 medical centres. Consecutive patients with an asymptomatic or symptomatic infrarenal AAA who underwent EVAR between January 2007 and January 2012 will be included in this study with follow-up until December 2018. Clinical variables and all follow-up information will be retrieved in extensive data collection from the patient's medical records. In addition, an e-survey was sent to vascular surgeons at the 17 participating centres to gauge their opinions regarding the possibility of safely reducing the frequency of imaging surveillance. Primary endpoints are intervention after EVAR and aneurysm-related mortality. The initial estimated sample size is 1997 patients. The study has been approved by the Medical Ethics Review Committee of the Amsterdam UMC, location Academic Medical Centre, Amsterdam, the Netherlands. Study findings will be disseminated via presentations at conferences and publications in peer-reviewed journal. The Netherlands Trial Registry, NL6953 (old: NTR28773).


Endocrine cell proliferation and carcinoid development: a review of new aspects of hypergastrinaemic atrophic gastritis.
The accumulating evidence of an association between antrum-sparing hypergastrinaemic atrophic gastritis, frequently associated with pernicious anaemia, and the occurrence of gastric carcinoid tumours is briefly reviewed. The development of argyrophil cell carcinoid tumours in the atrophic fundic mucosa seems to be related to argyrophil cell hyperplasia caused by hypergastrinaemia. Epidemiologic considerations indicate that the gastric carcinoid generally is underdiagnosed and that the incidence of this tumour is higher than previously recognized. The clinical relevance of minute gastric carcinoids, or endocrine cell 'adenomas', is obscure. However, larger tumours should be regarded as potentially malignant. These findings are relevant to the aspect of long-term medically induced achlorhydria leading to hypergastrinaemia.


Early life exposure to fructose and offspring phenotype: implications for long term metabolic homeostasis.
The consumption of artificially sweetened processed foods, particularly high in fructose or high fructose corn syrup, has increased significantly in the past few decades. As such, interest into the long term outcomes of consuming high levels of fructose has increased significantly, particularly when the exposure is early in life. Epidemiological and experimental evidence has linked fructose consumption to the metabolic syndrome and associated comorbidities-implicating fructose as a potential factor in the obesity epidemic. Yet, despite the widespread consumption of fructose-containing foods and beverages and the rising incidence of maternal obesity, little attention has been paid to the possible adverse effects of maternal fructose consumption on the developing fetus and long term effects on offspring. In this paper we review studies investigating the effects of fructose intake on metabolic outcomes in both mother and offspring using human and experimental studies.


Effect of beta-adrenoceptor blockade on thermoregulation during prolonged exercise.
The effect of clinically used equipotent doses of nonselective (beta 1/beta 2; propranolol) and selective (beta 1; atenolol) beta-adrenoceptor blockers on thermoregulation was studied during prolonged exercise in the heat. Oral propranolol (160 mg/day), atenolol (100 mg/day) or matching placebo were taken for 6 days each by 11 healthy young adult caucasian males. Subjects participated in 2 h of block-stepping at a work rate of 54 W in an environmental chamber with a temperature of 33.2 +/- 0.3 degree C dry bulb and 31.7 /+- 0.3 degree C wet bulb, 2 h after ingestion of the final dose of each drug. Both active agents produced similar marked (P less than 0.001) increases in subjective perception of effort, the mechanism of which was not immediately evident from changes in serum electrolytes, blood glucose, blood lactate, or ventilatory parameters. Propranolol did, however, cause a greater rise in serum K+ than placebo (P less than 0.02) and atenolol (P = NS) after exercise. Although rectal and mean skin temperatures were insignificantly altered by beta-adrenoceptor blockade, an increased total sweat production was noted with propranolol (P less than 0.01 vs. placebo) and to a lesser degree atenolol (P = NS vs. placebo) therapy. Analysis of the time course of sweat production showed the propranolol-mediated enhancement of sweating to ensue largely during the initial hour of block-stepping and to be transient in nature. The scientific and clinical implications of this observation will be dependent upon the precise underlying mechanism, a factor not identified by the present study.


T-bet-deficient NOD mice are protected from diabetes due to defects in both T cell and innate immune system function.
The transcription factor T-bet (Tbx21) is critical for Th1 polarization of CD4(+) T cells. Genetic deletion of Tbx21 can cause either exacerbation or attenuation of different autoimmune diseases in animal models. In the nonobese diabetic (NOD) mouse, genetic deletion of the Ifng or the Il12b (IL-12p40) genes, which are both critical Th1 cytokines, does not reduce the incidence of autoimmune diabetes. These results suggest that autoimmune diabetes in the NOD may not be a Th1-driven disease. However, we report that Tbx21 deficiency in the NOD mouse completely blocks insulitis and diabetes due to defects both in the initiation of the anti-islet immune response and in the function of CD4(+) effector T cells. We find defective priming of naive islet-reactive T cells by the innate immune system in Tbx21(-/-) animals. By contrast to naive cells, activated islet-reactive BDC2.5 TCR-transgenic T cells do not require Tbx21 in recipient animals for efficient adoptive transfer of diabetes. However, when these BDC2.5 TCR-transgenic effector cells lack Tbx21, they are less effective at entering the pancreas and promoting diabetes than Tbx21(+/+) cells. Tbx21(-/-) regulatory T cells function normally in vitro and diabetes can be restored in Tbx21(-/-) mice by reducing regulatory T cell numbers. Thus, the absence of diabetes in the NOD.Tbx21(-/-) is due to intrinsic defects in both T cells and cells of the innate immune system paired with the relative preservation of regulatory T cell function.


How to improve patient safety and quality of care in breast implant surgery? First outcomes from the Dutch Breast Implant Registry (2015-2017).
Although the use of breast implants is generally considered to be safe, breast implants are associated with short- and long-term complications. To evaluate and improve the quality of breast implant surgery, and increase our knowledge of implant performance, the national Dutch Breast Implant Registry (DBIR) was established in 2015. DBIR is one of the first up-and-running breast implant registries worldwide and follows an opt-out structure. This article provides an overview of the first outcomes and experiences of the DBIR. The national coverage of DBIR was studied using data from the Dutch Health and Youth Care Inspectorate. The incidence rate of breast implants was calculated for 2016 and 2017, and patient, device, and surgery characteristics were compared between cosmetic breast augmentations or reconstructive indications. Four infection control, measures were selected to demonstrate the variation in the Dutch clinical practice. In 2016, 95% of the hospitals and 78% of the private clinics participated in DBIR. Between 2015 and 2017, a total of 15,049 patients and 30,541 breast implants were included. A minimum breast implant incidence rate of 1 per 1,691 women could be determined for 2017. The majority of devices were inserted for a cosmetic indication (85.2%). In general, patient, device, and surgery characteristics differed per indication group. Substantial variation was seen in the use of infection control measures (range 0-100%). Preliminary results obtained from DBIR show high national participation rates and support further developments toward the improvement of breast implant surgery and patient safety.


Incidence of the initiation of comfort care immediately following emergent neurosurgical and endovascular procedures.
It is unknown what proportion of patients who undergo emergent neurosurgical procedures initiate comfort care (CC) measures shortly after the operation. The purpose of the present study was to analyze the proportion and predictive factors of patients who initiated CC measures within the same hospital admission after undergoing emergent neurosurgery. This retrospective cohort study included all adult patients who underwent emergent neurosurgical and endovascular procedures at a single center between 2009 and 2014. Primary and secondary outcomes were initiation of CC measures during the initial hospitalization and determination of predictive factors, respectively. Of the 1295 operations, comfort care was initiated in 111 (8.6%) during the initial admission. On average, CC was initiated 9.3 ± 10.0 days postoperatively. One-third of the patients switched to CC within 3 days. In multivariate analysis, patients > 70 years of age were significantly more likely to undergo CC than those < 50 years (70-79 years, p = 0.004; > 80 years, p = 0.0001). Two-thirds of CC patients had been admitted with a cerebrovascular pathology (p < 0.001). Admission diagnosis of cerebrovascular pathology was a significant predictor of initiating CC (p < 0.0001). A high Hunt and Hess grade of IV or V in patients with subarachnoid hemorrhage was significantly associated with initiation of CC compared to a low grade (27.1% vs 2.9%, p < 0.001). Surgery starting between 15:01 and 06:59 hours had a 1.70 times greater odds of initiating CC compared to surgery between 07:00 and 15:00. Initiation of CC after emergent neurosurgical and endovascular procedures is relatively common, particularly when an elderly patient presents with a cerebrovascular pathology after typical operating hours.


Association between consumption of dairy products and incident type 2 diabetes--insights from the European Prospective Investigation into Cancer study.
The public health burden of type 2 diabetes has risen unabated over the past decades, fueled by obesity and lifestyle influences, including diet quality. Epidemiological evidence is accumulating for an inverse association between dairy product intake and type 2 diabetes risk; this is somewhat counterintuitive to the saturated fat and cardiometabolic disease paradigm. The present report reviews the contribution that the findings of the European Prospective Investigation into Cancer (EPIC) study have made to this debate, noting that types of dairy products, particularly fermented dairy products including yogurt, may be more relevant than overall dairy intake for the prevention of type 2 diabetes. The EPIC study has contributed evidence through complementary approaches of a large prospective study across 8 European countries with heterogeneous dietary intakes assessed using food-frequency questionnaires (EPIC-InterAct study) and through a more detailed examination of diet assessed using a 7-day food diary (EPIC-Norfolk study). The implications of these findings are placed in the wider context, including the use of individual fatty acid blood biomarkers in the EPIC-InterAct study and an appraisal of current research gaps and suggestions for future research directions.


[Detection of t(14;18) chromosome translocation in follicular lymphoma by polymerase chain reaction].
In most cases of centroblastic/centrocytic follicular lymphomas the bcl-2 proto-oncogene (18q21) is translocated to the immunoglobulin JH region of chromosome 14 (14q32). About three quarters of the translocations are concentrated on the 3' nontranslated, a few hundred basepare-long region of bcl-2, the so called major breakpoint region (mbr), the remaining 20-25% is located about 30 kilobases downstream of bcl-2 coding sequences in the minor cluster region (mcr). The majority of the immunoglobulin breakpoints can be found in JH6-4 genes. The polymerase chain reaction method can detect the translocation already in a very few number of cells (> 10(3)). This very sensitive technique makes it possible to detect the translocation in lymphoid/lymphoma of peripheral blood and bone marrow that are missed by other diagnostic methods. This way one can perform a quick, early diagnosis, examine the result of treatments as well as detect the remissions and the possible relapses right at the beginning. All the advantages of this method contribute to a more successful treatment of follicular lymphoma. This present work describes a polymerase chain reaction technique which is capable of a detection of the t(14;18) translocation in a patient of centroblastic/centrocytic lymphoma, moreover shows how this translocation disappears after 4 week of radiotherapy of the patient.


Supramolecular assemblies of mRNA direct the coordinated synthesis of type I procollagen chains.
Registration of the three procollagen alpha chains and assembly of the triple-helical procollagen molecules takes place in the rough endoplasmic reticulum, but the exact location and timing of assembly is not known. As part of a study of the mechanism of molecular assembly, intact collagen-producing polyribosomes from embryonic chicken tendon fibroblasts have been examined by the techniques of rotary shadowing and electron microscopy. Intact mRNA strands corresponding in length to approximately 4500 bases and complete procollagen alpha (I) chains have been observed. The mRNA strands are comprised of two mRNA chains. The ribosomes are present in pairs separated along the duplex strand by about 100 nm. The intact polysome is asymmetric; two duplex strands join, and large ribosome aggregates appear. These aggregates are dispersed by collagenase digestion, leaving separate duplex strands with ribosome pairs intact. Ribonuclease digestion yields mixtures of monosomes and ribosome aggregates. Sequential ribonuclease and collagenase digestions yield only monosomes. We propose that each ribosome reads one mRNA chain, so that each pair is thus translating two chains in synchrony. Thus, the complex morphology of the collagen-producing polyribosomes suggests that the organization of a single molecule begins by the organization of the mRNA chains themselves.


Construction of efficient dual activating ratiometric YVO4:Nd3+/Eu3+ nanothermometers using co-doped and mixed phosphors.
The development of new contactless thermal nanosensors based on a ratiometric approach is of significant interest. To overcome the intrinsic limitations of thermally coupled levels, a dual activation strategy was applied. Dual activation was performed using co-doped single nanoparticles and a binary mixture of single-doped nanoparticles. Co-doped and mixed YVO4:Nd3+/Eu3+ nanoparticles were successfully demonstrated as luminescent nanothermometers and their thermometric performance, in terms of thermal sensitivity, temperature resolution and repeatability, was studied and compared.


Functional neuroimaging of sex differences in autobiographical memory recall.
Autobiographical memory (AM) is episodic memory for personally experienced events. The brain areas underlying AM retrieval are known to include several prefrontal cortical and medial temporal lobe regions. Sex differences in AM recall have been reported in several behavioral studies, but the functional anatomical correlates underlying such differences remain unclear. This study used fMRI to compare the neural correlates of AM recall between healthy male and female participants (n = 20 per group). AM recall in response to positive, negative, and neutral cue words was compared to a semantic memory task involving the generation of examples from a category using emotionally valenced cues. Behaviorally, females recalled more negative and fewer positive AMs compared with males, while ratings of arousal, vividness, and memory age did not differ significantly between sexes. Males and females also did not differ significantly in their performance on control tasks. Neurophysiologically, females showed increased hemodynamic activity compared to males in the dorsolateral prefrontal cortex (DLPFC), dorsal anterior insula, and precuneus while recalling specific AMs (all valences combined); increased activity in the DLPFC, transverse temporal gyrus, and precuneus while recalling positive AMs; and increased activity in the anterior cingulate cortex, precuneus, amygdala, and temporopolar cortex when recalling negative AMs. When comparing positive to negative AMs directly, males and females differed in their BOLD responses in the hippocampus and DLPFC. We propose that the differential hemodynamic changes may reflect sex-specific cognitive strategies during recall of AMs irrespective of the phenomenological properties of those memories.


Stable Quantitative Resistance Loci to Blackleg Disease in Canola (Brassica napus L.) Over Continents.
The hemibiotrophic fungus, Leptosphaeria maculans is the most devastating pathogen, causing blackleg disease in canola (Brassica napus L). To study the genomic regions involved in quantitative resistance (QR), 259-276 DH lines from Darmor-bzh/Yudal (DYDH) population were assessed for resistance to blackleg under shade house and field conditions across 3 years. In different experiments, the broad sense heritability varied from 43 to 95%. A total of 27 significant quantitative trait loci (QTL) for QR were detected on 12 chromosomes and explained between 2.14 and 10.13% of the genotypic variance. Of the significant QTL, at least seven were repeatedly detected across different experiments on chromosomes A02, A07, A09, A10, C01, and C09. Resistance alleles were mainly contributed by 'Darmor-bzh' but 'Yudal' also contributed few of them. Our results suggest that plant maturity and plant height may have a pleiotropic effect on QR in our conditions. We confirmed that Rlm9 which is present in 'Darmor-bzh' is not effective to confer resistance in our Australian field conditions. Comparative mapping showed that several R genes coding for nucleotide-binding leucine-rich repeat (LRR) receptors map in close proximity (within 200 Kb) of the significant trait-marker associations on the reference 'Darmor-bzh' genome assembly. More importantly, eight significant QTL regions were detected across diverse growing environments: Australia, France, and United Kingdom. These stable QTL identified herein can be utilized for enhancing QR in elite canola germplasm via marker- assisted or genomic selection strategies.


Identification and characterization of two Campylobacter jejuni adhesins for cellular and mucous substrates.
Campylobacter jejuni is able to colonize the human intestinal mucosa and cause disease. For this reason, it was important to investigate mechanisms by which C. jejuni adheres to epithelial cells and intestinal mucus gel. All strains of C. jejuni used were able to adhere to INT 407 epithelial cells and mucus, but high adherence to one substrate did not necessarily indicate comparable adherence to the other. The adherence of C. jejuni to cells was inhibited partially by treating the bacterial cells with proteases or glutaraldehyde or by adding a certain carbohydrate (fucose or mannose) to the medium. The flagellum of C. jejuni was identified as a potential adhesin by comparing adherence of flagellated and aflagellated variants. Shearing of the bacterial cells to remove the flagella reduced bacterial adhesion, whereas immobilization of the flagellum with KCN increased adhesion. Purified flagella showed specific, fucose-resistant binding to epithelial cells but not to intestinal mucus. The presence of a second, nonproteinaceous adhesin was suggested because no single treatment of the bacteria completely inhibited adhesion. Lipopolysaccharide (LPS) was identified as another C. jejuni adhesin. [3H]LPS specifically bound to epithelial cells, and this phenomenon was inhibited by periodate oxidation of the LPS or glutaraldehyde fixation of the epithelial cells. LPS, unlike flagella, was fucose sensitive and inhibited binding of whole bacterial cells to INT 407 cells. LPS was also able to bind to intestinal mucus gel. These data indicate that both flagella and LPS are important in adhesion to the mucosal surface.


Thoracic ossified meningioma and osteoporotic burst fracture: treatment with combined vertebroplasty and laminectomy without instrumentation: case report.
Although spinal meningioma is a common benign neoplasm, the ossified variant is rare. No more than 20 sporadic cases were reported in the literature between 1977 and January 2005. Recently, the authors treated a patient with a symptomatic ossified meningioma located in the posterior aspect of T-11 and an associated osteoporotic T-11 burst fracture. The tumor was completely removed by T10-11 laminectomy and transpedicular vertebroplasty was performed. The kyphotic deformity of the T-11 burst fracture was partially reduced and maintained for at least 2 months after vertebroplasty and laminectomy. The clinical presentation and management of this case are reported.


Ginsenoside Rb1 improves cardiac function and remodeling in heart failure.
We investigated the effect of ginsenoside Rb1 on cardiac function and remodeling in heart failure (HF). Four weeks after HF induction, the rats were administrated with ginsenoside Rb1 (35 and 70 mg/kg) and losartan (4.5 mg/kg) for 8 weeks. Losartan was used as a positive control. Cardiac function was assessed by measuring hemodynamic parameters. Histological changes were analyzed by HE and Masson's trichrome staining. Cardiac hypertrophy, fibrosis, mitochondrial membrane potential and glucose transporter type 4 (GLUT4) levels were evaluated. In the present study, high dose of (H-) ginsenoside Rb1 decreased heart rate, improved cardiac function and alleviated histological changes induced by HF. H-ginsenoside Rb1 attenuated cardiac hypertrophy and myocardial fibrosis by decreasing left ventricular (LV) weight/heart weight ratio and cardiomyocyte cross-sectional area and reducing the levels of atrial natriuretic factor (ANF), β-myosin heavy chain (β-MHC), periostin, collagen I, Angiotensin II (Ang II), Angiotensin converting enzyme (ACE) and Ang II type 1 (AT1) receptor. Moreover, H-ginsenoside Rb1 decreased mitochondrial membrane potential and enhanced the translocation of GLUT4 to plasma membrane. The TGF-β1/Smad and ERK signaling pathways were inhibited and the Akt pathway was activated. These findings suggest that ginsenoside Rb1 might restore cardiac/mitochondrial function, increase glucose uptake and protect against cardiac remodeling via the TGF-β1/Smad, ERK and Akt signaling pathways.


Biofabrication of Ag nanoparticles using Sterculia foetida L. seed extract and their toxic potential against mosquito vectors and HeLa cancer cells.
A one-step and eco-friendly process for the synthesis of silver-(protein-lipid) nanoparticles (Ag-PL NPs) (core-shell) has been developed using the seed extract from wild Indian Almond tree, Sterculia foetida (L.) (Sterculiaceae). The reaction temperature played a major role in controlling the size and shell formation of NPs. The amount of NPs synthesized and qualitative characterization was done by UV-vis spectroscopy and transmission electron microscopy (TEM), respectively. TEM studies exhibited controlled dispersity of spherical shaped NPs with an average size of 6.9±0.2nm. Selected area electron diffraction (SAED) and X-ray diffraction (XRD) revealed 'fcc' phase and crystallinity of the particles. X-ray photoelectron spectroscopy (XPS) was used to identify the protein-lipid (PL) bilayer that appears as a shell around the Ag core particles. The thermal stability of the Ag-PL NPs was examined using thermogravimetric analysis (TGA). Further analysis was carried out by using Fourier transform infrared spectroscopy (FTIR), where the spectra provided evidence for the presence of proteins and lipid moieties ((2n-octylcycloprop-1-enyl)-octanoic acid (I)), and their role in synthesis and stabilization of Ag NPs. This is the first report of plant seed assisted synthesis of PL conjugated Ag NPs. These formed Ag-PL NPs showed potential mosquito larvicidal activity against Aedes aegypti (L.), Anopheles stephensi Liston and Culex quinquefasciatus Say. These Ag-PL NPs can also act as promising agents in cancer therapy. They exhibited anti-proliferative activity against HeLa cancer cell lines and a promising toxicity was observed in a dose dependent manner. Toxicity studies were further supported by the cellular DNA fragmentation in the Ag-PL NPs treated HeLa cells.


Theoretical calculations of rotationally inelastic collisions of He with NaK(A (1)Σ(+)): Transfer of population, orientation, and alignment.
We have performed extensive calculations to investigate thermal energy, rotationally inelastic collisions of NaK (A(1)Σ(+)) with He. We determined a potential energy surface using a multi-reference configuration interaction wave function as implemented by the GAMESS electronic structure code, and we have performed coupled channel scattering calculations using the Arthurs and Dalgarno formalism. We also calculate the Grawert coefficients B(λ)(j, j') for each j → j' transition. These coefficients are used to determine the probability that orientation and alignment are preserved in collisions taking place in a cell environment. The calculations include all rotational levels with j or j' between 0 and 50, and total (translational and rotational) energies in the range 0.0002-0.0025 a.u. (∼44-550 cm(-1)). The calculated cross sections for transitions with even values of Δj tend to be larger than those for transitions with odd Δj, in agreement with the recent experiments of Wolfe et al. (J. Chem. Phys. 134, 174301 (2011)). The calculations of the energy dependence of the cross sections and the calculations of the fraction of orientation and alignment preserved in collisions also exhibit distinctly different behaviors for odd and even values of Δj. The calculations also indicate that the average fraction of orientation or alignment preserved in a transition becomes larger as j increases. We interpret this behavior using the semiclassical model of Derouard, which also leads to a simple way of visualizing the distribution of the angles between the initial and final angular momentum vectors j and j'. Finally, we compare the exact quantum results for j → j' transitions with results based on the simpler, energy sudden approximation. That approximation is shown to be quite accurate.


Helicobacter pylori and stomach cancer: a case-control study in Venezuela.
The role of Helicobacter pylori infection in gastric cancer was evaluated in a high-risk population in Venezuela using serological assays in a study of 302 cases and 483 neighborhood controls. To investigate the claim that assays for H. pylori should use antigens derived from local strains, four different assays derived from Venezuelan and European strains were used. Prevalence of IgG H. pylori antibodies in controls was very high, with estimates between 72 and 92%. Prevalence was similar in cases and controls. However, cases had lower antibody titers. This effect was observed only in subjects with low pepsinogen (PG) levels PGI/PGII <3.0), which suggested that extensive atrophy in cases causes a loss of H. pylori infection, with a consequent reduction in antibody titer. In addition, advanced cases (stage II or higher) had lower antibody titers than less advanced cases, which indicated that the lower antibody titers in cases may be attributable partially to a diminished immune response. All of the four assays for anti-H. pylori antibodies gave similar results. No evidence was found for the superiority of the assay based on Venezuelan strains. These results are consistent with other case-control studies in high-risk populations and highlight the difficulties of investigating H. pylori infection in retrospective studies.


Long-Term Follow up of Cancer Patients.
The long-term follow up of cancer patients should be based on the natural history of the disease and its known recurrence rates, patterns, and timing. Information from follow-up trials should be used in the context of diagnostic capabilities and practice setting. The increased involvement of family practitioners in the follow up of cancer patients is desirable, and some recommendations for follow-up procedures are presented.


Vps34p is required for the decline of extracellular fructose-1,6-bisphosphatase in the vacuole import and degradation pathway.
When Saccharomyces cerevisiae are starved of glucose for a prolonged period of time, gluconeogenic enzymes such as fructose-1,6-bisphosphatase (FBPase), malate dehydrogenase, isocitrate lyase, and phosphoenolpyruvate carboxykinase are induced. However, when glucose is added to prolonged-starved cells, these enzymes are degraded in the vacuole via the vacuole import and degradation (Vid) pathway. The Vid pathway merges with the endocytic pathway to remove intracellular and extracellular proteins simultaneously. Ultrastructural and cell extraction studies indicate that substantial amounts of FBPase were in the extracellular fraction (periplasm) during glucose starvation. FBPase levels in the extracellular fraction decreased after glucose re-feeding in wild-type cells. The decline of FBPase in the extracellular fraction was dependent on the SLA1 and ARC18 genes involved in actin polymerization and endocytosis. Moreover, the reduction of extracellular FBPase was also dependent on the VPS34 gene. VPS34 encodes the PI3 kinase and is also required for the Vid pathway. Vps34p co-localized with actin patches in prolonged-starved cells. In the absence of this gene, FBPase and the Vid vesicle protein Vid24p associated with actin patches before and after the addition of glucose. Furthermore, high levels of FBPase remained in the extracellular fraction in the Δvps34 mutant during glucose re-feeding. When the Asn-736 residue of Vps34p was mutated and when the C-terminal 11 amino acids were deleted, mutant proteins failed to co-localize with actin patches, and FBPase in the extracellular fraction did not decrease as rapidly. We suggest that VPS34 plays a critical role in the decline of extracellular FBPase in response to glucose.


Psychosocial Barriers to Care: Recognizing and Responding Through a Trauma-Informed Care Approach.
Healthcare providers caring for patients undergoing intensive oncologic care may experience challenges related to psychosocial barriers to care, which can negatively affect access to treatment and health outcomes. Recognizing and responding to these barriers caused by the experience of adversity and trauma are important considerations to ensure safe and effective patient care. The objective of this article is to demonstrate how a trauma-informed approach can be used to develop supportive interventions. Consideration of this approach not only ensures high-quality patient care, but also promotes health equity by navigating the difficult barriers that may have prevented access to care.


Measurement of pressure and flow rates during irrigation of a root canal ex vivo with three endodontic needles.
To monitor ex vivo intra-canal irrigation with three endodontic needles (25, 27 and 30 gauge) and compare them in terms of irrigant flow rate, intra-barrel pressure, duration of irrigation and volume of irrigant delivered. A testing system was constructed to allow measurement of selected variables with pressure and displacement transducers during ex vivo intra-canal irrigation with a syringe and three different needles (groups A, B, C) into a prepared root canal. Ten specialist endodontists performed the irrigation procedure. Each operator performed ten procedures with each needle. Data recorded by the transducers were analysed using Friedman's test, Wilcoxon Signed Rank test, Mann-Whitney U-test and Kendall's T(b) test. The level of significance was set to 95%. Significant differences were detected among the three needles for most variables. Duration of delivery and flow rates significantly decreased as the needle diameter increased, whilst pressure increased up to 400-550 kPa. Gender of the operator had a significant impact on the results. Experience of the operators (years) were negatively correlated to volume of irrigant (all groups), to the duration of delivery (groups A, B) and to the average flow rate (group A). Finer diameter needles require increased effort to deliver the irrigant and result in higher intra-barrel pressure. The syringe and needles used tolerated the pressure developed. Irrigant flow rate should be considered as a factor directly influencing flow beyond the needle. Wide variations of flow rate were observed among operators. Syringe irrigation appears difficult to standardize and control.


Renal tubular acidosis in two horses: diagnostic studies.
An 11-year-old Quarter Horse mare and a 2-year-old Quarter Horse colt with clinical diagnoses of renal tubular acidosis (RTA) were donated to the University of California Veterinary Medical Teaching Hospital. A series of diagnostic tests was performed in an attempt to characterize the type and cause of RTA in these horses. Endogenous creatinine clearance and sodium sulfanilate clearance were within reference ranges; thus, no abnormality of glomerular function was detected. To assess renal tubular function in response to acid loading, each horse was given 0.1 g of NH4Cl/kg of body weight via nasogastric tube in 6 L of water. Urine acidification in response to the oral acid load was less than that observed in control horses. The urinary clearance ratio for sodium also was found to be greater for the principals than for the controls. These findings supported a diagnosis of RTA that closely resembled type 1 or distal RTA. In an attempt to determine the cause of RTA, renal ultrasonography, renal biopsy, and a mating study were performed. No abnormalities were identified, and the cause of RTA in these cases remained unknown.


A new method to measure higher visual functions in an immersive environment.
Higher visual functions can be defined as cognitive processes responsible for object recognition, color and shape perception, and motion detection. People with impaired higher visual functions after unilateral brain lesion are often tested with paper pencil tests, but such tests do not assess the degree of interaction between the healthy brain hemisphere and the impaired one. Hence, visual functions are not tested separately in the contralesional and ipsilesional visual hemifields. A new measurement setup, that involves real-time comparisons of shape and size of objects, orientation of lines, speed and direction of moving patterns, in the right or left visual hemifield, has been developed. The setup was implemented in an immersive environment like a hemisphere to take into account the effects of peripheral and central vision, and eventual visual field losses. Due to the non-flat screen of the hemisphere, a distortion algorithm was needed to adapt the projected images to the surface. Several approaches were studied and, based on a comparison between projected images and original ones, the best one was used for the implementation of the test. Fifty-seven healthy volunteers were then tested in a pilot study. A Satisfaction Questionnaire was used to assess the usability of the new measurement setup. The results of the distortion algorithm showed a structural similarity between the warped images and the original ones higher than 97%. The results of the pilot study showed an accuracy in comparing images in the two visual hemifields of 0.18 visual degrees and 0.19 visual degrees for size and shape discrimination, respectively, 2.56° for line orientation, 0.33 visual degrees/s for speed perception and 7.41° for recognition of motion direction. The outcome of the Satisfaction Questionnaire showed a high acceptance of the battery by the participants. A new method to measure higher visual functions in an immersive environment was presented. The study focused on the usability of the developed battery rather than the performance at the visual tasks. A battery of five subtasks to study the perception of size, shape, orientation, speed and motion direction was developed. The test setup is now ready to be tested in neurological patients.


Hereditary lobular breast cancer with an emphasis on E-cadherin genetic defect.
Recent studies have reported germline CDH1 mutations in cases of lobular breast cancer (LBC) not associated with the classical hereditary diffuse gastric cancer syndrome. A multidisciplinary workgroup discussed genetic susceptibility, pathophysiology and clinical management of hereditary LBC (HLBC). The team has established the clinical criteria for CDH1 screening and results' interpretation, and created consensus guidelines regarding genetic counselling, breast surveillance and imaging techniques, clinicopathological findings, psychological and decisional support, as well as prophylactic surgery and plastic reconstruction. Based on a review of current evidence for the identification of HLBC cases/families, CDH1 genetic testing is recommended in patients fulfilling the following criteria: (A) bilateral LBC with or without family history of LBC, with age at onset <50 years, and (B) unilateral LBC with family history of LBC, with age at onset <45 years. In CDH1 asymptomatic mutant carriers, breast surveillance with clinical examination, yearly mammography, contrast-enhanced breast MRI and breast ultrasonography (US) with 6-month interval between the US and the MRI should be implemented as a first approach. In selected cases with personal history, family history of LBC and CDH1 mutations, prophylactic mastectomy could be discussed with an integrative group of clinical experts. Psychodecisional support also plays a pivotal role in the management of individuals with or without CDH1 germline alterations. Ultimately, the definition of a specific protocol for CDH1 genetic screening and ongoing coordinated management of patients with HLBC is crucial for the effective surveillance and early detection of LBC.


Determining pediatric hypertension criteria: concordance between observed physician methods and guideline-recommended methods.
To determine and evaluate the accuracy of methods physicians use to detect diagnostic criteria for pediatric hypertension [hypertensive blood pressures (BPs) on three or more occasions] in electronic health records (EHRs). Methods used by pediatric-trained physicians (n = 12) to detect diagnostic criteria for hypertension in a simulation using a child's EHR data were directly observed, timed, and evaluated for accuracy. All physicians were given the same information regarding diagnostic criteria to eliminate knowledge gaps. Then, computer modeling and EHR data from 41 654 3-18-year-olds were used to simulate and compare the accuracy of detecting hypertension criteria using an observed-shorthand method vs. the guideline-recommended/gold-standard method. No physician used the guideline-recommended method of determining multiple time-of-care hypertension thresholds for child age/height at the time of each BP measure. One physician estimated the child's BP diagnosis without computing thresholds; 11 of 12 physicians determined the child's hypertension threshold from age/height data at the time of a current visit and applied/imputed this threshold to BP measured at all visits (current-visit threshold used to assess historical-visit BPs) to detect three separate BP elevations. Physicians took 2.3 min (95% confidence interval, 1.5-3.0) to declare a diagnosis. Sensitivity was 83.1% when applying the current-visit threshold to detect the guideline-recommended-BP-threshold diagnosis using EHR data. Specificity and positive-predictive/negative-predictive values ranged from 98.5 to 99.9%. Physicians applied a shorthand method to evaluate pediatric BPs. Computer-simulated comparison of the shorthand and guideline methods using clinical data suggest the shorthand method could yield an inaccurate impression of a child's BP history in 17% of pediatric ambulatory visits.


What makes protein indigestible from tissue-related, cellular, and molecular aspects?
This paper gives an insight into key factors, which impair enzymatic protein digestion. By nature, some proteins in raw products are already poorly digestible because of structural peculiarities, or due to their occurrence in plant cytoplasmic organelles or in cell membranes. In plant-based protein, molecular and structural changes can be induced by genetic engineering, even if protein is not a target compound class of the genetic modification. Other proteins only become difficult to digest due to changes that occur during the processing of proteinaceous products, such as extruding, boiling, or acidic or alkaline treatment. The utilization of proteinaceous raw materials in industrial fermentations can also have negative impacts on protein digestibility, when reused as fermentation by-products for animal nutrition, such as brewers' grains. After consumption, protein digestion can be impeded in the intestine by the presence of antinutritional factors, which are ingested together with the food or feedstuff. It is concluded that the encircling matrix, but also molecular, chemical, and structural peculiarities or modifications to amino acids and proteins obstruct protein digestion by common proteolytic enzymes in humans and animals.


First Clinical Use of Lenzilumab to Neutralize GM-CSF in Patients with Severe COVID-19 Pneumonia.
In COVID-19, high levels of granulocyte macrophage-colony stimulating factor (GM-CSF) and inflammatory myeloid cells correlate with disease severity, cytokine storm, and respiratory failure. With this rationale, we used lenzilumab, an anti-human GM-CSF monoclonal antibody, to treat patients with severe COVID-19 pneumonia. Hospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use IND application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. All patients receiving lenzilumab through May 1, 2020 were included in this report. Twelve patients were treated with lenzilumab. Clinical improvement was observed in 11 out of 12 (92%), with a median time to discharge of 5 days. There was a significant improvement in oxygenation: The proportion of patients with SpO2/FiO2 < 315 at the end of observation was 8% vs. compared to 67% at baseline (p=0.00015). A significant improvement in mean CRP and IL-6 values on day 3 following lenzilumab administration was also observed (137.3 mg/L vs 51.2 mg/L, p = 0.040; 26.8 pg/mL vs 16.1 pg/mL, p = 0.035; respectively). Cytokine analysis showed a reduction in inflammatory myeloid cells two days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab, and no mortality in this cohort of patients with severe COVID-19 pneumonia. In high-risk COVID-19 patients with severe pneumonia, GM-CSF neutralization with lenzilumab was safe and associated with improved clinical outcomes, oxygen requirement, and cytokine storm.


[Suicide: an update].
The authors relate etiological and epidemiological data on suicide. They also discuss cognitive and psychodynamic as well as biological factors involved. In the second part, they described different ways of predicting and dealing with suicide. They propose the use of a scale as a useful way for the assessment of suicide risk.


[Diagnosis and therapy of idiopathic Parkinson's disease].
The diagnosis of idiopathic Parkinson's disease is based on a thorough clinical examination with demonstration of the presence of bradykinesia, as well as tremor, rigidity, postural instability and hyposmia. Symptomatic forms and atypical Parkinson syndrome should be ruled out. Nuclear medical analyses of the dopamine metabolism and the dopamine receptors are used only in exceptions to clarify difficult cases of differential diagnoses. For young patients, dopamine-agonists and, indeed, once again increasingly MAO-B inhibitors, such as rasagiline, are mainly used for therapy. Older patients und patients in advanced stages receive levodopa and a COMT inhibitor. As supplemental therapy, amantadine is given for dyskinesia and apathy and budipine is given for tremor-dominant type of Parkinson's disease. In advanced stages with motor fluctuations, apomorphine or Duodopa pumps or deep brain stimulation are employed.


Familial occurrence of renal and intestinal disease associated with tissue autoantibodies.
Chronic tubulointerstitial renal disease and villous atrophy of the small intestine occurred in two first cousins. Both had protracted diarrhea with malabsorption and died despite intensive parenteral alimentation. In one patient signs of generalized proximal tubular dysfunction developed, followed by nephrotic syndrome and progressive renal insufficiency. A renal biopsy specimen disclosed severe tubulointerstitial disease and membranous glomerulopathy. In this patient, circulating immune complexes were detected and granular deposits of IgG and C3 were seen in the intestinal epithelial cells by direct immunofluorescence. Antiintestinal antibodies (IgG class) were demonstrated by indirect immunofluorescence. The other patient had interstitial nephritis but no glomerular abnormality. On direct immunofluorescence, both patients had confluent granular staining of the renal tubular basement membranes. These immunopathologic studies suggest a common immunologic mechanism in the pathogenesis of the renal and gastrointestinal disorders in these infants.


Quality of life of patients with lung cancer.
Lung cancer is the major cause of oncologic-related death worldwide. Due to delayed diagnosis, 5-year survival rate accounts for only 15%. Treatment includes surgery, adjuvant chemotherapy, and radiation therapy; however, it is burdened by many side effects. Progress of the disease, severity of its symptoms, and side effects decrease significantly the quality of life (QoL) in those patients. The level of self-assessed QoL helps in predicting survival, which is especially important among patients receiving palliative care. Patients assess their functioning in five dimensions (physical, psychological, cognitive, social, and life roles), severity of symptoms, financial problems, and overall QoL. The QoL in lung cancer patients is lower than in healthy population and patients suffering from other malignancies. It is affected by the severity and the number of symptoms such as fatigue, loss of appetite, dyspnea, cough, pain, and blood in sputum, which are specific for lung tumors. Fatigue and respiratory problems reduce psychological dimension of QoL, while sleep problems reduce cognitive functioning. Physical dimension (related to growing disability) decreases in most of the patients. Also, most of them are unable to play their family and social roles. The disease is a frequent reason of irritation, distress, and depression. Management of the disease symptoms may improve QoL. Controlling the level of fatigue, pulmonary rehabilitation, and social and spiritual support are recommended. Early introduction of tailored palliative treatment is a strategy of choice for improvement of QoL in lung cancer patients.


New Evidence for the Diversity of Mechanisms and Protonated Schiff Bases Formed in the Non-Enzymatic Covalent Protein Modification (NECPM) of HbA by the Hydrate and Aldehydic Forms of Acetaldehyde and Glyceraldehyde.
Acetaldehyde is a physiological species existing in blood. Glyceraldehyde is a commonly-used surrogate for glucose in studies of nonenzymatic glycation. Both species exist in dynamic equilibrium between two forms, an aldehyde and a hydrate. Nonenzymatic covalent protein modification (NECPM) is a process whereby a protein is covalently modified by a non-glucose species. The purpose here was to elucidate the NECPM mechanism(s) for acetaldehyde and glyceraldehyde with human hemoglobin (HbA). For the first time, both aldehydic and hydrate forms of acetaldehyde and glyceraldehyde were considered. Computations and model reactions followed by 1H NMR were employed. Results demonstrated that the aldehyde and hydrate forms of acetaldehyde bind and covalently-modify Val1 of HbA via different chemical mechanisms, yet generated an identical protonated Schiff base (PSB). The aldehyde and hydrate of glyceraldehyde also covalently-modified Val1 via mechanisms distinct from one another, yet generated an identical PSB. It is noteworthy that the PSB from acetaldehyde and glyceraldehyde were different structures. The PSB from acetaldehyde is proposed to proceed to covalent adducts that have been implicated in alcohol toxicity. Conversely, the PSB generated from glyceraldehyde can form an Amadori which has been implicated in diabetic complications. Thus, the PSB structure generated from acetaldehyde versus glyceraldehyde may be central to pathophysiological outcomes because it determines the structure of the stable covalent adduct formed.


Antioxidant nanozyme: a facile synthesis and evaluation of the reactive oxygen species scavenging potential of nanoceria encapsulated albumin nanoparticles.
Several diseases and disorders, including cancer are endorsed by excessive oxidative stress caused due to the incomplete removal of reactive oxygen species (ROS) by the antioxidant defense system of the body. Therefore, present interest among the scientific community lies in the development of a highly stable, biocompatible artificial enzymatic system that possesses a high ROS scavenging activity over a period of time. In recent years, catalytic nanoparticles emerged as a potential candidate in the field of nanomedicine. Due to their inherent catalytic properties, they are exploited as an artificial enzyme (nanozyme), to reinstate or correct aberrant enzymatic activities in patients. Among them, cerium oxide nanoparticles/nanoceria (CNPs) emerged as a potent artificial redox enzyme, mimicking the activity of superoxide dismutase (SOD) and catalase and endure a tremendous ROS scavenging potential as depicted in a surfeit of human cell lines and animal models. In the present article, a facile synthesis of biocompatible nanoceria encapsulated albumin nanoparticles (BCNPs) via desolvation technique that lead to the abatement of intracellular ROS is reported. Physico-chemical characterizations of as-prepared BCNPs corroborate the formation of a highly monodispersed, spherical and stable aqueous delivery system. Interestingly, such entrapment does not affect the enzyme mimetic activity of CNPs, as demonstrated by SOD assay. The biocompatibility and ROS scavenging potential of BCNPs were further assessed in vitro against human lung epithelial cells by cell viability assay and flow cytometric analysis, respectively. The quantitative and qualitative assessments of cellular uptake of BCNPs were done by inductively coupled plasma mass spectrometry (ICP-MS), transmission electron microscopy (TEM) and field emission scanning electron microscopy (FE-SEM) analysis. Furthermore, the BCNPs preserve the cell's antioxidant defense system and protect them from oxidant-mediated apoptosis as confirmed by semi-quantitative RT-PCR analysis. Thus, the as-prepared BCNPs could provide an opportunity to be utilized as a potential candidate against ROS induced diseases and disorders.