Two-start design within a Sephadex inflammatory model--a means to generate reliable ED50 data whilst significantly reducing the number of animals used.
Pulmonary inflammation disorders represent a major healthcare burden, and novel anti-inflammatory agents are critically needed for the treatment of patients unresponsive to current therapies. In vivo animal models play a key role in the preclinical assessment of novel anti-inflammatory compounds. The implementation of streamlined in vivo experimental designs that are time-and cost-efficient, while keeping animal usage low, is a key consideration for drug optimization programs. The Sephadex rat model of pulmonary inflammation captures many pathophysiologic characteristics of clinical asthma and allergy, such as eosinophilic infiltration andinterstitial edema. Using the in vivo Sephadex model, we compared two different study designs that were implemented to screen and select two novel candidate drugs for a drug discovery project. The traditional one-start design, which utilizes few dose-testing groups with many animals per group, was used to select the first candidate drug. Due to tight timelines, the selection process for the second candidate drug had to be optimized, leading to the development of the novel two-start design, an approach whereby dose ranges are optimized in two experimental phases. Here we show that both study designs were comparable in their generation of robust median effective dose values for selected candidate drugs, as represented by similar confidence interval ratios. However, implementation of the two-start design resulted in approximately 50% fewer animals and 50% less time taken to assess the efficacy of an equal number of compounds compared with the one-start design. These results demonstrate that the two-start design is a more efficient experimental approach, and its widespread implementation in drug optimization programs will impact upon the selection process for candidate drugs with regards to time, cost, and animal usage.


Pediatric MR Urography: Indications, Techniques, and Approach to Review.
Magnetic resonance (MR) urography is a valuable imaging modality for assessing disorders of the pediatric urinary tract. It allows comprehensive evaluation of the kidneys and urinary tract in children by providing both morphologic and functional information without exposing the child to ionizing radiation. Pediatric MR urography can be used to thoroughly evaluate renal and urinary tract abnormalities that are difficult to identify or fully characterize with other imaging techniques, and it has the potential to allow earlier diagnosis while decreasing the number of imaging studies performed. Common indications for pediatric MR urography include evaluation of complex renal and urinary tract anatomy, suspected urinary tract obstruction, operative planning, and postoperative assessment. MR hydrography (T2-weighted imaging of urine) excellently depicts dilated or obstructed urinary systems, whereas postcontrast imaging (gadolinium-enhanced T1-weighted imaging of the kidneys and urinary system) excellently depicts nondilated or nonobstructed urinary systems. Postcontrast MR urography also allows a functional evaluation of the kidneys and urinary tract that includes estimation of differential renal function. The authors review common indications for pediatric MR urography, detail MR urography techniques, compare the strengths and weaknesses of MR urography with those of alternative imaging strategies for children, and describe numerous common and uncommon abnormalities of the pediatric kidneys and urinary tract.


[Genital infections in girls with type 1 diabetes].
The aim of the study was to investigate the relation between genital infections (frequency, etiology, clinical presentation) among girls with type 1 diabetes and some factors as age of the girls, duration and metabolic control of diabetes. Forty-three girls with type 1 diabetes and twelve healthy girls for controls were involved in the study. Methods used are: genital tract inspection, direct microscopy and cultures from genital discharge and urine. Glycaemic control in the diabetic girls was assessed by measuring total glycosylated haemoglobin. The results show vulvovaginal candidiasis in 27 (62.8%) in diabetic girls versus 2 (16.6%) in controls (p < 0.01). There was clear prevalence of non-albicans Candida species. Concomitant infection with bacterial pathogens were proved in only 6 (13.9%) of diabetic girls and 1 (8.5%) of the controls. The clinical presentation of genital candidiasis was vulvovaginitis and most of the affected diabetic girls (88.9%) were in puberty period. There was no relation between duration and metabolic control of diabetes and genital infections.


"Ring-fencing" BRCA1 tumor suppressor activity.
BRCA1 is a crucial human breast and ovarian cancer tumor suppressor gene. The article by Drost et al. in this issue of Cancer Cell together with a recent paper in Science now provide a clearer picture of how this large and complex protein suppresses tumorigenesis.


Scanning electron microscopic study of virulent and avirulent colonies of Neisseria gonorrhoeae.
A preparation procedure for scanning electron microscopy was developed by which gononcoccal colonies can be studied directly on the agar surface. After glutaraldehyde fixation directly in petri dishes, small agar pieces were cut out and dehydrated stepwise in increasing concentrations of ethanol. The blocks were thereafter transferred to a critical-point drying apparatus, via steps of increased gradients up to 100% amyl acetate. By this method five different gonococcal colony types could be distinguished analogous to light microscopic observations made by others. At higher magnifications an abundance of intercellular strands was found between the cells in virulent type 1 and 2 colonies, but not in the avirulent types 3 through 5. These strands seemed to anchor the cells to each other and to the agar surface. The presence of such structures probably explains the highly convex surface of virulent colonies and explains why colonies of avirulent strains exhibit a radial extension and a flat upper surface. The nature of these filamentous intercellular strands is discussed.


[Research Progress of Cancer-associated Fibroblasts in Hematolo- gic Malignancies --Review].
Cancer-associated fibroblasts (CAF) are a key component of the tumor microenvironment, which can secrete a variety of cytokines, chemokines and growth factors, directly and indirectly support cancer cells, also alter the immune cellular environment by inhibiting the activity of immune effector cells and recruiting immunosuppressive cells, thereby allowing cancer cells to evade immune surveillance. CAF has been proven to be associated with the development, progression, and poor prognosis of solid tumors. However, the role of CAF in hematological malignancies is still unclear. This article reviews the research progress of CAF in hematological malignancies.


Induction chemotherapy for head and neck cancer: is there still a role?
Integration and optimization of active systemic agents and radiosensitizers into the therapeutic regimen for head and neck cancer remains a topic of active investigation. Recent trials have not consistently supported the use of induction chemotherapy. There are several clinical scenarios in which there is a strong rationale for induction chemotherapy, such as larynx preservation, unfavorable sites and bulky locally advanced disease. The increasing prevalence of HPV-positive malignancies, impacts both interpretation of clinical research and the design of future trials. In the broad spectrum of this disease the prognosis is often dismal, with substantial room for improvement over current therapy. In the face of conflicting clinical data, we address the question of whether there remains a role for induction chemotherapy.


Histone modifications during the life cycle of the brown alga Ectocarpus.
Brown algae evolved complex multicellularity independently of the animal and land plant lineages and are the third most developmentally complex phylogenetic group on the planet. An understanding of developmental processes in this group is expected to provide important insights into the evolutionary events necessary for the emergence of complex multicellularity. Here, we focus on mechanisms of epigenetic regulation involving post-translational modifications of histone proteins. A total of 47 histone post-translational modifications are identified, including a novel mark H2AZR38me1, but Ectocarpus lacks both H3K27me3 and the major polycomb complexes. ChIP-seq identifies modifications associated with transcription start sites and gene bodies of active genes and with transposons. H3K79me2 exhibits an unusual pattern, often marking large genomic regions spanning several genes. Transcription start sites of closely spaced, divergently transcribed gene pairs share a common nucleosome-depleted region and exhibit shared histone modification peaks. Overall, patterns of histone modifications are stable through the life cycle. Analysis of histone modifications at generation-biased genes identifies a correlation between the presence of specific chromatin marks and the level of gene expression. The overview of histone post-translational modifications in the brown alga presented here will provide a foundation for future studies aimed at understanding the role of chromatin modifications in the regulation of brown algal genomes.


Kinetics of HCV viremia in kidney transplant recipients during and after alpha-interferon therapy.
Fifteen kidney transplant recipients with chronic hepatitis C were given 3 million units recombinant alpha2b-interferon for 142+/-35 days. There were significant decreases in hepatitis C virus (HCV) RNA 1 month after the initiation of treatment (p < 0.01), and at the end of treatment (p < 0.05). HCV RNA was undetectable by PCR analysis during treatment in 5 patients. But HCV RNA reappeared in all patients 1 month after the cessation of therapy, and the level of viremia returned to baseline. While all patients had normalized alanine aminotransferase (ALT) activities at the end of therapy, 11 experienced a relapse during the follow-up period (1 year). There was a correlation between the amount of HCV RNA at the end of treatment and the time of relapse. Serum IgM against core protein of HCV were detected in 7/15 patients. Anti-core IgM remained detectable during treatment and afterwards. There was no correlation between IgM status and other virological parameters, or ALT activity.


Applicability of an In-Vitro Digestion Model to Assess the Bioaccessibility of Phenolic Compounds from Olive-Related Products.
The Mediterranean diet includes virgin olive oil (VOO) as the main fat and olives as snacks. In addition to providing nutritional and organoleptic properties, VOO and the fruits (olives) contain an extensive number of bioactive compounds, mainly phenolic compounds, which are considered to be powerful antioxidants. Furthermore, olive byproducts, such as olive leaves, olive pomace, and olive mill wastewater, considered also as rich sources of phenolic compounds, are now valorized due to being mainly applied in the pharmaceutical and nutraceutical industries. The digestive system must physically and chemically break down these ingested olive-related products to release their phenolic compounds, which will be further metabolized to be used by the human organism. The first purpose of this review is to provide an overview of the current status of in-vitro static digestion models for olive-related products. In this sense, the in-vitro gastrointestinal digestion methods are widely used with the following aims: (i) to study how phenolic compounds are released from their matrices and to identify structural changes of phenolic compounds after the digestion of olive fruits and oils and (ii) to support the functional value of olive leaves and byproducts generated in the olive industry by assessing their health properties before and after the gastrointestinal process. The second purpose of this review is to survey and discuss all the results available to date.


Autophagic dysfunction in mucolipidosis type IV patients.
Mutations in Mucolipin 1 (MCOLN1) have been linked to mucolipidosis type IV (MLIV), a lysosomal storage disease characterized by several neurological and ophthalmological abnormalities. It has been proposed that MCOLN1 might regulate transport of membrane components in the late endosomal-lysosomal pathway; however, the mechanisms by which defects of MCOLN1 function result in mental and psychomotor retardation remain largely unknown. In this study, we show constitutive activation of autophagy in fibroblasts obtained from MLIV patients. Accumulation of autophagosomes in MLIV cells was due to the increased de novo autophagosome formation and to delayed fusion of autophagosomes with late endosomes/lysosomes. Impairment of the autophagic pathway led to increased levels and aggregation of p62, suggesting that abnormal accumulation of ubiquitin proteins may contribute to the neurodegeneration observed in MLIV patients. In addition, we found that delivery of platelet-derived growth factor receptor to lysosomes is delayed in MCOLN1-deficient cells, suggesting that MCOLN1 is necessary for efficient fusion of both autophagosomes and late endosomes with lysosomes. Our data are in agreement with recent evidence showing that autophagic defects may be a common characteristic of many neurodegenerative disorders.


Detection of immunoglobulin M antibody to Epstein-Barr virus by use of an enzyme-labeled antigen.
Immunoglobulin M (IgM) antibodies to Epstein-Barr virus were detected by using microtiter plates coated with anti-mu-chain antiserum and enzyme-labeled Epstein-Barr virus antigen. Optimum conditions for labeling were determined. The addition of unlabeled control antigen to the enzyme-labeled antigen was effective in reducing background reactions. Rheumatoid factor no longer interfered. Blocking of specific IgM antibody by IgG also was no longer observed. Four different methods for the detection of acute Epstein-Barr virus infections were compared. A combination of the enzyme-labeled antigen-IgM test with the detection of antibodies to either Epstein-Barr nuclear antigen or heterophile antigen was highly sensitive and specific. By changing the solid phase, IgA antibodies to Epstein-Barr virus could be detected.


Treatment With Medicinal Mushroom Extract Mixture Inhibits Translation and Reprograms Metabolism in Advanced Colorectal Cancer Animal Model as Evidenced by Tandem Mass Tags Proteomics Analysis.
Colorectal cancer (CRC) is the third most frequent cancer type in both males and females, with about 35% of patients being diagnosed in stage IV metastatic disease. Despite advancements in treatment, life expectancy in patients with metastatic disease is still not satisfying. Due to frequent drug resistance during conventional and targeted cancer treatments, the development and testing of multi-target therapies is an important research field. Medicinal mushrooms specific isolated compounds as well as complex extract mixtures have been studied in depth, and many mushroom species have been proven to be non-toxic multi-target inhibitors of specific oncogenic pathways, as well as potent immunomodulators. In this study, we have performed a tandem mass tags qualitative and quantitative proteomic analyses of CT26.WT colon cancer tumor tissues from Balb/c mice treated with the studied medicinal mushroom extract mixture, with or without 5-fluorouracil. Besides significantly improved survival, obtained results reveal that Agarikon.1 alone, and in combination with 5-fluorouracil exert their anticancer effects by affecting several fundamental processes important in CRC progression. Bioinformatic analysis of up- and downregulated proteins revealed that ribosomal biogenesis and translation is downregulated in treatment groups, while the unfolded protein response (UPR), lipid metabolism and tricarboxylic acid cycle (TCA) are upregulated. Moreover, we found that many known clinical biomarkers and protein clusters important in CRC progression and prognosis are affected, which are a good basis for an expanded translational study of the herein presented treatment.


A spiking neural network model of an actor-critic learning agent.
The ability to adapt behavior to maximize reward as a result of interactions with the environment is crucial for the survival of any higher organism. In the framework of reinforcement learning, temporal-difference learning algorithms provide an effective strategy for such goal-directed adaptation, but it is unclear to what extent these algorithms are compatible with neural computation. In this article, we present a spiking neural network model that implements actor-critic temporal-difference learning by combining local plasticity rules with a global reward signal. The network is capable of solving a nontrivial gridworld task with sparse rewards. We derive a quantitative mapping of plasticity parameters and synaptic weights to the corresponding variables in the standard algorithmic formulation and demonstrate that the network learns with a similar speed to its discrete time counterpart and attains the same equilibrium performance.


Dietary fat and sex modify heterozygote effects of the rat fatty (fa) allele.
Rats carrying one copy of the obesity gene fa may exhibit intermediate phenotypes between lean (+/+) and homozygous mutants (fa/fa). Previous data suggested to us that fa heterozygotes may be more sensitive than wild-type rats to high fat diets. To test this hypothesis, we generated +/+ and fa/+ rats and fed them diets containing 12% or 48% energy as fat for 7 wk. Energy efficiency was significantly greater in males than in females and in high fat-fed vs. low fat-fed rats. Perirenal fat pad weights were significantly greater in males than in females, in high fat-vs. low fat-fed rats and in fa/+ vs. +/+ rats. Adipose and soleus plasma membrane calcium-ATPase concentrations were significantly lower in rats fed the high fat diet. This protein was also lower in soleus of fa/+ rats compared with +/+ rats. There were significant diet x genotype interactions such that the high fat diet had the greatest effect on fat pads and calcium-ATPase in fa/+ rats. The results of the present study show heterozygote effects of the fa allele and suggest that these effects may be modulated by both sex-related factors and dietary manipulation.


Further attenuation of endothelium-dependent relaxation imparted by natriuretic peptide receptor antagonism.
Nitric oxide (NO) is an important endothelium-derived relaxing factor that functions via activation of soluble guanylyl cyclase and cGMP generation in vascular smooth muscle. Recently, studies have described the synthesis and secretion of C-type natriuretic peptide (CNP) from endothelial cells. This peptide also mediates relaxation via cGMP but through activation of particulate guanylyl cyclase. We tested the hypothesis that endothelium-dependent relaxations to acetylcholine or bradykinin in isolated canine coronary arteries involve both releases of NO and CNP. Rings of canine coronary arteries were incubated with either inhibitors of NO production (N(G)-monomethyl-L-arginine, L-NMMA) or the natriuretic peptide receptor antagonist HS-142-1. CNP caused concentration-dependent relaxations of rings with and without endothelium. These relaxations were attenuated by HS-142-1. Relaxations to acetylcholine and bradykinin were attenuated by L-NMMA alone but not attenuated by HS-142-1 alone. Coinhibition with L-NMMA and HS-142-1 significantly inhibited acetylcholine- and bradykinin-induced relaxation to a magnitude greater than either inhibitor alone. In summary, a novel interaction between the NO and the natriuretic peptide system is demonstrated by increased attenuation of endothelium-dependent relaxations to acetylcholine and bradykinin when both NO synthase and natriuretic peptide receptors are inhibited. These investigations support the concept of release of multiple endothelium-derived factors in response to acetylcholine- and bradykinin-receptor stimulation in endothelial cells, which may include CNP, as well as NO.


Effects of a combination of rhGH and metformin on adiponectin levels in patients with metabolic syndrome.
Adiponectin is a recently discovered adipocytokine that correlates negatively with body mass index and body fat. In patients with GH deficiency, treatment with recombinant human growth hormone (rhGH) reduces body fat mass and thus may also have a favorable effect in patients with metabolic syndrome, and would also be expected to increase adiponectin levels. However, due to its diabetogenic effect, rhGH treatment also bears an increased risk for the development of type 2 diabetes mellitus. We conducted a 18-month randomized, double-blind, placebo-controlled study to assess the effect of rhGH in combination with metformin (MGH) in 14 obese men (7 MGH; 7 Metformin+Placebo, 54 +/- 2 years, BMI 33.0 +/- 1.2 kg/m(2)) with mildly elevated fasting plasma glucose (FPG) at screening (6.1-8.0 mmol/l). All patients received metformin (850 mg twice daily) for treatment of type 2 diabetes mellitus/impaired glucose tolerance, either alone or in combination with rhGH (daily dose 9.5 mug/kg body weight). Glucose disposal rate (GDR) was measured using the euglycemic hyperinsulinemic clamp technique, and body composition was measured by DEXA at 0 and 18 months. After 18 months, the mean adiponectin concentration increased by 32 +/- 11 % (p = 0.018) in the MGH group and did not change in the MP group (- 10 +/- 13 %; p = n. s.). The difference in relative changes in adiponectin levels between the two groups after 18 months was statistically significant (p = 0.026). Improvement in insulin sensitivity (GDR) correlated positively with adiponectin levels (r = 0.73; p = 0.004). In conclusion, the additional administration of rhGH increased adiponectin levels in patients with metabolic syndrome, indicating its potential role in adiponectin-associated insulin sensitivity alterations.


A novel pollen-specific alpha-tubulin in sunflower: structure and characterization.
We describe here a new alpha-tubulin isoform from sunflower we named alpha(pi)-tubulin. Alpha(pi)-tubulin is the most divergent higher-plant alpha-tubulin described so far, having an unusual deletion in the H1/B2 loop and a glutamine-rich C-terminus. We constructed a three-dimensional model and discuss its implications. Using specific antibodies, we show that alpha(pi)-tubulin expression is restricted to the male gametophyte. Alpha(pi)-tubulin mRNA represents 90% of alpha-tubulin mRNA and a small percentage of total pollen mRNA. Among the plants tested, alpha(pi)-tubulin was only detected in sunflower and in Cosmos. Since both plants are Asteraceae, we propose that alpha(pi)-tubulin is specific to this family. Our results suggest that alpha(pi)-tubulin can inhibit tubulin assembly in pollen. This hypothesis is reinforced by the fact that alpha(pi)-tubulin is found in a complex with beta-tubulin in mature sunflower pollen.


Acute Effects of the Consumption of Passiflora setacea Juice on Metabolic Risk Factors and Gene Expression Profile in Humans.
Passiflora setacea (PS) is a passionfruit variety of the Brazilian savannah and is a rich source of plant food bioactives with potential anti-inflammatory activity. This study aimed to investigate the effect of an acute intake of PS juice upon inflammation, metabolic parameters, and gene expression on circulating immune cells in humans. Overweight male volunteers (n = 12) were enrolled in two double-blind placebo-controlled studies. Blood samples were collected from fasting volunteers 3 h after the consumption of 250 mL of PS juice or placebo (PB). Metabolic parameters (insulin, glucose, total cholesterol, high-density lipoprotein (LDL), high-density lipoprotein (HDL), and total triglycerides) and circulating cytokines were evaluated (study 1). Peripheral blood mononuclear cell (PBMC) from the same subjects were isolated and RNA was extracted for transcriptomic analyses using microarrays (study 2). Insulin and homeostatic model assessment for insulin resistance (HOMA-IR) levels decreased statistically after the PS juice intake, whereas HDL level increased significantly. Interleukin (IL)-17A level increased after placebo consumption, whereas its level remained unchanged after PS juice consumption. Nutrigenomic analyses revealed 1327 differentially expressed genes after PS consumption, with modulated genes involved in processes such as inflammation, cell adhesion, or cytokine-cytokine receptor. Taken together, these clinical results support the hypothesis that PS consumption may help the prevention of cardiometabolic diseases.


Management of out-of-hours calls by a general practice cooperative: a geographical analysis of telephone access and consultation.
Centralization of urgent care services may reduce access for patients living further away from primary care centres (PCCs). Telephone-based access is often proposed to remedy this. To examine the effect of distance and rurality on the doctor's decision to manage the call by telephone or face-to-face. Geographical analysis of routine data on calls to an out-of-hours cooperative, including logistic regression to examine the effects of distance and rurality on triage decisions. For distances >6 km, the likelihood of receiving telephone advice only increased progressively with increasing distance from the PCC (Model 1). However, for those patients seen face-to-face, overall, there was increased likelihood of receiving a home visit (compared with PCC attendance) with increasing distance (Model 2). Patients experience differences in how their call to out-of-hours services is managed depending on where they live. Telephone access and consultation can be used to overcome geographical barriers but do not necessarily make access geographically equitable. Those who live furthest away are more likely to receive telephone advice rather than being seen face-to-face, but paradoxically, those who do get a home visit are more likely to live at a greater distance from the PCC. These findings present important challenges to proposals to integrate urgent care services and increase telephone-based provision and suggest that attention should be given to configuring services to ensure geographical equity of access, regardless of how far away people live from health services.


[Some thoughts on influenza vaccine and regular influenza vaccination for healthcare workers].
It has been 100 years since the 1918 influenza pandemic but influenza is still an uncontrolled infectious disease. In some developed countries, the coverage rate of influenza vaccine can reach as high as 60%-70%, and even up to 90% or higher in some specific population, such as the elderly and healthcare workers. The coverage rate of influenza vaccination in Chinese people, however, is very low, only about 2%-3% per year. The limitations of influenza vaccine, and the purpose and significance of influenza vaccination, the imbalance of vaccine information and the importance of inoculation for healthcare workers are discussed in this paper. The resistance to popularize influenza vaccination is explored from different perspectives. It is hoped that more people will recognize the objective epidemiological data, and get rid of misunderstandings based on their experiences. Healthcare workers in particular, and the general population, should be encouraged to have an influenza vaccination.


Imprinted H19 oncofetal RNA is a candidate tumour marker for hepatocellular carcinoma.
To study the expression of the H19 gene in hepatocellular carcinoma. H19 is an imprinted, maternally expressed gene, which is tightly linked, both physically and functionally, to the paternally expressed insulin-like growth factor 2 (IGF II). IGF II is known to be involved in liver carcinogenesis. H19 was first discovered in the fetal mouse liver to be under the same regulatory genes as alpha fetoprotein (alpha FP), a widely used tumour marker for hepatocellular carcinoma. Using both radioactive and non-radioactive in situ hybridisation, the expression of the H19 gene was compared with the presence of alpha FP, as demonstrated by immunohistochemistry, in 18 cases of hepatocellular carcinoma. H19 expression was present in 13 of 18 cases, whereas staining for alpha FP was positive in only nine of 18 cases. Concordance was found in 12 of 18 tumours (66.7%). In general, the staining pattern for H19 was more diffuse than the immunohistochemical staining for alpha FP. The addition of a non-radioactive in situ hybridisation assay for H19 RNA to the panel of tumour markers used for the histopathological and cytological diagnosis of hepatocellular carcinoma might be useful.


Our experience of liver Epithelioid Hemangioendothelioma: from a misdiagnosis to liver transplantation with long term follow-up.
Malignant Hepatic Epithelioid hemangioendothelioma (HEHE) is an uncommon vascular tumor of intermediate malignant potential. HEHE is a rare tumor and it is difficult to diagnose for surgeons, hepatologists, radiologists and pathologists. So, misdiagnosis with a delay of the treatment is not uncommon. We describe a case of a young woman with a diagnosis of HEHE made 6 years after the first evidence of liver mass with a very long term follow-up after surgical treatment. She had two diagnoses of Hepatocellurar carcinoma (HCC) and a diagnosis of Cholangiocarcinoma after three different fine needle biopsies. After clinical observation, a new laparoscopic core biopsy was performed. In a first time approach, considering clinical and radiological patterns, a diagnosis of Budd-Chiari Syndrome was finally made. For that the patient underwent an orthotopicliver transplantation (OLTx). The surgical sample histological analysis allowed a definitive diagnosis of HEHE. At last, at follow up 7 years after three OLTx the patient is still alive and in good health with no evidence of recurrence.


Advances in breast cancer risk modeling: integrating clinics, imaging, pathology and artificial intelligence for personalized risk assessment.
Breast cancer risk models represent the likelihood of developing breast cancer based on risk factors. They enable personalized interventions to improve screening programs. Radiologists identify mammographic density as a significant risk factor and test new imaging techniques. Pathologists provide data for risk assessment. Clinicians conduct individual risk assessments and adopt prevention strategies for high-risk subjects. Tumor genetic testing guides personalized screening and treatment decisions. Artificial intelligence in mammography integrates imaging, clinical, genetic and pathological data to develop risk models. Emerging imaging technologies, genetic testing and molecular profiling improve risk model accuracy. The complexity of the disease, limited data availability and model inputs are discussed. A multidisciplinary approach is essential for earlier detection and improved outcomes.


The effects of multi-strain probiotic compound on symptoms and quality-of-life in patients with irritable bowel syndrome: A randomized placebo-controlled trial.
Evidence has shown beneficial effects of probiotics in the treatment of irritable bowel syndrome (IBS); however, there is still a lack of data in this regard. We evaluated the efficacy of a multi-strain probiotic compound on IBS symptoms and quality-of-life (QOL). Adult IBS patients (n = 132) were randomized to receive a probiotic compound containing seven bacteria species including Lactobacillus strains, Bifidobacterium strains and Streptococcus thermophiles or similar placebo, twice daily after a meal for 14 consecutive days. Improvement of IBS symptoms was assessed in categories of abdominal pain and distension and improvement of bowel habit. Improvement in patients QOL was assessed by the IBS-QOL instrument. Patients were evaluated for symptoms and QOL at baseline and then 1 month after completion of the treatment. After treatment, there was a decrease in abdominal pain and distension severity in both probiotic and the placebo groups (P<0.001), but there was no difference between the two groups in this regard (P>0.05). Improvement in bowel habit was observed in 33.3% of the probiotic and 36.5% of the placebo group (P = 0.910). There was no significant difference between the two groups in QOL after the treatment (P >0.05). We found no beneficial effects over placebo for a 2-week treatment with the above mentioned multi-strain probiotic compound in the treatment of IBS. Further, trials are yet required before a clear conclusion in this regards.


A 12-month follow-up split-scalp study comparing calcipotriol-assisted MAL-PDT with conventional MAL-PDT for the treatment of actinic keratosis: a randomized controlled trial.
To enhance the efficacy of photodynamic therapy (PDT) for actinic keratosis (AKs), physical and chemical pre-treatments, such as calcipotriol (CAL) have been suggested. To compare the long-term 12-month efficacy and safety between methylaminolevulinate (MAL)-PDT and prior application of topical CAL versus conventional MAL-PDT for AKs of the scalp. Twenty patients with multiple AKs on the scalp were randomized to receive conventional PDT on one side of the scalp and CAL-assisted PDT, in which CAL was applied daily for 15 days beforehand, on the other side. Patients were evaluated for AK clearance at three, six and 12 months thereafter. All 20 patients completed the study. At three months, overall AK clearance was 92.07% and 82.04% for CAL-PDT and conventional PDT, respectively (p < 0.001). Similar results were found at six and 12 months: 92.07% and 81.69% (p < 0.001), and 90.69% and 77.46% (p < 0.001) for CAL-PDT and conventional PDT, respectively. Grade I AKs showed a similar response rate for both sides (p = 0.055) at three months and significant differences were obtained at six (p = 0.001) and 12 months (p < 0.001) for CAL-PDT and conventional PDT. Grade II AKs showed greater improvement on the CAL-PDT side (89.55% vs 62.90%) (p < 0.001) at three months. No difference was found at six and 12 months. CAL-PDT proved to be safe and more effective than conventional PDT for the treatment of AKs on the scalp after 12 months. CAL pre-treatment may have enhanced the efficacy of PDT for AK treatment, however, larger trials are needed to corroborate our findings.


Identification of the optimal parameters for recording cortical potentials evoked by mechanical stimulation of the human oesophagus.
Cortical evoked potentials (CEP) have been recorded in response to both electrical stimulation (ES) and mechanical stimulation (MS) of the oesophagus. While the optimal parameters for recording reproducible oesophageal CEP to ES have recently been established, they have not yet been determined for MS, and reported CEP to MS show considerable variability. This study aimed to identify the optimal parameters required to record reproducible MS induced CEP. CEP were recorded from the vertex (Cz) in six subjects (one female; age range 23-47 years). MS was performed 5 cm above the lower oesophageal sphincter by rapidly inflating a 2-cm long silicone balloon at a frequency of 0.2 Hz. The rise time to maximum inflation was 165 ms. In order to determine the minimum number of stimuli required to produce optimal signal-to-noise quality, we acquired data in runs of 25, 50, 100 and 300 stimuli and to determine the stimulation intensity that produced the shortest latency and the largest amplitude CEP, we averaged four runs of 50 stimuli at five different intensities ranging from sensory threshold to pain. CEP reproducibility was then assessed in three subjects on three separate occasions using parameters determined from these measurements. We found that optimal signal-to-noise quality was achieved by averaging four runs of 50 stimuli; that P1 latency was shortest and P1-N1 amplitude largest at intensities of 75% and pain threshold and that highly reproducible CEP were obtained in all individuals. We conclude that it is possible to obtain highly reproducible oesophageal CEP to MS which can now be compared to those obtained by ES in order to identify which is most suitable for clinical studies.


Recent advances in the diagnosis and management of autoimmune pancreatitis: similarities and differences in Japan and Korea.
Two subtypes (types 1 and 2) of autoimmune pancreatitis (AIP) are currently recognized. Type 1 AIP is related to immunoglobulin G4 (lymphoplasmacytic sclerosing pancreatitis), and type 2 AIP is characterized by neutrophilic infiltration into the epithelium of the pancreatic duct (idiopathic duct-centric pancreatitis). Although type 2 AIP is sometimes observed in the United States and Europe, most cases of AIP in Japan and Korea are type 1. The international consensus diagnostic criteria for AIP were created to be applicable worldwide and to distinguish between the two types of AIP. AIP is diagnosed based on the presence of at least one of the five cardinal features (i.e., imaging, serology, other organ involvement, histology, and response to steroid therapy). Oral steroids are the standard therapy for AIP, but immunomodulatory drugs or rituximab have been successfully used for patients with relapsed AIP in the United States and Europe. Generally, the clinical manifestations and demography of AIP are similar between Japan and Korea. However, there are differences in some aspects of the disease, including the proportion of other organ involvement, the prevalence of type 2 AIP, diagnostic criteria and maintenance therapy between the two countries.


Potentiation of Antibiotic Activity by a Novel Cationic Peptide: Potency and Spectrum of Activity of SPR741.
Novel approaches for the treatment of multidrug-resistant Gram-negative bacterial infections are urgently required. One approach is to potentiate the efficacy of existing antibiotics whose spectrum of activity is limited by the permeability barrier presented by the Gram-negative outer membrane. Cationic peptides derived from polymyxin B have been used to permeabilize the outer membrane, granting antibiotics that would otherwise be excluded access to their targets. We assessed the in vitro efficacies of combinations of SPR741 with conventional antibiotics against Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii Of 35 antibiotics tested, the MICs of 8 of them were reduced 32- to 8,000-fold against E. coli and K. pneumoniae in the presence of SPR741. The eight antibiotics, azithromycin, clarithromycin, erythromycin, fusidic acid, mupirocin, retapamulin, rifampin, and telithromycin, had diverse targets and mechanisms of action. Against A. baumannii, similar potentiation was achieved with clarithromycin, erythromycin, fusidic acid, retapamulin, and rifampin. Susceptibility testing of the most effective antibiotic-SPR741 combinations was extended to 25 additional multidrug-resistant or clinical isolates of E. coli and K. pneumoniae and 17 additional A. baumannii isolates in order to rank the potentiated antibiotics. SPR741 was also able to potentiate antibiotics that are substrates of the AcrAB-TolC efflux pump in E. coli, effectively circumventing the contribution of this pump to intrinsic antibiotic resistance. These studies support the further development of SPR741 in combination with conventional antibiotics for the treatment of Gram-negative bacterial infections.


Transfer function analysis of dynamic cerebral autoregulation: A CARNet white paper 2022 update.
Cerebral autoregulation (CA) refers to the control of cerebral tissue blood flow (CBF) in response to changes in perfusion pressure. Due to the challenges of measuring intracranial pressure, CA is often described as the relationship between mean arterial pressure (MAP) and CBF. Dynamic CA (dCA) can be assessed using multiple techniques, with transfer function analysis (TFA) being the most common. A 2016 white paper by members of an international Cerebrovascular Research Network (CARNet) that is focused on CA strove to improve TFA standardization by way of introducing data acquisition, analysis, and reporting guidelines. Since then, additional evidence has allowed for the improvement and refinement of the original recommendations, as well as for the inclusion of new guidelines to reflect recent advances in the field. This second edition of the white paper contains more robust, evidence-based recommendations, which have been expanded to address current streams of inquiry, including optimizing MAP variability, acquiring CBF estimates from alternative methods, estimating alternative dCA metrics, and incorporating dCA quantification into clinical trials. Implementation of these new and revised recommendations is important to improve the reliability and reproducibility of dCA studies, and to facilitate inter-institutional collaboration and the comparison of results between studies.


Risk factors for opioid-induced respiratory depression in surgical patients: a systematic review and meta-analyses.
This systematic review and meta-analysis aim to evaluate the risk factors associated with postoperative opioid-induced respiratory depression (OIRD). Systematic review and meta-analysis. PubMed-MEDLINE, MEDLINE in-process, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed and Clinicaltrials.gov (January 1946 to November 2017). The inclusion criteria were: (1) adult patients 18 years or older who were administered opioids after surgery and developed postoperative OIRD (OIRD group); (2) all studies which reported both OIRD events and associated risk factors; (3) all studies with reported data for each risk factor on patients with no OIRD (control group) and (4) published articles in English language. We used a random effects inverse variance analysis to evaluate the existing evidence of risk factors associated with OIRD. Newcastle-Ottawa scale scoring system was used to assess quality of study. Twelve observational studies were included from 8690 citations. The incidence of postoperative OIRD was 5.0 cases per 1000 anaesthetics administered (95% CI: 4.8 to 5.1; total patients: 841 424; OIRD: 4194). Eighty-five per cent of OIRD occurred within the first 24 hours postoperatively. Increased risk for OIRD was associated with pre-existing cardiac disease (OIRD vs control: 42.8% vs 29.6%; OR: 1.7; 95% CI: 1.2 to 2.5; I2: 0%; p<0.002), pulmonary disease (OIRD vs control: 17.8% vs 10.3%; OR: 2.2; 95% CI: 1.3 to 3.6; I2: 0%; p<0.001) and obstructive sleep apnoea (OIRD vs control: 17.9% vs 16.5%; OR: 1.4; 95% CI: 1.2 to 1.7; I2: 31%; p=0.0003). The morphine equivalent daily dose of the postoperative opioids was higher in the OIRD group than in the control; (24.7±14 mg vs 18.9±13.0 mg; mean difference: 2.8; 95% CI: 0.4 to 5.3; I2: 98%; p=0.02). There was no significant association between OIRD and age, gender, body mass index or American Society of Anesthesiologists physical status. Patients with cardiac, respiratory disease and/or obstructive sleep apnoea were at increased risk for OIRD. Patients with postoperative OIRD received higher doses of morphine equivalent daily dose.


Report from the UK and Eire Association of Genetic Nurses and Counsellors (AGNC) supervision working group on genetic counselling supervision.
The Association of Genetic Nurses and Counsellors (AGNC) is the professional organisation which represents genetic counsellors and genetic nurses in the United Kingdom (UK) and Eire. The AGNC recognises that genetic counselling supervision is instrumental to the practice, training and registration of genetic counsellors in the UK. The AGNC formed a Supervision Working Group, whose terms of reference were to collate information on supervision and create a list of 'best practice' recommendations for its genetic counsellor members. This report delivers the findings from the Supervision Working Group and has been peer reviewed by the AGNC membership in the UK and Eire and ratified by the AGNC Committee. It offers a working definition of genetic counselling supervision, gives an overview of some of the literature on supervision and concludes with practice recommendations.


[Effects of local induction of ipt-gene in roots on cytokinins content in leaf cells tobacco plants].
Identification of cytokinins in differentiated leaf cells has received little attention. We have carried out immunohistochemical localization of cytokinins in leaves of transgenic tobacco plants in which the level of increased due to induced in their roots the expression of ipt-gene controlling cytokinin synthesis. Immuno-labeling of cytokinins with the help of antibodies raised against zeatin riboside was characteristic of mesophyll cells. The label was localized in cytoplasm adjacent to cell walls and was absent in vacuoles. Immunohistochemical staining also revealed the presence of cytokinins in guard cells. Induction of cytokinin synthesis enhanced the immunohistochemical staining of both mesophyll cells and guard cells, which was accompanied by elevated stomatal conductance. The possibility of a direct effect of cytokinins on stomatal conductance and their indirect influence through photosynthesis in the mesophyll cells is discussed.


Evaluation of programmed cell death ligand 1 expression in a contemporary cohort of penile squamous cell carcinoma and its correlation with clinicopathologic and survival parameters: A study of 134 patients.
Penile squamous cell carcinomas (PCs) are rare malignancies with a dismal prognosis in a metastatic setting; therefore, novel immunotherapeutic modalities are an unmet need. One such modality is the immune checkpoint molecule programmed cell death ligand 1 (PD-L1). We sought to analyze PD-L1 expression and its correlation with various clinicopathologic parameters in a contemporary cohort of 134 patients with PC. A cohort of 134 patients with PC was studied for PD-L1 immunohistochemistry. The PD-L1 expression was evaluated using a combined proportion score with a cutoff of 1 or higher to define positivity. The results were correlated with various clinicopathologic parameters. Overall, 77 (57%) patients had positive PD-L1 expression. Significantly high PD-L1 expression was observed in high-grade tumors (P = .006). We found that 37% of human papillomavirus (HPV)-associated subtypes and 73% of other histotype tumors expressed PD-L1, while 63% of HPV-associated tumors and 27% of other histotype tumors did not (odds ratio, 1.35; P = .002 when compared for HPV-associated groups vs all others). Similarly, PD-L1-positive tumors had a 3.61-times higher chance of being node positive than PD-L1-negative tumors (P = .0009). In addition, PD-L1 high-positive tumors had a 5-times higher chance of being p16ink4a negative than PD-L1 low-positive tumors (P = .004). The PD-L1-positive tumors had a lower overall survival and cancer-specific survival than PD-L1-negative tumors. Overall, PD-L1 expression is associated with high-grade and metastatic tumors. Lower PD-L1 expression is observed more frequently in HPV-associated (warty or basaloid) subtypes than in other, predominantly HPV-independent types. As a result, PD-L1 positivity, including higher expression, portends lower overall and cancer-specific survival. These data provide a rational for further investigating PD-L1-based immunotherapeutics in PC.


Retinoic acid and transforming growth factor beta differentially inhibit platelet-derived-growth-factor-induced Ito-cell activation.
Sinusoidal Ito cells (stellate or fat-storing cells) undergo excessive cellular proliferation before the establishment and progression of hepatic fibrosis and cirrhosis. Retinoic acid and transforming growth factor beta (TGF beta) both inhibit Ito-cell [3H]thymidine incorporation in serum-containing media. Serum-induced mitogenicity was dependent on platelet-derived growth factor (PDGF). Additionally, pre-treatment of Ito cells with retinoic acid and TGF beta blocked PDGF-induced cell proliferation. TGF beta, but not retinoic acid, diminished PDGF-receptor and smooth-muscle alpha-actin abundance.


Cross-cultural adaptation and psychometric validation of the Indonesian version of the Oxford Hip Score.
The aim of this study was to perform a cross-cultural adaptation of Oxford Hip Score (OHS) to Indonesian, and to evaluate its psychometric properties. We performed a cross-cultural adaptation of Oxford Hip Score into Indonesian language (OHS-ID) and determined its internal consistency, test-retest reliability, measurement error, floor-ceiling effect, responsiveness, and construct validity by hypotheses testing of its correlation with Harris Hip Score (HHS), vsual analogue scale (VAS), and Short Form-36 (SF-36). Adults (> 17 years old) with chronic hip pain (osteoarthritis or osteonecrosis) were included. A total of 125 patients were included, including 50 total hip arthroplasty (THA) patients with six months follow-up. The OHS questionnaire was translated into Indonesian and showed good internal consistency (Cronbach's alpha = 0.89) and good reliability (intraclass correlation = 0.98). The standard error of measurement value of 2.11 resulted in minimal detectable change score of 5.8. Ten out of ten (100%) a priori hypotheses were met, confirming the construct validity. A strong correlation was found with two subscales of SF-36 (pain and physical function), HHS (0.94), and VAS (-0.83). OHS-ID also showed good responsiveness for post-THA series. Floor and ceiling effect was not found. The Indonesian version of OHS showed similar reliability and validity with the original OHS. This questionnaire will be suitable to assess chronic hip pain in Indonesian-speaking patients. Cite this article: Bone Jt Open 2021;2(9):765-772.


Energy system contribution to 400-metre and 800-metre track running.
As a wide range of values has been reported for the relative energetics of 400-m and 800-m track running events, this study aimed to quantify the respective aerobic and anaerobic energy contributions to these events during track running. Sixteen trained 400-m (11 males, 5 females) and 11 trained 800-m (9 males, 2 females) athletes participated in this study. The participants performed (on separate days) a laboratory graded exercsie test and multiple race time-trials. The relative energy system contribution was calculated by multiple methods based upon measures of race VO2, accumulated oxygen deficit (AOD), blood lactate and estimated phosphocreatine degradation (lactate/PCr). The aerobic/anaerobic energy system contribution (AOD method) to the 400-m event was calculated as 41/59% (male) and 45/55% (female). For the 800-m event, an increased aerobic involvement was noted with a 60/40% (male) and 70/30% (female) respective contribution. Significant (P < 0.05) negative correlations were noted between race performance and anaerobic energy system involvement (lactate/PCr) for the male 800-m and female 400-m events (r = - 0.77 and - 0.87 respectively). These track running data compare well with previous estimates of the relative energy system contributions to the 400-m and 800-m events. Additionally, the relative importance and speed of interaction of the respective metabolic pathways has implications to training for these events.


Hardware-amenable structural learning for spike-based pattern classification using a simple model of active dendrites.
This letter presents a spike-based model that employs neurons with functionally distinct dendritic compartments for classifying high-dimensional binary patterns. The synaptic inputs arriving on each dendritic subunit are nonlinearly processed before being linearly integrated at the soma, giving the neuron the capacity to perform a large number of input-output mappings. The model uses sparse synaptic connectivity, where each synapse takes a binary value. The optimal connection pattern of a neuron is learned by using a simple hardware-friendly, margin-enhancing learning algorithm inspired by the mechanism of structural plasticity in biological neurons. The learning algorithm groups correlated synaptic inputs on the same dendritic branch. Since the learning results in modified connection patterns, it can be incorporated into current event-based neuromorphic systems with little overhead. This work also presents a branch-specific spike-based version of this structural plasticity rule. The proposed model is evaluated on benchmark binary classification problems, and its performance is compared against that achieved using support vector machine and extreme learning machine techniques. Our proposed method attains comparable performance while using 10% to 50% less in computational resource than the other reported techniques.


Transcription factors C/EBP alpha, C/EBP beta, and CHOP (Gadd153) expressed during the differentiation program of keratinocytes in vitro and in vivo.
CCAAT-enhancer binding proteins (C/EBP) are basic region/leucine zipper (bZIP) transcription factors selectively expressed during the differentiation of liver, adipose tissue, blood cells, and the endocrine pancreas. Here we show that C/EBP isoforms are differentially expressed in the skin. BALB/MK keratinocytes incubated in 0.12 mM calcium medium undergo a differentiation program featuring growth-arrest at 24-48 h, keratin K10 gene expression beginning at 24 h, and apoptosis commencing at 48 h. Within this framework, western immunoblot analysis and immunohistochemistry reveal that C/EBP alpha increases 5-fold at 1-2 d and remains elevated, C/EBP beta rises 2-fold at 2-4 d and gradually falls, and CHOP rises 9-fold in the first 24 h then returns rapidly to baseline. Several products of alternative translation are observed in BALB/MK cells, i.e., 42 kDa and 30 kDa forms of C/EBP alpha, and 32 kDa and 20 kDa forms of C/EBP beta. By immunohistologic examination of human, rat, and mouse skin, all three transcription factors are highly expressed within epithelial compartments in a spatially restricted distribution. C/EBP alpha is concentrated in the upper epidermis in a predominantly cytoplasmic location within cells, whereas the highest levels of C/EBP beta and CHOP are seen in the mid-epidermis, mainly within nuclei. High levels of C/EBP beta and CHOP (but not C/EBP alpha) are also observed in hair follicles and sebaceous glands. The identity of these factors in the epidermis is confirmed by western immunoblot analyses. In summary, C/EBP are expressed in a differentiation-associated manner in the skin, and may play an important role in regulating one or more aspects of the epidermal differentiation program.


Availability and Suitability of Digital Health Tools in Africa for Pandemic Control: Scoping Review and Cluster Analysis.
Gaining oversight into the rapidly growing number of mobile health tools for surveillance or outbreak management in Africa has become a challenge. The aim of this study is to map the functional portfolio of mobile health tools used for surveillance or outbreak management of communicable diseases in Africa. We conducted a scoping review by combining data from a systematic review of the literature and a telephone survey of experts. We applied the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines by searching for articles published between January 2010 and December 2020. In addition, we used the respondent-driven sampling method and conducted a telephone survey from October 2019 to February 2020 among representatives from national public health institutes from all African countries. We combined the findings and used a hierarchical clustering method to group the tools based on their functionalities (attributes). We identified 30 tools from 1914 publications and 45 responses from 52% (28/54) of African countries. Approximately 13% of the tools (4/30; Surveillance Outbreak Response Management and Analysis System, Go.Data, CommCare, and District Health Information Software 2) covered 93% (14/15) of the identified attributes. Of the 30 tools, 17 (59%) tools managed health event data, 20 (67%) managed case-based data, and 28 (97%) offered a dashboard. Clustering identified 2 exceptional attributes for outbreak management, namely contact follow-up (offered by 8/30, 27%, of the tools) and transmission network visualization (offered by Surveillance Outbreak Response Management and Analysis System and Go.Data). There is a large range of tools in use; however, most of them do not offer a comprehensive set of attributes, resulting in the need for public health workers having to use multiple tools in parallel. Only 13% (4/30) of the tools cover most of the attributes, including those most relevant for response to the COVID-19 pandemic, such as laboratory interface, contact follow-up, and transmission network visualization.


Post-exercise Supplementation of Sodium Bicarbonate Improves Acid Base Balance Recovery and Subsequent High-Intensity Boxing Specific Performance.
The aim of this study was to assess the effects of post-exercise sodium bicarbonate (NaHCO3) ingestion (0.3 g.kg-1 body mass) on the recovery of acid-base balance (pH, HCO 3 - , and the SID) and subsequent exercise performance in elite boxers. Seven elite male professional boxers performed an initial bout of exhaustive exercise comprising of a boxing specific high-intensity interval running (HIIR) protocol, followed by a high-intensity run to volitional exhaustion (TLIM1). A 75 min passive recovery then ensued, whereby after 10 min recovery, participants ingested either 0.3 g.kg-1 body mass NaHCO3, or 0.1 g.kg-1 body mass sodium chloride (PLA). Solutions were taste matched and administered double-blind. Participants then completed a boxing specific punch combination protocol, followed by a second high-intensity run to volitional exhaustion (TLIM2). Both initial bouts of TLIM1 were well matched between PLA and NaHCO3 (ICC; r = 0.94, p = 0.002). The change in performance from TLIM1 to TLIM2 was greater following NaHCO3 compared to PLA (+164 ± 90 vs. +73 ± 78 sec; p = 0.02, CI = 45.1, 428.8, g = 1.0). Following ingestion of NaHCO3, pH was greater prior to TLIM2 by 0.11 ± 0.02 units (1.4%) (p < 0.001, CI = 0.09, 0.13, g = 3.4), whilst HCO 3 - was greater by 8.8 ± 1.5 mmol.l-1 (26.3%) compared to PLA (p < 0.001, CI = 7.3, 10.2, g = 5.1). The current study suggests that these significant increases in acid base balance during post-exercise recovery facilitated the improvement in the subsequent bout of exercise. Future research should continue to explore the role of NaHCO3 supplementation as a recovery aid in boxing and other combat sports.


Direct effect of pholyphenol-rich plants, rooibos and ginkgo, on porcine ovarian cell functions.
The polyphenol-rich plants rooibos and ginkgo are widely used in folk medicine and in preparation of foods and drinks, but their effect on reproduction has not been properly studied yet. The aim of our in vitro experiments was to examine the possible direct effect of rooibos and ginkgo on the basic ovarian cell functions-proliferation, apoptosis and release of hormones progesterone (P4) and leptin (L). Porcine ovarian granulosa cells were cultured in the presence of rooibos or ginkgo extract (0, 1, 10 and 100 μg/ml of medium). The accumulation of markers of proliferation (PCNA and cyclin B1) and apoptosis (bax) and their mRNAs was analysed using immunocytochemistry and by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Release of P4 and L was evaluated by radioimmunoassay. It was observed that rooibos or ginkgo addition was able to inhibit proliferation (down-regulates PCNA, cyclin B1 and their mRNAs), to promote apoptosis (accumulation of bax) and to suppress both L and P4 release by ovarian cells. These data suggest a direct inhibitory (anti-proliferative, pro-apoptotic and hormone-suppressing) effect of polyphenol-containing plants rooibos and ginkgo on ovarian functions. The potential anti-reproductive effect of these medical plants is to be taken into account by their consumption.


Fully synthetic carbohydrate-based vaccines in biochemically relapsed prostate cancer: clinical trial results with alpha-N-acetylgalactosamine-O-serine/threonine conjugate vaccine.
We report the synthesis of a mucin-related O-linked glycopeptide, alpha-N-acetylgalactosamine-O-serine/threonine (Tn), which is highly simplistic in its structure and can induce a relevant humoral response when given in a trimer or clustered (c) formation. We tested for an antitumor effect, in the form of a change in the posttreatment versus pretreatment prostate-specific antigen (PSA) slopes, that might serve as a surrogate for effectiveness of vaccines in delaying the time to radiographic progression. We compared the antibody response to immunization with two conjugates, Tn(c)-keyhole limpet hemocyanin (KLH) and Tn(c)-palmitic acid (PAM) with the saponin immunologic adjuvant QS21, in a phase I clinical trial in patients with biochemically relapsed prostate cancer. Patients received Tn(c)-KLH vaccine containing either 3, 7, or 15 microg of Tn(c) per vaccination. Ten patients received 100 microg of Tn(c)-PAM. QS21 was included in all vaccines. Five vaccinations were administered subcutaneously during 26 weeks with an additional booster vaccine at week 50. Tn(c), when given with the carrier molecule KLH and QS21, stimulated the production of high-titer immunoglobulin M (IgM) and IgG antibodies. Inferior antibody responses were seen with T(c)-PAM. There was no evidence of enhanced immunogenicity with increasing doses of vaccine. An antitumor effect in the form of a decline in posttreatment versus pretreatment PSA slopes was also observed. A safe synthetic conjugate vaccine in a trimer formation was developed that can break immunologic tolerance by inducing specific humoral responses. It seemed to affect the biochemical progression of the disease as determined by a change in PSA log slope.


Inhibitory effects of ascorbic acid on AP-1 activity and transformation of JB6 cells.
Ascorbic acid (vitamin C) has been reported as an anti-cancer agent. Previous in vitro studies using either primary cell cultures from cancer patients or tumor cell lines have indicated that different kinds of tumor cells may have different sensitivities to ascorbic acid for the inhibition of tumorigeneity or growth. Because the JB6 mouse epidermal cell system has been used extensively as an in vitro model for the study of tumor promotion and progression, we assessed the effects of ascorbic acid on transformation in JB6 cell variants. The results show that ascorbic acid could inhibit 5.5% to 97.1% of transformation of JB6 P+ cell Cl 41-19 induced by TPA, EGF or EGF + insulin, but has no effect on anchorage-independent growth of JB6 transformed cell A33. Since our previous results indicated that induced AP-1 activity is required for tumor promoter induced-transformation, we tested whether inhibition of tumor promoter-induced transformation by ascorbic acid is through an AP-1 inhibition mechanism. Our results indicated that ascorbic acid inhibited AP-I activity at the same dose range for inhibition of transformation. These results demonstrated that ascorbic acid has inhibitory effects on JB6 cell tumor promoter-induced transformation, but no influence on tumor cell phenotype expression and provided the basic knowledge for understanding of vitamin C action on tumor prevention.


In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs.
TRAIL/Apo-2L has shown promise as an anti-glioma drug, based on investigations of TRAIL sensitivity in established glioma cell lines, but it is not known how accurately TRAIL signalling pathways of glioma cells in vivo are reproduced in these cell lines in vitro. To replicate as closely as possible the in vivo behaviour of malignant glioma cells, 17 early passage glioma cell lines and 5 freshly resected gliomas were exposed to TRAIL-based agents and/or chemotherapeutic drugs. Normal human hepatocytes and astrocytes and established glioma cell lines were also tested. Cross-linked TRAIL, but not soluble TRAIL, killed both normal cell types and cells from three tumours. Cells from only one glioma were killed by soluble TRAIL, although only inefficiently. High concentrations of cisplatin were lethal to glioma cells, hepatocytes and astrocytes. Isolated combinations of TRAIL and chemotherapy drugs were more toxic to particular gliomas than normal cells, but no combination was generally selective for glioma cells. This study highlights the widespread resistance of glioma cells to TRAIL-based agents, but suggests that a minority of high-grade glioma patients may benefit from particular combinations of TRAIL and chemotherapy drugs. In vitro sensitivity assays may help identify effective drug combinations for individual glioma patients.


Effect of alpha-linolenic acid in the human diet on linoleic acid metabolism and prostaglandin biosynthesis.
The effect of dietary alpha-linolenic acid intake on linoleic acid metabolism and prostaglandin (PG) biosynthesis was investigated in two groups of six healthy females (25-32 yr). They were given isocaloric formula diets (FD) containing linoleic acid at a constant intake (4% of calories), with different amounts of alpha-linolenic acid: 0% (FD4/0), 4% (FD4/4), 8% (FD4/8) (group I) and 12% (FD4/12) or 16% (FD4/16) (group II); the diets were given for 2 weeks each. Comparing diet FD4/0 to FD4/16, enrichment of alpha-linolenic acid was greatest in cholesteryl esters (+6.8% in plasma, +7.1% in low density lipoproteins (LDL), +5.9% in high density lipoproteins (HDL)), less in phosphatidylcholine (+2.5% in plasma, +2.9% in LDL, +2.7% in HDL), and least in platelet lipids (+0.7%). The accumulation of alpha-linolenic acid was compensated by a decrease of oleic acid. Eicosapentaenoic acid (EPA), which was excluded from the diet, increased in all plasma lipids with augmented alpha-linolenic acid intake, indicating a chain elongation and desaturation of alpha-linolenic acid to EPA. However, even at the end of FD4/16, EPA was less than 2% of total fatty acids in all plasma lipids. Plasma linoleic acid levels were constant during all dietary regimes, according to the constant dietary intake of this fatty acid. No replacement of linoleic acid by alpha-linolenic acid could be observed. The percentage of arachidonic acid in all lipids was unaffected by alpha-linolenic acid intake. As arachidonic acid was not provided by the diet, it can be concluded that alpha-linolenic acid does not inhibit chain elongation and desaturation of linoleic acid to arachidonic acid in man.(ABSTRACT TRUNCATED AT 250 WORDS)


The evolution of hummock-depression micro-topography in an alpine marshy wetland in Sanjiangyuan as inferred from vegetation and soil characteristics.
The hummock-depression micro-topography characteristics of the alpine marshy wetland in Sanjiangyuan are indicative of wetland degradation and the process by which healthy wetlands are transformed into flat grasslands. The aim of the present study was to examine changes in plant community structure and soil characteristics in a hummock-depression micro-topography along a degradation gradient. We observed that: (a) the height and cover of dominant hydrophytes decreased gradually with an increase in degradation severity, leading to replacement by xerophytes; (b) with the transition from healthy to degraded wetlands, hummocks became sparser, shorter, and broader and became merged with nearby depressions; water reserves in the depressions shifted from perennial to seasonal, until they dried out completely; and (c) soil moisture content, porosity, hardness, and organic matter gradually decreased by 30.61%, 19.06%, 37.04%, and 73.27%, respectively, in hummocks and by 33.25%, 8.19%, 47.72%, and 76.79%, respectively, in depressions. Soil bulk density, soil electrical conductivity, and soil dry weight increased by 31%, 83.33%, and 105.44%, respectively, in hummocks, but by only 11.93%, 7.14%, and 97.72%, respectively, in depressions. The results show that hummock soils in healthy wetlands have strong water absorption properties, through which plant roots can penetrate easily. Wetland degradation reduces the water absorption capacity of hummock soil and soil saturation capacity of depressions, thus enhancing soil erosion potential and susceptibility to external factors. Soil moisture is a key environmental factor influencing wetland degradation, and grazing accelerates the process. Based on the changes observed in hummock morphology, vegetation, and soil properties along a degradation gradient, a conceptual model is proposed to illustrate the process of gradual degradation of marshy wetlands from healthy to transitional wetlands and finally to a degenerated state. Thus, our research provides insights into the degradation process of the alpine marshy wetland ecosystem in Sanjiangyuan.


High-harmonic spectroscopy of oriented OCS molecules: emission of even and odd harmonics.
We study the emission of even and odd high-harmonic orders from oriented OCS molecules. We use an intense, nonresonant femtosecond laser pulse superimposed with its phase-controlled second harmonic field to impulsively align and orient a dense sample of molecules from which we subsequently generate high-order harmonics. The even harmonics appear around the full revivals of the rotational dynamics. We demonstrate perfect coherent control over their intensity through the subcycle delay of the two-color fields. The odd harmonics are insensitive to the degree of orientation, but modulate with the degree of axis alignment, in agreement with calculated photorecombination dipole moments. We further compare the shape of the even and odd harmonic spectra with our calculations and determine the degree of orientation.


The cytotoxic response to murine cytomegalovirus. III. Lymphokine release and cytotoxicity are dependent upon phenotypically similar immune cell populations.
Murine cytomegalovirus (MCMV)-immune lymph node (LN) cells were generated following 4 days culture of draining popliteal LN cells removed after bilateral hind footpad inoculation of mice with 4 X 10(2) p.f.u. MCMV. This cell population expressed both cytotoxic activity against MCMV-infected mouse embryo fibroblasts (MEF) and the capacity to release lymphokine upon stimulation with MCMV-infected MEF. Cytotoxicity and lymphokine release were Class I, H-2-restricted, virus-specific and dependent upon Thy1. 2+, Lyt2+ cells. Mixing of 5 X 10(5) MCMV-immune T cells with an excess of syngeneic MCMV-infected MEF stimulators produced detectable levels of the lymphokine interleukin-3 by 1 h, with a maximum rate of its release between 1 and 6 h and plateau levels by 14 h. The capacity to stimulate virus-specific MCMV-immune T cells was acquired by MEF at 1 h after MCMV infection with maximum stimulator ability attained by 8 h. In the presence of a fixed number of MCMV-immune T cells, and titration to excess of syngeneic 3 h or 18 h MCMV-infected MEF, lower interleukin-3 plateau levels were obtained with 3 h than with 18 h MCMV-infected stimulators. This suggested that fewer T cells responded to 3 h than to 18 h MCMV-infected MEF.


Evaluation of a rapid-format antibody test and the tuberculin skin test for diagnosis of tuberculosis in two contrasting endemic settings.
We evaluated a rapid-format antibody card test and the tuberculin skin test for diagnosis of active tuberculosis (TB) in high (Cairo, Egypt) and low (St. Louis, USA) prevalence areas. Prospective study of hospitalized TB patients and controls with other chest diseases. Test performance varied significantly in the two study sites. The antibody test detected 87% of 71 smear-positive pulmonary TB cases (86% of smear-negative pulmonary cases and 48% of TB meningitis cases) in Egypt; specificity was 82%. The tuberculin test was highly sensitive in Egypt in subjects with pulmonary TB (100%) but not in those with meningitis (23%); specificity was 70%. The sensitivity and specificity of the antibody test in St. Louis were 29% and 79%, respectively; 50% of St. Louis TB cases and 15% of controls had positive tuberculin tests. This convenient antibody card test may have value for diagnosis of patients suspected of having TB in high prevalence areas like Egypt. However, the specificity of the test is too low for it to be useful as a screening test. Our results suggest that neither the antibody test nor the tuberculin test have much diagnostic utility in low prevalence settings like St. Louis.


[Heat-related problems in the elderly].
In particular in the elderly patient, exposure to heat can lead to disturbances of the circulatory system and of the water and electrolyte balance. Provided that certain prophylactic measures are taken, serious problems are unlikely to occur. Food and drink should be matched to the ambient temperature, and permanent medication should be checked. In the case of confused persons, nursing personnel should substitute for any failure to make the necessary acclimatization changes (appropriate clothing). In the case of incontinent patients, it must be remembered that the diapered area is not available for radiating off heat.


An overview of research in cancer diagnosis.
The diagnostic research program of the National Cancer Institute encompasses detection or screening, methods of diagnosis, and prognosis. The present objective of this program is diagnosis of 75% of all cancers at a time when 90% of these have not metastasized. The Institute's Divison of Cancer Biology and Diagnosis has directed its attention toward general diagnostic methods (immunologic, chemical, cytologic, imaging, and endoscopic) and organ site programs (breast, lung, cervix, bowel, bladder, and pancreas). The organ site programs usually involve multiple diagnostic techniques applied to a specific organ. Screening for asymptomatic cancer seems an important immediate objective. Optimum frequency of screening should be established for individual organ sites and for combinations of sites, to determine whether multi-site screening programs can significantly reduce mortality from cancer.


[Review on the development of periodontology in China].
Chinese Journal of Stomatology has gone through 70 years of ups and downs, witnessing the development of periodontics in China from a faltering start to twists and turns, and finally innovative development. This article aims to review the periodontology-related papers published in the Chinese Journal of Stomatology. Based on the characteristics of the times, they are summarized into five stages: staggering start, forced stagnation, vigorous development, standardized innovation, and disciplinary integration. Researches on periodontal diseases in China initially focused on learning and reference, gradually caught up with the international level, and finally created in-depth insights and innovations. Eventually, Chinese periodontology has formed a research system with Chinese characteristics and achieved substantial achievements in clinical diagnosis and treatment, basic research, periodontal medicine, and disciplinary integration. Although the current status of Chinese periodontology still lags behind that of developed countries, these representative studies demonstrate the unremitting efforts and hard work of periodontists for generations, laying a solid foundation for the innovation and development of periodontology in our country.


Diarrhea During COVID-19 Infection: Pathogenesis, Epidemiology, Prevention, and Management.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/COVID-19) pandemic is a worldwide emergency. An increasing number of diarrhea cases is reported. Here we investigate the epidemiology, clinical presentation, molecular mechanisms, management, and prevention of SARS-CoV-2 associated diarrhea. We searched on PubMed, EMBASE, and Web of Science up to March 2020 to identify studies documenting diarrhea and mechanism of intestinal inflammation in patients with confirmed diagnosis of SARS-CoV-2 infection. Clinical studies show an incidence rate of diarrhea ranging from 2% to 50% of cases. It may precede or trail respiratory symptoms. A pooled analysis revealed an overall percentage of diarrhea onset of 10.4%. SARS-CoV uses the angiotensin-converting enzyme 2 (ACE2) and the serine protease TMPRSS2 for S protein priming. ACE2 and TMPRSS2 are not only expressed in lung, but also in the small intestinal epithelia. ACE2 is expressed furthermore in the upper esophagus, liver, and colon. SARS-CoV-2 binding affinity to ACE2 is significantly higher (10-20 times) compared with SARS-CoV. Several reports indicate viral RNA shedding in stool detectable longer time period than in nasopharyngeal swabs. Current treatment is supportive, but several options appear promising and are the subject of investigation. Diarrhea is a frequent presenting symptom in patients infected with SARS-CoV-2. Increasing evidence indicates possible fecal oral transmission, indicating the need for a rapid and effective modification of the screening and diagnostic algorithms. The optimal methods to prevent, manage, and treat diarrhea in COVID-19 infected patients are subjects of intensive research.


[Ending life at the patient's request: who sets the standards?].
Under the Dutch Termination of Life on Request and Assisted Suicide Act of 2002, independent review committees assess all reported cases of euthanasia and assisted suicide. These committees apply and conceptualise the criteria mentioned in the Act. Recently, the Royal Dutch Medical Association questioned a number of decisions made by the committees. This is a confusing situation for physicians: should they follow the 'jurisprudence' of the committees or the standards as defined by their professional organisation?


MOD-LSP, MODIS-based parameters for hydrologic modeling of North American land cover change.
Earth systems models require gridded land surface properties to compute fluxes of water, energy, and carbon within the landscape and to the atmosphere. However, most parameter sets contain time-invariant properties despite their known variability. Here we present new MODerate Resolution Imaging Spectroradiometer (MODIS)-based land surface parameters (MOD-LSP) formatted for the Variable Infiltration Capacity (VIC) hydrologic model that account for seasonal and interannual variability and longer-term change over the continental United States, Mexico, and southern Canada at 0.0625° spatial resolution and monthly temporal resolution. MOD-LSP improves over previously-available parameter sets via: (1) land cover maps of higher native spatial resolution; (2) multiple versions corresponding to the land cover of years 1992, 2001, and 2011; (3) spatially-explicit mean annual cycles of land surface properties, including leaf area index, canopy fraction, and albedo, derived from 17 years of observations; and (4) additional 17-year time series of these properties. The MOD-LSP parameters are useful as inputs to the VIC model, as an example land surface scheme, to assess the hydrologic impacts of land cover change from interannual to decadal scales; and as stand-alone datasets characterizing the temporal variability of these properties as a function of land cover class.


Corticotropin-releasing hormone, proopiomelanocortin, and glucocorticoid receptor gene expression in adrenocorticotropin-producing tumors in vitro.
To differentiate between ectopic ACTH syndrome and Cushing's disease, gene expression of corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), and glucocorticoid receptor was examined in 10 pituitary adenomas (Cushing's disease) and in 10 ectopic ACTH-producing tumors. CRH increased plasma ACTH levels in all patients with Cushing's disease and in five patients with ectopic ACTH syndrome whose tumors contained CRH and CRH mRNA. In five CRH nonresponders, CRH was not detected in tumors that contained no CRH mRNA or that contained only long-size CRH mRNA. Dexamethasone (Dex) decreased plasma ACTH levels in all patients with Cushing's disease and in three patients with ectopic ACTH-producing bronchial carcinoid. These tumors contained glucocorticoid receptor mRNA. CRH increased and Dex decreased ACTH release and POMC mRNA levels in pituitary adenoma and bronchial carcinoid cells. PMA increased POMC mRNA levels only in carcinoid cells. These results reveal characteristics of ectopic ACTH-producing tumors: long-size CRH mRNA and PMA-induced POMC gene expression. In addition, there are two ectopic ACTH syndrome subtypes: tumors containing ACTH with CRH (CRH responder) and tumors without CRH. Dex decreases ACTH release and POMC mRNA levels in some bronchial carcinoids. Therefore, CRH and Dex tests have limited usefulness in differentiating between Cushing's disease and ectopic ACTH syndrome.


The relationship between early personality and midlife psychological well-being: evidence from a UK birth cohort study.
Individual differences in personality influence the occurrence, reporting and outcome of mental health problems across the life course, but little is known about the effects on adult psychological well-being. The aim of this study was to examine long range associations between Eysenck's personality dimensions and psychological well-being in midlife. The study sample comprised 1,134 women from the 1946 British birth cohort. Extraversion and neuroticism were assessed using the Maudsley Personality Inventory in adolescence (age 16 years) and early adulthood (age 26). Psychological well-being was assessed at age 52 with a 42-item version of Ryff's Psychological Well-being Scale. Analyses were undertaken within a structural equation modelling framework that allowed for an ordinal treatment of well-being and personality items, and latent variable modelling of longitudinal data on emotional adjustment. The contribution of mental health problems in linking personality variations to later well-being was assessed using a summary measure of mental health (emotional adjustment) created from multiple time-point assessments. Women who were more socially outgoing (extravert) reported higher well-being on all dimensions. Neuroticism was associated with lower well-being on all dimensions. The effect of early neuroticism on midlife well-being was almost entirely mediated through emotional adjustment defined in terms of continuities in psychological/ psychiatric distress. The effect of extraversion was not mediated by emotional adjustment, nor attenuated after adjustment for neuroticism. Individual differences in extraversion and neuroticism in early adult life influence levels of well-being reported in midlife.


High-Resolution Imaging of C + He Collisions using Zeeman Deceleration and Vacuum-Ultraviolet Detection.
High-resolution measurements of angular scattering distributions provide a sensitive test for theoretical descriptions of collision processes. Crossed beam experiments employing a decelerator and velocity map imaging have proven successful to probe collision cross sections with extraordinary resolution. However, a prerequisite to exploit these possibilities is the availability of a near-threshold state-selective ionization scheme to detect the collision products, which for many species is either absent or inefficient. We present the first implementation of recoil-free vacuum ultraviolet (VUV) based detection in scattering experiments involving a decelerator and velocity map imaging. This allowed for high-resolution measurements of state-resolved angular scattering distributions for inelastic collisions between Zeeman-decelerated carbon C(3P1) atoms and helium atoms. We fully resolved diffraction oscillations in the angular distributions, which showed excellent agreement with the distributions predicted by quantum scattering calculations. Our approach offers exciting prospects to investigate a large range of scattering processes with unprecedented precision.


[Diagnosis and treatment of disorders in pancreatic enzyme secretion, liver function and gastric motor activity in diabetes mellitus].
Examination of 106 patients with medium severe and severe forms of diabetes mellitus with a history of the disease of more than 3 years revealed a consistent reduction in the liver blood flow rate, in hepatocyte absorption and metabolic functions, pancreatic enzyme secretion, and gastric contractility. The bromsulphthalein, ujoviridin, and pancreozymin tests, as well as synthetic peptide benzoyl-tyrosyl-para-aminobenzoic acid tolerance test, electromanometric measurements of the cardial and pyloric sphincters tones, intracavitary pressure in the stomach and the rate of the test solution evacuation by the stomach are reliable and sensitive indices of the disturbances in the liver, exocrine portion of the pancreas, and gastric contractility in diabetes patients. Pancreozymin showed hepatotrophic properties, and metoclopramid (cerucal, reglan) increased gastric motility reduced in diabetes.


Magnetic resonance imaging assessment of renal flow distribution patterns during ex vivo normothermic machine perfusion in porcine and human kidneys.
Acceptance criteria of deceased donor organs have gradually been extended toward suboptimal quality, posing an urgent need for more objective pre-transplant organ assessment. Ex vivo normothermic machine perfusion (NMP) combined with magnetic resonance imaging (MRI) could assist clinicians in deciding whether a donor kidney is suitable for transplantation. Aim of this study was to characterize the regional distribution of perfusate flow during NMP, to better understand how ex vivo kidney assessment protocols should eventually be designed. Nine porcine and 4 human discarded kidneys underwent 3 h of NMP in an MRI-compatible perfusion setup. Arterial spin labeling scans were performed every 15 min, resulting in perfusion-weighted images that visualize intrarenal flow distribution. At the start of NMP, all kidneys were mainly centrally perfused and it took time for the outer cortex to reach its physiological dominant perfusion state. Calculated corticomedullary ratios based on the perfusion maps reached a physiological range comparable to in vivo observations, but only after 1 to 2 h after the start of NMP. Before that, the functionally important renal cortex appeared severely underperfused. Our findings suggest that early functional NMP quality assessment markers may not reflect actual physiology and should therefore be interpreted with caution.


The tip of the iceberg: improving the quality of rank order lists for the match.
Many factors limit the ability of resident selection committees to reliably determine which medical student applicants will be top performers in their internship and residency programs. Resident selection committees expend significant time and effort to read applications and then interview and score applicants, all with the goal of creating a rank order list (ROL) for the National Residency Matching Program. Although much of the information used in this process is outside the control of the selection committee, one factor they can control is how they use committee member scores to create the ROL. ROLs are typically generated using the average score assigned by committee members. With this approach, a single harsh faculty member can strongly influence the rank order of applicants if he or she scores only some of the applicants.The author of this commentary discusses the challenges inherent in the creation of ROLs and examines a new approach, described by Ross and Moore in this issue, that can eliminate the problem of biased scoring. ROLs created using this new ROSS-MOORE (Recruitment Outcomes Simulation System-Moore Optimized Ordinal Rank Estimator) approach will better represent the rank ordering of each faculty member of the selection committee. However, ROLs will remain poorly predictive of future performance in internship and residency programs until evaluative data supplied by medical schools are more accurate in predicting which students will become excellent physicians.


Input feature selection for classification problems.
Feature selection plays an important role in classifying systems such as neural networks (NNs). We use a set of attributes which are relevant, irrelevant or redundant and from the viewpoint of managing a dataset which can be huge, reducing the number of attributes by selecting only the relevant ones is desirable. In doing so, higher performances with lower computational effort is expected. In this paper, we propose two feature selection algorithms. The limitation of mutual information feature selector (MIFS) is analyzed and a method to overcome this limitation is studied. One of the proposed algorithms makes more considered use of mutual information between input attributes and output classes than the MIFS. What is demonstrated is that the proposed method can provide the performance of the ideal greedy selection algorithm when information is distributed uniformly. The computational load for this algorithm is nearly the same as that of MIFS. In addition, another feature selection algorithm using the Taguchi method is proposed. This is advanced as a solution to the question as to how to identify good features with as few experiments as possible. The proposed algorithms are applied to several classification problems and compared with MIFS. These two algorithms can be combined to complement each other's limitations. The combined algorithm performed well in several experiments and should prove to be a useful method in selecting features for classification problems.


Clinical assessment of the Roche SARS-CoV-2 rapid antigen test.
Novel point-of-care antigen assays present a promising opportunity for rapid screening of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The purpose of this study was the clinical assessment of the new Roche SARS-CoV-2 Rapid Antigen Test. The clinical performance of Roche SARS-CoV-2 Rapid Antigen Test was evaluated vs. a reverse transcription polymerase chain reaction (RT-PCR) laboratory-based assay (Seegene AllplexTM2019-nCoV) in nasopharyngeal swabs collected from a series of consecutive patients referred for SARS-CoV-2 diagnostics to the Pederzoli Hospital (Peschiera del Garda, Verona, Italy) over a 2-week period. The final study population consisted of 321 consecutive patients (mean age, 46 years and IQR, 32-56 years; 181 women, 56.4%), with 149/321 (46.4%) positive for SARS-CoV-2 RNA via the Seegene AllplexTM2019-nCoV Assay, and 109/321 (34.0%) positive with Roche SARS-CoV-2 Rapid Antigen Test, respectively. The overall accuracy of Roche SARS-CoV-2 Rapid Antigen Test compared to molecular testing was 86.9%, with 72.5% sensitivity and 99.4% specificity. Progressive decline in performance was observed as cycle threshold (Ct) values of different SARS-CoV-2 gene targets increased. The sensitivity was found to range between 97-100% in clinical samples with Ct values <25, between 50-81% in those with Ct values between 25 and <30, but low as 12-18% in samples with Ct values between 30 and <37. The clinical performance of Roche SARS-CoV-2 Rapid Antigen Test is excellent in nasopharyngeal swabs with Ct values <25, which makes it a reliable screening test in patients with high viral load. However, mass community screening would require the use of more sensitive techniques.


Soft ultrasound priors in optoacoustic reconstruction: Improving clinical vascular imaging.
Using the same ultrasound detector, hybrid optoacoustic-ultrasound (OPUS) imaging provides concurrent scans of tissue slices or volumes and visualizes complementary sound- and light-based contrast at similar resolutions. In addition to the benefit of hybrid contrast, spatial co-registration enables images from one modality to be employed as prior information for improving an aspect of the performance of the other modality. We consider herein a handheld OPUS system and utilize structural information from ultrasound images to guide regional Laplacian regularization-based reconstruction of optoacoustic images. Using phantoms and data from OPUS scans of human radial and carotid arteries, we show that ultrasound-driven optoacoustic inversion reduces limited-view artefacts and improves image contrast. In phantoms, prior-integrated reconstruction leads to a 50 % higher contrast-to-noise ratio (CNR) of the image than standard reconstruction, and a 17 % higher structural similarity (SSIM) index. In clinical data, prior-integrated reconstruction detects deep-seated radial arteries with higher CNR than the standard method at three different depths. In this way, the prior-integrated method offers unique insights into atherosclerotic carotid plaques in humans (with p<0.01 between patients and healthy volunteers), potentially paving the way for new abilities in vascular imaging and more generally in optoacoustic imaging.


Synthetic melanin bound to subunit vaccine antigens significantly enhances CD8+ T-cell responses.
Cytotoxic T-lymphocytes (CTLs) play a key role in immunity against cancer; however, the induction of CTL responses with currently available vaccines remains difficult. Because several reports have suggested that pigmentation and immunity might be functionally linked, we investigated whether melanin can act as an adjuvant in vaccines. Short synthetic peptides (8-35 amino acids long) containing T-cell epitopes were mixed with a solution of L-Dopa, a precursor of melanin. The mixture was then oxidized to generate nanoparticles of melanin-bound peptides. Immunization with melanin-bound peptides efficiently triggered CTL responses in mice, even against self-antigens and at a very low dose of peptides (microgram range). Immunization against a tumor antigen inhibited the growth of established tumors in mice, an effect that was abrogated by the depletion of CD8+ lymphocytes. These results demonstrate the efficacy of melanin as a vaccine adjuvant.


An examination of the measurement properties of the pediatric volitional questionnaire.
The Pediatric Volitional Questionnaire (PVQ) is a 15- item play-based assessment of a child's motivational strengths and weaknesses in various settings based on the Model of Human Occupation. A previous study examined the PVQ's ability to provide a valid measure of volition in ten non-disabled children. This study combined data from the previous study with data on eight children with disabilities to further test the instrument's psychometric properties. Data on 36 observations of the 18 participants were observed by a total of 20 raters. Each rater was randomly assigned to rate videotapes. Data were analyzed using the Rasch Measurement Model. Results indicate that the 15 items of the scale work well together to measure volition and were well matched to the volitional levels of the sample group. Nineteen of the twenty raters used the scale in a valid manner, though scores were affected by the extent of severity/leniency of the rater. All eighteen participants were validly rated and the scale items effectively differentiated levels of volition among the eighteen children. These findings supported the conclusion that the PVQ provides a valid and sensitive measure of volition. The study also found that the 4-point rating scale operated as a 3-point scale in this study and that raters differentiated in their severity/ leniency. These latter findings indicate the need to further clarify the rating scale.


Inhibition of in vivo leishmanicidal mechanisms by tempol: nitric oxide down-regulation and oxidant scavenging.
Tempol (4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy) has long been known to protect experimental animals from the injury associated with oxidative and inflammatory conditions. In the latter case, a parallel decrease in tissue protein nitration levels has been observed. Protein nitration represents a shift in nitric oxide actions from physiological to pathophysiological and potentially damaging pathways involving its derived oxidants such as nitrogen dioxide and peroxynitrite. In infectious diseases, protein tyrosine nitration of tissues and cells has been taken as evidence for the involvement of nitric oxide-derived oxidants in microbicidal mechanisms. To examine whether tempol inhibits the microbicidal action of macrophages, we investigated its effects on Leishmania amazonensis infection in vitro (RAW 264.7 murine macrophages) and in vivo (C57Bl/6 mice). Tempol was administered in the drinking water at 2 mM throughout the experiments and shown to reach infected footpads as the nitroxide plus the hydroxylamine derivative by EPR analysis. At the time of maximum infection (6 weeks), tempol increased footpad lesion size (120%) and parasite burden (150%). In lesion extracts, tempol decreased overall nitric oxide products and expression of inducible nitric oxide synthase to about 80% of the levels in control animals. Nitric oxide-derived products produced by radical mechanisms, such as 3-nitrotyrosine and nitrosothiol, decreased to about 40% of the levels in control mice. The results indicate that tempol worsened L. amazonensis infection by a dual mechanism involving down-regulation of iNOS expression and scavenging of nitric oxide-derived oxidants. Thus, the development of therapeutic strategies based on nitroxides should take into account the potential risk of altering host resistance to parasite infection.