Active centrum hypothesis: the origin of chiral homogeneity and the RNA-world.
I propose a hypothesis on the origin of chiral homogeneity of bio-molecules based on chiral catalysis. The first chiral active centre may have formed on the surface of complexes comprising metal ions, amino acids, other coenzymes and oligomers (short RNAs). The complexes must have been dominated by short RNAs capable of self-reproduction with ligation. Most of the first complexes may have catalysed the production of nucleotides. A basic assumption is that such complexes can be assembled from their components almost freely, in a huge variety of combinations. This assumption implies that "a few" components can constitute "a huge" number of active centre types. Moreover, an experiment is proposed to test the performance of such complexes in vitro. If the complexes were built up freely from their elements, then Darwinian evolution would operate on the assembly mechanism of complexes. For the production of complexes, first their parts had to appear by forming a proper three-dimensional structure. Three possible re-building mechanisms of the proper geometric structure of complexes are proposed. First, the integration of RNA parts of complexes was assisted presumably by a pre-intron. Second, the binding of RNA parts of a complex may give rise to a "polluted" RNA world. Third, the pairing of short RNA parts and their geometric conformation may have been supported by a pre-genetic code. Finally, an evolutionary step-by-step scenario of the origin of homochirality and a "polluted" RNA world is also introduced based on the proposed combinatorial complex chemistry. Homochirality is evolved by Darwinian selection whenever the efficiency of the reflexive autocatalysis of a dynamical combinatorial library increases with the homochirality of the active centres of reactions cascades and the homochirality of the elements of the dynamical combinatorial library. Moreover, the potential importance of phospholipid membrane is also discussed.


Nodal sampling in pancreaticoduodenectomy: does it change our management?
Lymph node involvement in periampullary malignancy is the single most important factor in predicting survival in pancreaticoduodenectomy (PD). The role of nodal sampling in PD has not been well evaluated. This study evaluates the utility of nodal sampling of nodal stations 8 and 12, which are easily dissected early in PD, in overall final nodal status. Fifty patients underwent PD at a single institution by a one surgeon over a 15 month period. Nodal stations 8 and 12 were sent separately for pathologic evaluation. Twenty-eight patients had a final diagnosis of periampullary malignancy. Demographic and pathologic data were collected retrospectively from patient charts. Positive and negative predictive values of nodes 8 and 12 were evaluated. Eighteen of 28 patients with a diagnosis of periampullary malignancy had pathologically negative nodes 8 and 12, and a final nodal status (all peripancreatic lymph nodes) negative for nodal involvement. Nine of 28 patients had a negative nodal sampling result, but a positive final nodal status for metastatic tumor. The remaining four patients had both positive nodal sampling and final nodal status for metastatic tumor. The negative predictive value of negative nodes 8 and 12 was 0.625. The negative predictive of a negative node 8 and 12 of 0.625 suggests that the decision to proceed with or abort PD should not be based on intraoperative evaluation of these nodes. Performance of PD should be undertaken if technically feasible, and not based on intraoperative nodal assessment.


First UK patient cohort treated with stereotactic ablative radiotherapy for primary kidney cancer.
Stereotactic ablative radiotherapy (SABR) for primary renal cell carcinoma (RCC) is a promising non-invasive ablative treatment option. A prospective interventional clinical trial published showed that treatment was feasible and well tolerated. We present the first single-institution UK cohort of patients with primary RCC receiving protocol-based SABR with prospective follow-up. We also present a protocol that could be used to facilitate more widespread use of the treatment. Nineteen biopsy-proven primary RCC patients were treated with either 42 Gy in three fractions on alternate days or 26 Gy in a single fraction based on predefined eligibility criteria using either Linear Accelerator or CyberKnife platform. Prospective toxicity data using CTCAE V4.0 and outcome data such as estimated glomerular filtration rate (eGFR) and tumour response using CT thorax, abdomen and pelvis (CT-TAP) were collected at 6 weeks, 3, 6, 12, 18 and 24 months post treatment. The 19 patients had a median age of 76 years (interquartile range [IQR] 64-82 years) and 47.4% were males, and they had a median tumour size of 4.5 cm (IQR 3.8-5.2 cm). Single and fractionated treatment was well tolerated and there were no significant acute side effects. The mean drop from baseline in eGFR at 6 months was 5.4 ml/min and that at 12 months was 8.7 ml/min. The overall local control rate at both 6 and 12 months was 94.4%. Overall survival at 6 and 12 months was 94.7% and 78.3%, respectively. After a median follow-up of 17 months, three patients experienced a Grade 3 toxicity, which was resolved with conservative management. SABR for primary RCC is a safe and feasible treatment for medically unfit patients, which can be delivered in most UK cancer centres using standard Linear Accelerator as well as CyberKnife platforms.


Higher Education and Health Investments: Does More Schooling Affect Preventive Health Care Use?
While it is well-known that individuals with higher levels of education consume more preventive medical care, there are several potential explanations for this stylized fact. These explanations include causal and non-causal mechanisms, and distinguishing among explanations is relevant for accessing the importance of educational spillovers on lifetime health outcomes as well as uncovering the determinants of preventive care. In this paper, we use regression analysis, sibling fixed effects, and matching estimators to examine the impact of education on preventive care. In particular, we use a cohort of 10,000 Wisconsin high school graduates that has been followed for nearly 50 years and find evidence that attending college is associated with an increase in the likelihood of using several types of preventive care by approximately five to fifteen percent for college attendees in the early 1960s. We also find that greater education may influence preventive care partly through occupational channels and access to care. These findings suggest that increases in education have the potential to spillover on long-term health choices.


Aorta and muscle metabolism in pigs with peripheral hyperinsulinaemia.
Peripheral hyperinsulinaemia usually found in conventionally treated Type 1 (insulin-dependent) diabetic patients may have deleterious metabolic effects. We have used a hyperinsulinaemic model to examine intermediary metabolism in two key peripheral tissues, aorta and muscle. Nine pigs were immunized with crystalline insulin. Subsequently, they showed an insulin-binding capacity of 86.2 +/- 25.0 pmol/l and fasting total serum insulin of 3.9 +/- 3.1 nmol/l (control range 0.034-0.072 nmol/l), impaired glucose tolerance after oral glucose tolerance testing, significantly elevated levels of peripheral venous serum free insulin and C-peptide, and increased mean post-prandial free insulin/glucose ratios. The immunized pigs showed marked elevation of aorta and muscle triglycerides compared with control pigs (n = 15) but similar levels of non-esterified fatty acids. The glucose-6-phosphate-dehydrogenase, malic enzyme and 3-hydroxyacyl-CoA-dehydrogenase activities were all increased significantly (by 50%-300%) in both aorta and muscle. Phosphofructokinase was decreased in both tissues. Hexokinase was increased in muscle alone whereas pyruvate kinase was significantly decreased in aorta. Glyceraldehyde-3-phosphate dehydrogenase activity was not significantly different in aorta and muscle. Thus in insulin immunized pigs with normal beta-cell function and pronounced peripheral hyperinsulinaemia there was increased peripheral lipogenic activity. These findings have potentially important implications with regard to macrovascular disease in diabetes.


Analysis of small RNA profiles during development.
Small RNAs ranging in size between 20 and 32 nt regulate gene expression through chromatin modification, mRNA degradation, and translational repression. Three major classes of small RNAs have been characterized: microRNAs (miRNAs), short interfering RNAs (siRNAs), and Piwi-interacting RNAs (piRNAs). miRNAs are expressed in a developmentally regulated and tissue-specific manner and are involved in development and cell differentiation. siRNAs are mainly involved in defense against transposons and viruses. piRNAs are expressed in germ cells and stem cells and are thought to repress transposition of retrotransposons. In this chapter, we describe the methods of small RNA cloning, annotation and classification, and their expression analysis during development.


Intralesional Vitamin D3 Versus Bleomycin for Difficult-to-Heal Palmoplantar Warts: A Comparative Study.
Difficult-to-heal or recalcitrant palmoplantar warts are notoriously resistant to treatment, making treatment difficult and challenging. To improve the outcome and overcome the difficulties, various treatment options have been tried, but none is gold standard. Many comparative studies have been undertaken to assess the efficacy of various drugs; however, none of them are standardized, and no single treatment is effective. Various comparative efficacy studies have been conducted but, to the best of our knowledge, no study has been conducted comparing intralesional (IL) injection (inj) vitamin D3 (Vit D3) with the chemotherapy drug IL inj Bleomycin for difficult-to-heal palmoplantar warts. We conducted a trial to evaluate the efficacy of IL inj Vit D3 versus IL inj Bleomycin in the treatment of difficult-to-heal palmoplantar warts. The purpose of this study was to compare the efficacy of IL inj vitamin D3 versus IL inj Bleomycin as biological response modifier therapy in difficult-to-heal palmoplantar warts. A cohort of 48 patients with difficult-to-heal warts were consecutively assigned to one of two groups: Group 1 IL inj Vit D3 (0.2-0.5 mL inj vitamin D3 600,000 IU solution 15 mg/mL) or Group 2 IL inj Bleomycin (0.2-0.4 mL of 1 U/mL solution) for a maximum of four treatments spaced 2 weeks apart, with a maximum of five warts treated at each visit for both groups. Warts were measured at baseline and at each subsequent visit. Wart's resolution was measured as 1-25%, 2-50%, 3-75%, and 4-100% reduction. Patients were followed-up for 3 months after treatment. All the 48 patients completed the study, with 26 receiving IL inj Vit D3 with complete resolution in 88.5%, partial resolution in 11.5%, and side effects in 6.2%. In 22 patients receiving IL inj Bleomycin, 95.5% had complete resolution, 4.5% had partial resolution, and 8.2% had side effects. Maximum resolution was observed in the third session. We found no recurrence after 3 months. IL inj Vit D3 and IL inj Bleomycin are both safe and effective in treating difficult-to-heal palmoplantar warts with better outcomes and patient satisfaction. IL Bleomycin was significantly more effective than IL Vit D3, although the difference was not statistically significant.


A Panel of Genetic Polymorphism for the Prediction of Prognosis in Patients with Early Stage Non-Small Cell Lung Cancer after Surgical Resection.
This study was conducted to investigate whether a panel of eight genetic polymorphisms can predict the prognosis of patients with early stage non-small cell lung cancer (NSCLC) after surgical resection. We selected eight single nucleotide polymorphisms (SNPs) which have been associated with the prognosis of lung cancer patients after surgery in our previous studies. A total of 814 patients with early stage NSCLC who underwent curative surgical resection were enrolled. The association of the eight SNPs with overall survival (OS) and disease-free survival (DFS) was analyzed. The eight SNPs (CD3EAP rs967591, TNFRSF10B rs1047266, AKT1 rs3803300, C3 rs2287845, HOMER2 rs1256428, GNB2L1 rs3756585, ADAMTSL3 rs11259927, and CD3D rs3181259) were significantly associated with OS and/or DFS. Combining those eight SNPs, we designed a prognostic index to predict the prognosis of patients. According to relative risk of death, a score value was assigned to each genotype of the SNPs. A worse prognosis corresponded to a higher score value, and the sum of score values of eight SNPs defined the prognostic index of a patient. When we categorized the patients into two groups based on the prognostic index, high risk group was significantly associated with worse OS and DFS compared to low risk group (aHR for OS = 2.21, 95% CI = 1.69-2.88, P = 8.0 x 10-9, and aHR for DFS = 1.58, 95% CI = 1.29-1.94, P = 1.0 x 10-5). Prognostic index using eight genetic polymorphisms may be useful for the prognostication of patients with surgically resected NSCLC.


Dupuytren's disease in diabetes mellitus.
Dupuytren's disease (DD) was demonstrated in 169 of 959 diabetics (17.6%) and in 9 of 1,396 non-diabetic patients (0.64%). One hundred and seventy-nine of the 185 patients with DD had overt or latent diabetes mellitus (96.7%). The relative frequency of DD increased with age, the conditions was seldom found under the age of 40. DD should be regarded as a non-hyperglycemic manifestation of diabetes mellitus and its presence in a patient should prompt the investigation of glucose metabolism.


Recombinant cholera toxin B subunit and gene fusion proteins for oral vaccination.
The B subunit portion of cholera toxin (CTB) is a safe and effective oral immunizing agent in humans, affording protection against both cholera and diarrhoea caused by enterotoxigenic Escherichia coli producing heat-labile toxin (LT) (Clemens et al., 1986; 1988). CTB may also be used as a carrier of various "foreign" antigens suitable for oral administration. To facilitate large-scale production of CTB for vaccine development purposes, we have constructed recombinant overexpression systems for CTB proteins in which the CTB gene is under the control of strong foreign (non-cholera) promoters and in which it is also possible to fuse oligonucleotides to the CTB gene and thereby achieve overexpression of hybrid proteins (Sanchez and Holmgren, 1989; Sanchez et al., 1988). We here expand these findings by describing overexpression of CTB by a constitutive tacP promoter as well as by the T7 RNA-polymerase promoter, and also by describing gene fusions leading to overexpression of several hybrid proteins between heat-stable E. coli enterotoxin (STa)-related peptides to either the amino or carboxy ends of CTB. Each of the hybrid proteins, when tested as immunogens in rabbits, stimulated significant anti-STa as well as anti-CTB antibody formation, although the anti-STa antibody levels attained (c.a. 1-15 micrograms/ml specific anti-STa immunoglobulin) were too low to give more than partial neutralization of STa intestinal challenge in baby mice. The hybrid proteins also had a near-native conformation, as apparent from their oligomeric nature and their strong reactivity with both a neutralizing antibody against the B subunit and a neutralizing monoclonal antibody (mAb) against STa.(ABSTRACT TRUNCATED AT 250 WORDS)


Colony, hanging drop, and methylcellulose three dimensional hypoxic growth optimization of renal cell carcinoma cell lines.
Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, comprising 3% of all human neoplasms, and the incidence of kidney cancer is rising annually. We need new approaches to target tumor cells that are resistant to current therapies and that give rise to recurrence and treatment failure. In this study, we focused on low oxygen tension and three-dimensional (3D) cell culture incorporation to develop a new RCC growth model. We used the hanging drop and colony formation methods, which are common in 3D culture, as well as a unique methylcellulose (MC) method. For the experiments, we used human primary RCC cell lines, metastatic RCC cell lines, human kidney cancer stem cells, and human healthy epithelial cells. In the hanging drop assay, we verified the potential of various cell lines to create solid aggregates in hypoxic and normoxic conditions. With the semi-soft agar method, we also determined the ability of various cell lines to create colonies under different oxygen conditions. Different cell behavior observed in the MC method versus the hanging drop and colony formation assays suggests that these three assays may be useful to test various cell properties. However, MC seems to be a particularly valuable alternative for 3D cell culture, as its higher efficiency of aggregate formation and serum independency are of interest in different areas of cancer biology.


Responsiveness and minimal clinically important differences after cholecystectomy: GIQLI versus SF-36.
To compare responsiveness and minimal clinically important differences (MCID) between the Gastrointestinal Quality of Life (GIQLI) and the Short Form 36 (SF-36), we prospectively analyze 159 patients undergoing cholecystectomy at two tertiary academic hospitals. All patients completed the disease-specific GIQLI and the generic SF-36 before and 3 months after surgery. Scores using these instruments were interpreted by generalized estimating equation before and after cholecystectomy. The bootstrap estimation was used to derive 95% confidence intervals for differences in the responsiveness estimates. Mean changes in all GIQLI and the SF-36 subscales were statistically significant (p < 0.05). Comparisons of effect size (ES), standardized response means (SRM), and relative efficiency (>1) indicated that the responsiveness of the GIQLI was superior to that of the SF-36. In the equivalence test, all lower or upper confidence limits presented no equivalence (>5), indicating good MCID. The ES and SRM for emotions and physical function in the GIQLI significantly differed from those of the SF-36 (p < 0.05). The data in this study indicate that clinicians and health researchers should weight disease-specific measures more heavily than generic measures when evaluating treatment outcomes.


Quantitative analysis of C-bands based on optical density profiles in human chromosomes.
A method of quantitative analysis of C segments in human chromosomes 1, 9, and 16 based on longitudinal densitometry has been developed. The way of fitting apparatus data to visual estimates is represented. Density curve parameters not dependent on stain intensity were used. The general C band length error is approx. 0.05 micrometer. Heteromorphic chromosome 16 pairs have been investigated with this method. A significant difference (about 0.18 micrometer) between C bands of the homologues has been detected in chromosome 16. It has been calculated that C bands can be distinquished if the mean difference between the length of the homologues is more than 15%.


Performance Evaluation of the Glunovo® Continuous Blood Glucose Monitoring System in Chinese Participants with Diabetes: A Multicenter, Self-Controlled Trial.
The present study was aimed to evaluate the performance and safety of the Glunovo® real-time continuous glucose monitoring system (CGMS) in monitoring interstitial fluid glucose in adult participants with diabetes (at least 18 years old) using venous blood glucose as control. This was a multicenter, self-controlled clinical trial, conducted in participants with diabetes from China, between March 2019 to October 2019. The CGMS was used by all the participants for a 14-day wear-in period. The real-time glucose values measured by Glunovo® CGMS were compared with venous blood glucose values measured by the Entwicklung, Konstruktion und Fertigung (EKF) blood glucose detector. The primary outcomes were the consistency rate of CGMS readings and venous blood glucose values (20/20% standard). A total of 78 participants (41 men, 37 women) and 156 CGMS sensors were included in the study. Among the included participants, 25 and 53 participants had type 1 and type 2 diabetes, respectively, with median age of 52.50 years (range 32-62 years). The overall agreement rate (20/20%) was 89.71% (95% CI 89.18-90.24%). It was observed that 99.08% (95% CI 98.91-99.24%) and 99.82% (95% CI 99.74-99.89%) of the measuring points fell within the A + B zones of the Clarke error grid analysis and Parkes/consensus error grid analysis, respectively. The mean absolute relative difference was 10.30% ± 4.86%. The probability of a glucose measurement falling within a range, when stratified by venous glucose measurements, ranged from 7.14% for 19.44-22.22 mmol/L to 79.21% for 4.44-6.67 mmol/L. There were 73 (41.24%) and 27 (57.45%) successful CGMS alarms for hypoglycemic and hyperglycemic events, respectively. From the results, Glunovo® CGMS had excellent accuracy and limited clinical risk compared with venous blood glucose in the range of 2.2-22.2 mmol/L over 14 days.


A case of acute interstitial pneumonia indistinguishable from bronchiolitis obliterans organizing pneumonia/cryptogenic organizing pneumonia: high-resolution CT findings and pathologic correlation.
We report a case of histologically proved acute interstitial pneumonia (AIP) with subacute onset whose high-resolution CT (HRCT) findings were indistinguishable from those of bronchiolitis obliterans organizing pneumonia (BOOP)/cryptogenic organizing pneumonia (COP). The HRCT findings were air-space consolidation with air-bronchiologram associated with little ground-glass attenuation, and nodules. Some cases of AIP present HRCT findings indistinguishable from those of BOOP/COP.


Cannabis Use, Polysubstance Use, and Psychosis Spectrum Symptoms in a Community-Based Sample of U.S. Youth.
To examine how cannabis use and polysubstance use among cannabis users relate to psychosis spectrum (PS) symptoms in a large community-based sample of U.S. youth. Four thousand one hundred seventy-one youths (aged 14-21 years; mean = 16.90 years, SD = 1.85; 55% female) from the Philadelphia Neurodevelopmental Cohort completed assessments of substance use, PS symptoms, and confounding variables (e.g., demographics, comorbid psychopathology, and trauma exposure). After adjusting for confounds, cannabis use by itself was not associated with increased odds of being classified as "psychosis spectrum." However, cannabis use in combination with tobacco or other substance use was associated with increased odds of PS classification (adjusted odds ratios [ORs] = 1.37-1.76). Follow-up symptom-level analyses revealed that cannabis use in combination with other substances was associated with subclinical positive symptoms (ORs = 1.95 and 2.24) and frequent cannabis use was associated with subclinical negative/disorganized symptoms (OR = 2.14). However, these symptom-level findings were reduced to trends after correction for multiple comparisons. Neither cannabis use nor polysubstance use was associated with threshold delusions or hallucinations. After adjusting for important confounds, there was minimal evidence for associations between cannabis use by itself and PS symptoms. More compelling evidence emerged for associations between polysubstance use among cannabis users and PS symptoms. This study highlights the importance of considering polysubstance use and confounds when examining associations between cannabis use and PS symptoms. Further longitudinal research is necessary to determine whether these findings represent causal associations or shared genetic and/or environmental vulnerability for substance use and PS symptoms.


Human spumavirus antibodies in sera from African patients.
Serum samples collected from patients with a wide variety of diseases from African and other countries were tested for antibodies to the human spumaretrovirus (HSRV). A spumaviral env-specific ELISA was employed as screening test. Out of 3020 human sera screened, 106 were found to be positive (3.2%). While the majority of patients' sera from Europe (1581) were negative, 26 were positive (1.6%). Sera from healthy adult blood donors (609), from patients with multiple sclerosis (48), Graves' disease (45), and chronic fatigue syndrome (41) were negative or showed a very low prevalence for spumaviral env antibodies. A higher percentage of seropositives (6.3%) were found among 1338 African patients from Tanzania, Kenya, and Gabon. Out of 1180 patients from Tanzania, 708 suffered from tumors, 75 from AIDS, and 128 had gynecological problems; 51 of the Tanzanian patients were HSRV seropositive (4.3%). A particularly high percentage of 16.6% seropositives were identified among nasopharyngeal carcinoma patients (NPC) from Kenya and Tanzania consistent with results reported 10 years ago. However, 20 nasopharyngeal carcinoma patients from Malaysia were HSRV-seronegative. In selected cases, sera from seropositive individuals were reacted with proteins from HSRV-infected cells in vitro. HSRV env- and gag-specific antibodies were specifically detected by these sera in Western blots. The results indicate spumavirus infections in human patients with various diseases at a relatively low prevalence worldwide; in African patients, however, the prevalence of spumavirus infections is markedly higher.


P-glycoprotein (MDR1/ABCB1) Restricts Brain Penetration of the Main Active Heroin Metabolites 6-monoacetylmorphine (6-MAM) and Morphine in Mice.
Heroin (diacetylmorphine; diamorphine) is a highly addictive opioid prodrug. Heroin prescription is possible in some countries for chronic, treatment-refractory opioid-dependent patients and as a potent analgesic for specific indications. We aimed to study the pharmacokinetic interactions of heroin and its main pharmacodynamically active metabolites, 6-monoacetylmorphine (6-MAM) and morphine, with the multidrug efflux transporters P-glycoprotein/ABCB1 and BCRP/ABCG2 using wild-type, Abcb1a/1b and Abcb1a/1b;Abcg2 knockout mice. Upon subcutaneous (s.c.) heroin administration, its blood levels decreased quickly, making it challenging to detect heroin even shortly after dosing. 6-MAM was the predominant active metabolite present in blood and most tissues. At 10 and 30 min after heroin administration, 6-MAM and morphine brain accumulation were increased about 2-fold when mouse (m)Abcb1a/1b and mAbcg2 were ablated. Fifteen minutes after direct s.c. administration of an equimolar dose of 6-MAM, we observed good intrinsic brain penetration of 6-MAM in wild-type mice. Still, mAbcb1 limited brain accumulation of 6-MAM and morphine without affecting their blood exposure, and possibly mediated their direct intestinal excretion. A minor contribution of mAbcg2 to these effects could not be excluded. We show that mAbcb1a/1b can limit 6-MAM and morphine brain exposure. Pharmacodynamic behavioral/postural observations, while non-quantitative, supported moderately increased brain levels of 6-MAM and morphine in the knockout mouse strains. Variation in ABCB1 activity due to genetic polymorphisms or environmental factors (e.g., drug interactions) might affect 6-MAM/morphine exposure in individuals, but only to a limited extent.


A pilot study of N-acetylcysteine as adjunctive therapy for severe malaria.
The case fatality rate of severe malaria remains unacceptably high. N-acetylcysteine (NAC) is a safe compound that inhibits tumour necrosis factor (TNF) and impedes cytoadherence, both of which have been implicated in the pathogenesis of malaria complications. To evaluate NAC as adjunctive therapy in severe malaria. A placebo-controlled, double-blind prospective study, with serum lactate level as the principal objective measure of response. Thirty adult males with severe, quinine-treated malaria received either 300 mg/kg of NAC or placebo, over 20 h. Serum lactate levels normalized twice as quickly after NAC (median 21 h, 95%CI 12-36 h) as after placebo (median 42 h, 95%CI 30-84 h; p=0.002, Mann-Whitney U test). Twenty-four hours after admission, 10/15 (67%) NAC-group patients but only 3/15 (20%) placebo-group patients had normal lactate concentrations (p=0.01, Fisher exact test). NAC-treated patients could be switched from intravenous to oral therapy earlier than individuals who received placebo (42 h vs. 51 h after admission) but the difference was not significant (p=0.28, Mann-Whitney U test). NAC's mechanism of action in malaria is unclear, since it did not markedly alter plasma cytokine profiles. Trials of NAC adjunctive therapy for complicated malaria, with mortality as an endpoint, appear to be warranted.


Endocytosis, signal transduction and proteolytic cleaving of human holotransferrin in Entamoeba histolytica.
Amoebiasis is a parasitic infection of the human large intestine caused by Entamoeba histolytica; this disease mainly affects people from developing countries. To survive, this primitive protozoan has a high demand for iron, and it uses host iron proteins upon invasion. Transferrin (Tf) is a plasma iron-binding protein that transports and delivers iron to all cells. Iron-loaded Tf (holoTf) in humans can support the proliferation of amoebae in vitro by binding to an amoebic TfR (EhTfR), and amoebae endocytose it inside clathrin-coated vesicles. In this study, it was found that EhTfR phosphorylation is required for human holoTf endocytosis by E. histolytica. Once this complex is endocytosed, human holoTf could be degraded with a nutritional purpose by cysteine proteases. HoloTf endocytosis initiates the activation of the mitogen-activated protein kinases (MAPKs) and focal adhesion kinase (FAK) pathways, which induce cell proliferation with phosphoinositide 3-kinase (PI-3 K) and Ca2+ involvement. In the first minutes after holoTf is endocytosed, several proteins are phosphorylated including transketolase, enolase, L-myo-inositol-1-phosphate synthase and phosphoglucomutase, which control carbohydrate metabolism, and heat shock protein-70. The study of these proteins and their signal transduction pathways could be useful for developing future therapies.


Effect of oestradiol replacement on swim-induced antinociception in ovariectomized mice.
1. A 30 s swim in water at 30 degrees C reduced the number of abdominal constrictions produced in female mice by intraperitoneally administered acetic acid and this antinociceptive effect was antagonized by naloxone. 2. Oophorectomy abolished the development of antinociceptive activity in response to swim. 3. The development of antinociceptive activity and naloxone antagonism were restored in oophorectomized mice maintained on daily oestradiol injection. 4. The present study indicates that the increase in abdominal constriction response to acetic acid in oophorectomized mice was due to the removal of the source of female sex hormone.


Post traumatic arterial occlusive mesenteric ischemia: a rare case report.
Mesenteric ischemia is an uncommon condition with very high mortality rates characterized by inadequate blood supply, inflammatory injury, and subsequent necrosis of the bowel wall. Acute arterial mesenteric ischemia is usually caused by cardiac emboli, atherosclerotic vascular disease, aortic aneurysm, or dissection. We report a case of a 60-year-old male who presented to the accident and emergency department complaining of abdominal pain following blunt abdominal trauma. An urgent contrast enhanced computed tomography scan demonstrated superior mesenteric artery thrombosis with ischemic small bowel. Surgical intervention was carried out with resection of the necrotic bowel followed by anastomosis. Acute occlusive mesenteric ischemia needs to be considered in cases of blunt trauma presenting with abdominal pain. Proper early diagnosis and management is essential as it carries a high risk of morbidity and mortality.


Correction to "Effect of probiotic Lactobacillus plantarum Dad-13 powder consumption on the gut microbiota and intestinal health of overweight adults". World J Gastroenterol 2021; 27(1): 107-128 [PMID: 33505154 DOI: 10.3748/wjg.v27.i1.107].
[This corrects the article on p. 107 in vol. 27, PMID: 33505154.].


Grassroots stakeholders' perception of participation in the Medium-Term Development Plan of District Assemblies in Ghana: The case of Sawla-Tuna-Kalba District.
Following Ghana's decentralisation policy, the District Assemblies, in consultation with communities, are required to prepare and implement Medium-Term Development Plans [MTDPs] to ensure the overall development of their respective jurisdictions. However, little consideration has been given to the participation of grassroots stakeholders in the development of MTDPs. Consequently, this study investigates the participation of grassroots stakeholders in developing MTDPs. A cross-sectional survey involving 139 respondents was deployed. The data were gathered using a questionnaire and an interview guide, and it was analyzed using descriptive statistics, Spearman's Rank Correlation, and thematic analysis. Results indicated that grassroots stakeholders were aware of their right to participate in the preparation of MTDPs. As such, they actively participated in the process that led to developing such plans addressing community needs. Additionally, awareness of MTDP, involvement, level of influence, satisfaction with the preparation of MTDPs, satisfaction with the quality of participation in the area council, level of confidence in the preparation of MTDP, representation adequacy, and capture of community needs had statistically significant associations at the 1% level with the associations being positive. Nonetheless, the implementation of MTDPs is jeopardised by limited funding, stakeholder commitment, and human capacity. To ensure the smooth implementation of the MTDPs, the Assembly must intensify its revenue mobilisation efforts, depoliticise the MTDP process, and build staff capacity on the involvement of the grassroots stakeholders.


SH2 domain-containing inositol 5-phosphatase (SHIP2) inhibition ameliorates high glucose-induced de-novo lipogenesis and VLDL production through regulating AMPK/mTOR/SREBP1 pathway and ROS production in HepG2 cells.
Hepatic de-novo lipogenesis and production of triglyceride rich very low density lipoprotein (VLDL) is increased in the state of insulin resistance, however, the role of a negative regulator of the insulin signaling pathway, the SH2 domain-containing inositol 5-phosphatase (SHIP2) in this process, remains unknown. In the present study, we studied the molecular mechanisms linking SHIP2 expression to metabolic dyslipidemia using overexpression or suppression of SHIP2 gene in HepG2 cells exposed to high glucose (33 mM). The results showed that high glucose induced SHIP2 mRNA and protein levels in HepG2 cells. Overexpression of the dominant negative mutant SHIP2 (SHIP2-DN) ameliorated high glucose-induced de-novo lipogenesis and secretion of apoB containing lipoprotein in HepG2 cells, as demonstrated by a reduction in both secreted apoB and MTP expression, and decreased triglyceride levels and the expression of lipogenic genes such as SREBP1c, FAS and ACC. Overexpression of the SHIP2-DN decreased high glucose-induced apoB containing lipoproteins secretion via reduction in ROS generation, JNK phosphorylation and Akt activation. Furthermore, using the specific inhibitor and activator, it was found that the AMPK/mTOR/SREBP1 is the signaling pathway that mediates the effects of SHIP2 modulation on hepatic de-novo lipogenesis. Taken together, these findings suggest that SHIP2 is an important regulator of hepatic lipogenesis and lipoprotein secretion in insulin resistance state.


Assessing reference conditions and physico-chemical status according to the European Water Framework Directive: a case-study from the Basque Country (Northern Spain).
The European Water Framework Directive requires the development of new and accurate methodologies, addressing the assessment of the physico-chemical status of transitional and coastal waters; these are considered by the Directive as the supporting elements for the final evaluation of the Ecological Quality Status. This contribution develops new approaches in the determination of the physico-chemical status, solving some problems detected in previous contributions, i.e.: (a) fitting the classification of water bodies and typologies, by means of the stretching of the typologies, according to the natural salinity gradient of types; (b) defining reference conditions, based upon the new approach to typologies, (c) proposing accurate multivariate methodologies, in determining the physico-chemical status of the transitional and coastal waters, based upon the defined typologies and references; and (d) discussion of the results obtained by reference to methodological aspects and water quality evolution in the Basque Country, Spain (as a case-study), during the last decade.


Vergence variability: a key to understanding oculomotor adaptability?
Vergence eye movements were recorded from three different populations: healthy young (ages 18-35 years), adaptive presbyopic and non-adaptive presbyopic(the presbyopic groups aged above 45 years) to determine how the variability of the eye movements made by the populations differs. The variability was determined using Shannon Entropy calculations of Wavelet transform coefficients, to yield a non-linear analysis of the vergence movement variability. The data were then fed through a k-means clustering algorithm to classify each subject, with no a priori knowledge of true subject classification. The results indicate a highly significant difference in the total entropy values between the three groups, indicating a difference in the level of information content, and thus hypothetically the oculomotor adaptability, between the three groups.Further, the frequency distribution of the entropy varied across groups.


Will clinical signs become myth? Developing structured Signs Circuits to improve medical students' exposure to and confidence examining clinical signs.
Correctly eliciting and interpreting physical examination (PEx) signs contributes to successful diagnosis and is fundamental to patient care. A significant decline in the time spent acquiring these skills by medical students, and the decreased ability to elicit and recognise signs is widely acknowledged. However, organising teaching to counteract this in the busy clinical environment is challenging. We evaluated the prior exposure to clinical signs, and experience of examination teaching among a cohort of final-year medical students. Following this, we assessed the utility of a structured circuit-based approach (Signs Circuits) using hospital inpatients and junior doctors to provide high-yield PEx teaching and overcome these limitations. Qualitative and quantitative survey feedback, including a standardised list of 62 clinical signs, was sought from final-year medical students during their rotations at a teaching hospital in London, UK, before and after the provision of Signs Circuits. Prior to the course the 63 students reported limited exposure to even the most common clinical signs. For example, the murmurs of mitral and tricuspid regurgitation and the sound of lung crackles eluded 43%, 87%, and 32%, respectively. From qualitative feedback, the reasons for this included that much of their prior PEx experience had focused on the performance of appropriate examination steps and techniques in patients without pathology. During the course, students were exposed to an average of 4.4 new signs, and left with increased confidence examining and eliciting signs, and a firmer belief in their importance to diagnosis. Medical students continue to have limited exposure to clinical signs in medical school. This signs-focused approach to PEx teaching is an effective and reproducible way to counter the deficiencies identified in signsexposure.


A CD 4: immunoglobulin fusion protein with antiviral effects against HIV.
Antibody-like molecules consisting of the human CD 4 extracellular domain fused to human IgG1 heavy chain constant regions were genetically constructed and expressed in a BHK cell stable transfectant. Purified chimeric antibodies bound to HIV particles as it was shown by immuno electron microscopy, inhibited fusions of HIV-1-infected cells with uninfected cells, neutralized HIV-1, and were able to inhibit the spread of a cellular HIV-1 infection in CD 4+ cells. Plaque reduction assays with CD 4(+)-transfected Hela-cells showed a comparable inhibition of HIV-1 and HIV-2. Inhibitory functions were enhanced in the presence of complement. HIV-1- and HIV-2-infected CD 4+ cells were efficiently lysed by a slow, complement-dependent mechanism, whereas uninfected CD 4+ cells and HLA-DR+ cells were not affected.


Effectiveness of cognitive orientation to (daily) occupational performance (CO-OP) on children with cerebral palsy: A mixed design.
Cerebral palsy (CP) is the most common cause of physical disabilities during childhood. Therapeutic interventions mainly focus on impairment reduction to address motor-based difficulties. In contrast, Cognitive Orientation to daily Occupational Performance (CO-OP) is a cognitive approach, providing intervention at the level of activity and participation. This study aims to determine whether the CO-OP approach improves motor skills and achievement in motor-based occupational performance goals in children with CP. In this mixed design research (i.e., a multiple baseline single case experimental design and a one-group pretest-posttest design), five children with CP participated in 12 CO-OP intervention sessions. Repeated measures of motor skills for the multiple baseline single case experimental design were taken using the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP); pre- and post-measures of parent/child perception of performance and satisfaction were identified using the Canadian Occupational Performance Measure (COPM); level of achievement was identified using Goal Attainment Scaling (GAS). According to the BOTMP results, all children were able to engage in the CO-OP intervention to improve motor performance. Significant differences after treatment were found in both performance and performance satisfaction ratings using the COPM as rated by parents and children. The GAS results showed progress in achievement levels for all children; all goals were achieved or exceeded. CO-OP intervention can be helpful in improving motor skills and achieving self-identified, motor-based goals in children with CP.


Special Issue "Sleep Disorders: From Clinical Research to Daily Practice".
Healthy sleep is indissolubly linked to both physical and mental health, as pointed out by evidence showing the negative impact of poor sleep on neurological, psychiatric, cardiovascular, respiratory, metabolic, and immune systems, among others [...].


Primary amelanotic mucosal melanoma of the oronasal region: report of two new cases and literature review.
Primary amelanotic mucosal melanoma is a rare entity with challenging histopathological features. Because these tumors are thought to be biologically more aggressive, they have a poorer prognosis than that of pigmented melanomas. In this work, we present a literature review about the clinical, histopathological, and immunohistochemical features of primary amelanotic mucosal melanoma of the oronasal region and report two new cases. Amelanotic mucosal melanoma commonly affects men in the seventh decade of life and tend to have a poor prognosis, as seen by the high incidence of metastasis, recurrences, and, ultimately, death. There is a similar pattern in the clinic-pathological predilections (such as age, gender, primary site, and metastatic potential) of amelanotic mucosal melanoma when comparing with data reported for pigmented lesions. This work reinforces knowledge about amelanotic mucosal melanomas and epidemiologic predilections. The optimal management of this lesion remains controversial.


Exploring walking differences by socioeconomic status using a spatial agent-based model.
We use an exploratory agent-based model of adults' walking behavior within a city to examine the possible impact of interventions on socioeconomic differences in walking. Simulated results show that for persons of low socioeconomic status, increases in walking resulting from increases in their positive attitude towards walking may diminish over time if other features of the environment are not conducive to walking. Similarly, improving the safety level for the lower SES neighborhoods may be effective in increasing walking, however, the magnitude of its effectiveness varies by levels of land use mix, such that effects of safety are greatest when persons live in areas with a large mix of uses.


Percutaneous splanchnic nerve neurolysis analgesic efficacy and safety for cancer-related pain: a systematic review and meta-analysis.
To perform a systematic review and meta-analysis of publications to evaluate the analgesic efficacy and safety of percutaneous splanchnic nerve neurolysis (SNN) for cancer-related pain. We searched PubMed, Cochrane Library, and Ichushi-Web for English or Japanese articles published up to July 2022 and reporting patients who underwent percutaneous SNN for cancer-related pain. The outcome measures assessed in the systematic review and meta-analysis were the pain measurement scales and morphine equivalents daily dose (MEDD) before and after the intervention and the rate of complications. Pooled pain measurement scores at pre-intervention, 1-2 weeks, and at 1, 2, 3, and 6 months post-intervention were 6.65 (95% confidence interval [CI], 5.77-7.67, I2 = 97%), 2.79 (95% CI, 2.00-3.88, I2 = 88%), 2.82 (95% CI, 2.49-3.20, I2 = 55%), 2.86 (95% CI, 2.64-3.10, I2 = 0%), 2.99 (95% CI, 2.56-3.46, I2 = 82%), and 3.09 (95% CI, 1.44-6.65, I2 = 70%), respectively. Mean MEDD was described in 8 of the 11 included articles. In all 8 articles, MEDD decreased up to 3 months post-intervention. The pooled minor complication rates for diarrhea and hypotension were 28% (95% CI, 13-49%, I2 = 85%) and 31% (95% CI, 16-51%, I2 = 80%), respectively. The pooled major complication rate was 2% (95% CI, 1-2%, I2 = 0%). Analysis indicates that percutaneous SNN for cancer-related pain can be performed safely with sustained reduction of pain measurement scales while reducing the administration of opioids.


MARC1 p.A165T variant is associated with decreased markers of liver injury and enhanced antioxidant capacity in autoimmune hepatitis.
The clinical picture of autoimmune hepatitis (AIH) varies markedly between patients, potentially due to genetic modifiers. The aim of this study was to evaluate genetic variants previously associated with fatty liver as potential modulators of the AIH phenotype. The study cohort comprised 313 non-transplanted adults with AIH. In all patients, the MARC1 (rs2642438), HSD17B13 (rs72613567), PNPLA3 (rs738409), TM6SF2 (rs58542926), and MBOAT7 (rs641738) variants were genotyped using TaqMan assays. Mitochondrial damage markers in serum were analyzed in relation to the MARC1 variant. Carriers of the protective MARC1 allele had lower ALT and AST (both P < 0.05). In patients treated for AIH for ≥ 6 months, MARC1 correlated with reduced AST, ALP, GGT (all P ≤ 0.01), and lower APRI (P = 0.02). Patients carrying the protective MARC1 genotype had higher total antioxidant activity (P < 0.01) and catalase levels (P = 0.02) in serum. The PNPLA3 risk variant was associated with higher MELD (P = 0.02) in treated patients, whereas MBOAT7 increased the odds for liver cancer (OR = 3.71). None of the variants modulated the risk of death or transplantation. In conclusion, the MARC1 polymorphism has protective effects in AIH. Genotyping of MARC1, PNPLA3, and MBOAT7 polymorphisms might help to stratify patients with AIH.


Acute lead acetate induces neurotoxicity through decreased synaptic plasticity-related protein expression and disordered dendritic formation in nerve cells.
Lead (Pb) is a widespread environmental heavy metal that can damage the cerebral cortex and hippocampus, and reduce the learning and memory ability in humans and animals. In vivo and in vitro models of acute lead acetate exposure were established to further study the mechanism of neurons injury. In this study, 4-week-old female Kunming mice were randomly divided into four groups. Each group was treated with distilled water with different Pb concentrations (0, 2.4, 4.8 and 9.6 mM). Mice were killed, and brain tissues were collected to detect the changes in synaptic plasticity-related protein expression. Furthermore, Neuro-2A cells were treated with 0, 5, 25 and 50 μM lead acetate for 24 h to observe the changes in cell morphology and function. In in vivo experiment, results showed that the expression levels of cytoskeleton-associated and neural function-related proteins decreased in a dose-dependent manner in the mouse brain tissue. In in vitro experiment, compared with the control group, Pb treatment groups were observed with smaller and round cells, decreased cell density and number of synapses. In the Pb exposure group, the survival rate of nerve cells decreased evidently, and the permeability of the cell membrane was increased. Western blot results showed that the expression of cytoskeleton-associated and function-related proteins decreased gradually with increased Pb exposure dose. Confocal laser scanning microscopy results revealed the morphological and volumetric changes in Neuro-2A cells, and a dose-dependent reduction in the number of axon and dendrites. These results suggested that abnormal neural structures and inhibiting expression of synaptic plasticity-related proteins might be the possible mechanisms of Pb-induced mental retardation in human and animals, thereby laying a foundation for the molecular mechanism of Pb neurotoxicity.


Effectiveness of transoral laser microsurgery for precancerous lesions and early glottic cancer guided by analysis of voice quality.
The purpose of this study was to show our comparison of the quality of voice obtained after superficial transoral endoscopic cordectomies (types I, II, and III) according to the European Laryngological Society classification versus the more extended cordectomy (types IV and V) among patients with glottic precancerous lesions or early glottic cancer. Sixty-two patients underwent vocal assessment after cordectomy (types I-V) for dysplasia, Tis, T1a, T1b, and T2 lesions. Cordectomy (types I-III) had good vocal outcomes. Cordectomy (types IV-V) showed less favorable outcomes, p < .005 in common parameters of voice range profile and symmetry in stroboscopy after cordectomy (types IV-V), with significant voice handicap index. Recurrences were found in 4 patients with T1b and T2 cancer. Two cases were managed by a higher type of cordectomy, and the other 2 by total laryngectomy. Effect of transoral laser microsurgery on quality of voice depends on the type of cordectomy and the site of the lesion.


Morphology led high dispersion of Pt icosahedral nanocrystals on carbon nanotubes for enhanced electro-catalytic activity and stability.
Icosahedra have small contact areas during packing, leading small icosahedral Pt nanoparticles to highly disperse on carbon nanotubes (CNT). The as-synthesized highly monodispersed Pt icosahedra on CNT exhibited superior catalytic activity and structural stability to their Pt nanocube counterparts on CNT towards methanol electro-oxidation.


HPV disrupt the cytoskeleton in oral squamous cell carcinomas from non-oropharyngeal sites via the E-cadherin/Mena/SMA pathway.
In this paper, we aimed to evaluate the mechanism of actin cytoskeleton disruption, in oral squamous cell carcinoma (OSCC). A total of 43 patients with surgically resected OSCCs located in non-oropharyngeal regions were randomly selected. The expression of E-cadherin, β-catenin, smooth muscle actin (SMA), Mena, maspin, V-set and immunoglobulin domain containing 1 (VSIG1), β human chorionic gonadotropin (βhCG), and angiotensin-converting enzyme (ACE) was assessed via immunohistochemistry (IHC) and evaluated in association with the prevalence of high-risk human papillomavirus (HPV). Mena positivity (n = 30; 69.77%) was more frequent in poorly differentiated OSCC of the tongue and lips with high-risk HPV viral DNA and a lymph node ratio (LNR) ≤ 2.5. Loss of E-cadherin was more prevalent among poorly differentiated stage pT4N1 tumors with an LNR ≤ 2.5 and perineural invasion. These cases were classified as SMA-high tumors. Independent negative prognostic factors included high Mena expression, loss of E-cadherin, high SMA expression, and the presence of high-risk HPV. No VSIG1 positivity was observed. In conclusion, in non-oropharyngeal OSCC, cytoskeleton activity might be driven by the Mena/E-cadherin/SMA axis, reflecting active epithelial-mesenchymal interaction. High Mena intensity is an indicator of poorly differentiated carcinomas with high-risk HPV and unfavorable prognosis.


Atypical dermoid sinus in a chow chow dog.
A case of multiple dermoid sinuses in the dorsal cervical and craniothoracic regions in an adult chow chow dog is described. One sinus did not open on the skin surface. This is the first reported case of the condition in this breed and the first time absence of the sinus opening on the skin is described. The use of the term pilonidal sinus to describe this condition is challenged.


Can we assess students' awareness of cultural diversity? A qualitative study of stakeholders' views.
Personal attitudes of doctors towards cultural diversity may influence the delivery of clinical care. Yet whether medical schools should assess a student's cultural awareness and if so, how, has not been specifically debated. To establish the views of key stakeholders in medical education on the assessment of awareness of cultural diversity within the undergraduate curriculum. Semi-structured interviews were undertaken, using sampling and snowballing, with 61 stakeholders, including policymakers, teachers of diversity, students, service users and carers. The data were analysed qualitatively using quasi-statistical and template approaches and themes identified. Three main themes emerged. The first was ambivalence over the need to assess students. Most felt students should be assessed to ensure the subject was taken seriously. Some were concerned that assessment might encourage false attitudes. The second theme was uncertainty over the best methodology. Objective structured clinical examinations (OSCEs) were the most favoured method. Significant concern was expressed that this alone was sufficient. The third theme was concern that current assessment methods do not identify students with inappropriate attitudes that are potentially detrimental to patient care. Assessment of cultural awareness should be attempted but it needs to be multifaceted. The OSCE alone is inadequate. Other tools, such as reflective portfolios, need evaluation.


The cardiopulmonary effects of sepsis on the trauma patient.
The cardiopulmonary effects of acute infection are inflammation-induced. Inflammatory mediators can both initiate and perpetuate the characteristic hyperdynamic, hypermetabolic state.


Armed Forces Radiobiology Research Institute/Uniformed Services University of the Health Sciences perspective on space radiation countermeasure discovery.
There is a need to develop and deploy medical countermeasures (MCMs) in order to support astronauts during space missions against excessive exposures to ionizing radiation exposure. The radiation environment of extraterrestrial space is complex and is characterized by nearly constant fluences of elemental atomic particles (protons being a dominant particle type) with widely different energies and ionization potentials. Chronic exposure to such ionizing radiation carries both near- and long-term health risks, which are generally related to the relative intensity and duration of exposure. These radiation-associated health risks can be managed only to a limited extent by physical means, but perhaps they might be more effectively managed biomedically. The Armed Forces Radiobiology Research Institute/Uniformed Services University of the Health Sciences has a long history of researching and developing MCMs specifically designed to support terrestrial-based military missions involving a radiation-threat component. The development of MCMs for both low and high doses of radiation are major aims of current research, and as such can provide lessons learned for the development of countermeasures applicable to future space missions and its extraterrestrial radiation environment.


Clinicopathologic factors and preoperative ultrasonographic characteristics for predicting central lymph node metastasis in papillary thyroid microcarcinoma: a single center retrospective study.
The treatment of papillary thyroid microcarcinoma remains controversial. Central lymph node metastasis is common in papillary thyroid microcarcinoma and it is an important consideration in treatment strategy selection. The aim of this study was to investigate clinicopathologic risk factors and thyroid nodule sonographic characteristics for central lymph node metastasis in papillary thyroid microcarcinoma. We retrospectively reviewed the data of 599 papillary thyroid microcarcinoma patients who underwent surgery from 2005 to 2017 at a single institution. Univariate and multivariate analyses were used to identify the clinicopathologic factors and preoperative sonographic features of central lymph node metastasis. A receiver-operating characteristic, ROC curve analysis, was performed to identify the efficacy of ultrasonographic features in predicting central lymph node metastasis. A nomogram based on the risk factors was established to predict central lymph node metastasis. The incidence of central lymph node metastasis was 22.4%. The univariate and multivariate analyses suggested that gender, age, multifocality, extrathyroidal invasion, and lateral lymph node metastasis were independent risk factors for central lymph node metastasis. The univariate and multivariate analyses revealed that nodular shape, margin, and calcification were independently associated with central lymph node metastasis. The ROC curve analysis revealed that the combination of shape, margin and calcification had excellent accuracy in predicting central lymph node metastasis. The nomogram was developed based on the identified risk factors for predicting central lymph node metastasis, and the calibration plot analysis indicated the good performance and clinical utility of the nomogram. Central lymph node metastasis is associated with male gender, younger age (<45 years), extrathyroidal invasion, multifocality and lateral lymph node metastasis in papillary thyroid microcarcinoma patients. The ultrasongraphic features, such as irregular shape, ill-defined margin and calcification, may improve the efficacy of predicting central lymph node metastasis. Surgeons and radiologists should pay close attention to the patients who have these risk factors. The nomogram may help guide surgical decision making in papillary thyroid microcarcinoma.


Bone marrow stimulation induces greater chondrogenesis in trochlear vs condylar cartilage defects in skeletally mature rabbits.
The aim of this study was to compare the early repair response of cartilage defects in trochlea (TR) and medial femoral condyle (MFC) at 2-3 weeks after bone marrow stimulation. Bilateral full-thickness cartilage defects were generated in central trochlear groove and MFC of skeletally mature rabbits. Four subchondral perforations were made on each defect, either by microfracture to 2 mm deep, or by drilling to 2 mm or 6 mm deep. Rabbits were sacrificed either on Day 14 post-operatively or on Day 21. Defects were analyzed by histology, stereology, histomorphometry and micro-computed tomography (CT). Intact femurs (N = 4) served as controls. Stromal cell density recruitment was similar in all defects, irrespective of defect location and surgical techniques used. There was a robust appearance of chondrocytes at Day 21 in TR defects with significantly higher volume fraction of chondrocytes in TR compared to MFC (P = 0.013). Chondrogenic foci were observed in marrow penetrating holes, with a significantly higher frequency and larger foci in TR vs MFC defects at Day 21 (P = 0.043 and P = 0.0014, respectively). Micro-CT analysis showed that deep drilling elicited significantly more mineralized bone fill compared to shallower perforations at 2 and 3 weeks repair (all at P ≤ 0.0008). Bone marrow stimulation induced greater chondrogenesis in TR vs MFC defects in adult rabbits, with more chondrocytes and larger chondrogenic foci appearing in TR vs MFC on Day 21 post-operation.


Study on awareness of COVID-19 and compliance with social distancing during COVID-19 pandemic in Indonesia.
Public compliance with social distancing policy is necessary to slow down the spread of coronavirus disease 2019 (COVID-19). One of the factors that contribute to compliance with social distancing policy is awareness of COVID-19. This study aimed to examine the relationship between awareness of COVID-19 and compliance with social distancing policy. The study used an online survey through Google Form to 404 respondents aged 18-63 years. The data were collected by using awareness on the COVID-19 scale and compliance with the social distancing scale. The data were analyzed using the Spearman correlation and Kruskal-Wallis, followed by Mann-Whitney U with Bonferroni correction. The awareness of COVID-19 was significantly and positively associated with compliance with social distancing order. Based on demographic variables found that the awareness was significantly higher in postgraduates. The awareness of COVID-19 was also significantly higher in working participants. The compliance with social distancing order was found higher in women. The study's primary result is that the awareness of COVID-19 positively correlates with public compliance on social distancing order. In particular, there is a need to provide means and interventions to raise public awareness of this challenging situation.


Multivariate path analysis of specific cognitive abilities in the Colorado Adoption Project: conditional path model of assortative mating.
A multivariate path model of genetic and environmental transmission employing a conditional path representation of assortative mating was fitted to specific cognitive abilities data from the Colorado Adoption Project and evaluated using a maximum-likelihood estimation procedure. In agreement with results obtained from a previous analysis of a smaller data set, significant genetic covariation among the cognitive variables was indicated and evidence for a general genetic factor was found. However, cultural transmission parameters are nonsignificant and environmental correlations among the measures are relatively small.


A new tabanid trap applying a modified concept of the old flypaper: linearly polarising sticky black surfaces as an effective tool to catch polarotactic horseflies.
Trapping flies with sticky paper sheets is an ancient method. The classic flypaper has four typical characteristics: (i) its sticky paper is bright (chamois, light yellow or white), (ii) it is strip-shaped, (iii) it hangs vertically, and (iv) it is positioned high (several metres) above ground level. Such flypapers, however, do not trap horseflies (tabanids). There is a great need to kill horseflies with efficient traps because they are vectors of dangerous diseases, and due to their continuous annoyance livestock cannot graze, horses cannot be ridden, and meat and milk production from cattle is drastically reduced. Based on earlier findings on the positive polarotaxis (attraction to linearly polarised light) in tabanid flies and modifying the concept of the old flypaper, we constructed a new horsefly trap called "horseflypaper". In four field experiments we showed that the ideal horseflypaper (i) is shiny black, (ii) has an appropriately large (75×75 cm(2)) surface area, (iii) has sticky black vertical and horizontal surfaces in an L-shaped arrangement, and (iv) its horizontal surface should be at ground level for maximum effectiveness. Using imaging polarimetry, we measured the reflection-polarisation characteristics of this new polarisation tabanid trap. The ideal optical and geometrical characteristics of this trap revealed in field experiments are also explained. The horizontal part of the trap captures water-seeking male and female tabanids, while the vertical part catches host-seeking female tabanids.


Evaluating cutaneous photoaging by use of multiphoton fluorescence and second-harmonic generation microscopy.
The photoaging process of facial skin is investigated by use of multiphoton fluorescence and second-harmonic generation (SHG) microscopy. We obtain the autofluorescence (AF) and SHG images of the superficial dermis from the facial skin of three patients aged 20, 40, and 70 years. The results show that areas of AF increase with age, whereas areas of SHG decrease with age. The results are consistent with the histological findings in which collagen is progressively replaced by elastic fibers. The AF and SHG changes in photoaging are quantified by a SHG to autofluorescence aging index of dermis (SAAID). Our results suggest that SAAID can be a good indicator of the severity of photoaging.


Subsensitivity of the rat striatal dopaminergic system after treatment with bromocriptine: effects on [3H]spiperone binding and dopamine-stimulated cyclic AMP formation.
Repeated daily administration of the dopamine (DA) agonist bromocriptine (15 mg/kg; s.cut.) to rats led to a time dependent decrease in the in vitro binding of [3H]spiperone to striatal membranes. Kinetic analysis of [3H]spiperone binding after 2 and 7 days of bromocriptine treatment showed a 25-50% reduction in the total number of binding sites with no changein their affinity for spiperone. There was also a decreased accumulation of cyclic AMP (cAMP) in striatal slices in response to DA after bromocriptine treatment. The DA-sensitive adenylate cyclase in striatal homogenates, however, remained unchanged in bromocriptine treated rats. There was also no change in cyclic nucleotide phosphodiesterase activity in striatal tissue after bromocriptine treatment. Furthermore, incubation of striatal slices in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine did not alter the decreased cAMP response to DA after 2 days of bromocriptine treatment. These results suggest that a decreased number of DA receptor sites may be responsible for the reduced cAMP response to DA in striatal slices after bromocriptine treatment.


Retrieval of droplet-size density distribution from multiple-field-of-view cross-polarized lidar signals: theory and experimental validation.
Multiple-field-of-view (MFOV) secondary-polarization lidar signals are used to calculate the particle-size density distribution (PSD) at the base of a cloud. At the cloud base, multiple scattering is weak and single backscattering is predominant by many orders of magnitude. Because secondary polarization is a direct measure of multiple scattering, it is therefore advantageous to use secondary polarization. A mathematical relation among the PSD, the lidar fields of view, the scattering angles, and the angular depolarization is derived to facilitate use of secondary polarization. The model is supported by experimental MFOV lidar measurements carried out in a controlled environment, and its limitations and restrictions are discussed.


Loneliness and depression among rural empty-nest elderly adults in Liuyang, China: a cross-sectional study.
To compare loneliness, depressive symptoms and major depressive episodes between empty-nest and not-empty-nest older adults in rural areas of Liuyang city, Hunan, China. A cross-sectional multi-stage random cluster survey was conducted from November 2011 to April 2012 in Liuyang, China. A total of 839 rural older residents aged 60 or above completed the survey (response rate 97.6%). In line with the definition of empty nest, 25 participants who had no children were excluded from the study, while the remaining 814 elderly adults with at least one child were included for analysis. Loneliness and depressive symptoms in rural elderly parents were assessed using the short-form UCLA Loneliness Scale (ULS-6) and the Geriatric Depression Scale (GDS). Major depressive episodes were diagnosed using the Structured Clinical Interview for DSM-IV (SCID-I). Significant differences were found between empty-nest and not-empty-nest older adults regarding loneliness (16.19±3.90 vs. 12.87±3.02, Cohen's d=0.97), depressive symptoms (8.50±6.26 vs. 6.92±5.19, Cohen's d=0.28) and the prevalence of major depressive episodes (10.1% vs. 4.6%) (all p<0.05). After controlling for demographic characteristics and physical disease, the differences in loneliness, depressive symptoms and major depressive episodes remained significant. Path analysis showed that loneliness mediated the relationship between empty-nest syndrome and depressive symptoms and major depressive episodes. Loneliness and depression are more severe among empty-nest than not-empty-nest rural elderly adults. Loneliness was a mediating variable between empty-nest syndrome and depression.


A comparison of Blalock-Taussig, Waterston, and polytetrafluoroethylene shunts in children less than two weeks of age.
Results obtained with Blalock-Taussig, Waterston, and polytetrafluoroethylene (PTFE) shunts were compared in 67 cyanotic infants less than 2 weeks of age. A different shunt was preferably used at each of three institutions. The incidences of early shunt failure (3 out of 21, 14%), mortality after revision of early shunt failure (0 out of 3), and overall hospital mortality (1 out of 21, 5%) were all lowest for the PTFE shunt. Incidence of congestive heart failure secondary to excessive flow was comparable for the Blalock-Taussig and PTFE shunts, both of which were lower than the Waterston shunt. Cumulative probabilities of late shunt adequacy were calculated for hospital survivors. At 1 year, all shunts provided comparable adequate palliation (greater than 80%). Probability of late shunt failure was significantly higher (p = 0.04) for the PTFE shunt at 3.5 years. Results suggest that the PTFE shunt may be the safest and most effective shunt in neonates, but that elective shunt replacement or total repair may be warranted in the first or second year of life.


"You are in Trouble!": A Discursive Psychological Analysis of Threatening Language in Chinese Cellphone Fraud Interactions.
Currently cellphone fraudsters often use language to threaten and bully victims. From discursive psychological perspective, the present study applies conversation analysis to discuss fraudsters' threatening language in Chinese cellphone fraud conversations. The authentic data are collected from Chinese media which report legal news or conduct public legal education on the battle against cellphone frauds. Results of the study show that: (1) cellphone fraudsters construct their false identities through information gap and information sharing in their turn-taking designs, which brings victims into the threatening fraud interactions; (2) fraudsters use such conversational skills in a threatening tone as repetition, interruption, higher pitch, louder speech and so on to trigger victims' psychological panic; (3) fraudsters' discursive practices are situated for the threatening actions based on prepared and designed scripts. The findings of the study are expected to provide references for preventing cellphone fraud and fighting against fraudsters' threats and bullies.


Fetal bradyarrhythmia: diagnosis and outcome.
Seventeen patients were referred to out ultrasound unit because of fetal bradyarrhythmia (less than 100 bpm). Duration of pregnancy varied between 21 and 40 weeks. Bradyarrhythmia was diagnosed as atrioventricular block (n = 12), mild sinus bradycardia (n = 3), and irregular bradycardia (n = 2). The association with maternal collagen disease was 29 per cent and with cardiac structural defects 59 per cent. The overall mortality was 41 per cent. There were three abnormal karyotypes (17 per cent) and four cases of cardiac compromise (23 per cent). Prognosis depends on the nature of the bradyarrhythmia and recognition of associated pathology such as cardiac structural defects, abnormal karyotype and degree of cardiac compromise.


Synthesis and Characterization of Hexafluorocyclopentane-Bridged Bisbutatrienes as Models for Longer Cumulenes: Various Transformations for the Construction of π-Conjugated Frameworks.
Cumulenes have attracted considerable attention due to their unique structural and electronic properties. Despite their high potential for constructing condensed π-conjugated molecules, the synthetic utility of longer cumulenes remains to be established owing to their inherently high reactivity. Conjugated bisbutatrienes having two cumulene moieties linked by a spacer as a mimic of a longer cumulene were evaluated. Here, the synthesis and characterization of hexafluorocyclopentane-bridged bisbutatrienes are described. These bisbutatrienes underwent various cyclizations, to construct the unique π-extended frameworks inaccessible by other methodologies. The bisbutatrienes were converted into fulvenes, pentalene, germacycle, and benzocyclobutene under various conditions. Furthermore, a cyclooctatetraene derivative was synthesized by a one-step dimerization of the bisbutatriene.


Weekend and holiday exercise testing in patients with chest pain.
To determine the outcome, safety, and possible cost savings of patients undergoing weekend or holiday exercise treadmill testing. Medical records of all 195 patients scheduled for weekend and holiday exercise testing were reviewed, and 77.9% of patients were contacted by telephone to ascertain medical outcomes and need for further emergency department or inpatient care. Costs were calculated from estimates of days of hospitalization saved and incremental costs incurred in conjunction with weekend or holiday testing. Urban tertiary care academic medical center. A total of 195 patients were scheduled for testing, and 181 tests were performed. Over three quarters (75.1%) of patients underwent testing for assessment of chest pain. Other indications included risk stratification after myocardial infarction or coronary angioplasty or prior to noncardiac surgery, or evaluation for arrhythmias, dyspnea, or syncope. Outcomes included results and complications of testing, hospital course after testing, subsequent emergency department visits and readmissions, myocardial infarction, need for cardiac catheterization or revascularization, and mortality. No complications were noted during testing. In 136 patients tested for the indication of chest pain, 90 (66.2%) had negative tests, 39 (28. 7%) were intermediate, and 6 (4.4%) were positive for ischemia. Same day discharge occurred in 115 (84.6%) of the patients, saving an estimated 185 days of hospitalization ($316.83 per patient tested). Event rates over the 6 months following discharge were low. Weekend and holiday exercise testing is a safe and effective means of risk stratification prior to hospital discharge for patients with chest pain. It also reduces length of stay and is cost saving.


Effect of in vitro aging on the modulation of protein and fibronectin biosynthesis by the elastin-laminin receptor in human skin fibroblasts.
The 67-kD elastin-laminin receptor (ELR) subunit which carries the recognition site for elastin peptides (EP) is a lectin. Its binding with galactosides can modulate the kinetics of its interaction with its ligand, EP. In this study the biosynthesis of proteins, collagen and fibronectin were evaluated in the presence of agonists and antagonists of the receptor on human skin fibroblasts. The biosynthesis of total proteins determined by 3H-proline incorporation and of fibronectin (by immunoprecipitation) were shown to increase with passage number. The presence of 1 microg/ml kappa-elastin (EP) in the culture medium increased both total proteins and fibronectin biosynthesis. Melibiose, an agonist of the receptor at 5 microg/ml (140 microM), decreased both proteins and fibronectin biosynthesis in the culture medium of human skin fibroblast at the 10th and 15th passage. These results show that the ELR can control the biosynthetic mechanisms of some of the macromolecular constituents of extracellular matrix such as fibronectin and moderate its age and passage-dependent upregulation.


Enhancement of apoptosis by nitric oxide released from alpha-phenyl-tert-butyl nitrone under hyperthermic conditions.
The aim of this study was to examine whether a neuroprotector, PBN (alpha-phenyl-tert-butyl nitrone), enhances apoptosis induced by hyperthermia, which generates superoxide (O2-) intracellularly, since the release of nitric oxide (NO) from PBN under oxidative stress has been reported. When human myelomonocytic lymphoma U937 cells were treated with hyperthermia (44 degrees C, 10 min) and PBN, an increase in the concentration of nitrite in the culture medium, and a decrease in the hyperthermia-induced production of O2- was observed. Imaging using a fluorescence dye for intracellular NO, diaminofluorescein-2 diacetate (DAF-2 DA), revealed the formation of NO in the apoptotic cells treated with hyperthermia and PBN combined. Apoptotic endpoints were significantly enhanced by the combined treatment: a decrease in mitochondrial trans-membrane potential, cleavage of Bid, release of cytochrome c, and activation of caspase-8 and -3. An increase in the intracellular Ca2+ concentration ([Ca2+]i), externalization of Fas, and decrease in Hsp70 and phosphorylated HSF1 were observed following the combined treatment. Furthermore, scavengers of NO an d ONOO- significantly inhibited the enhancement of apoptosis, the externalization of Fas and the increase in [Ca2+]i. These results suggest that, (1) NO is released from PBN by hyperthermia, and subsequently reacts with O2- to form ONOO-, (2) NO and ONOO- are involved in the enhancement of apoptosis through Fas-mitochondria-caspase and [Ca2+]i-dependent pathways, and (3) a decrease in Hsp70 and phosphorylated HSF1 also contributed to the enhancement of apoptosis.


Multi-view subspace clustering via adaptive graph learning and late fusion alignment.
Multi-view subspace clustering has attracted great attention due to its ability to explore data structure by utilizing complementary information from different views. Most of existing methods learn a sample representation coefficient matrix or an affinity graph for each single view, then the final clustering result is obtained from the spectral embedding of a consensus graph using certain traditional clustering techniques, such as k-means. However, clustering performance will be degenerated if the early fusion of partitions cannot fully exploit relationships between all samples. Different from existing methods, we propose a multi-view subspace clustering method via adaptive graph learning and late fusion alignment (AGLLFA). For each view, AGLLFA learns an affinity graph adaptively to capture the similarity relationship among samples. Moreover, a spectral embedding learning term is designed to exploit the latent feature space of different views. Furthermore, we design a late fusion alignment mechanism to generate an optimal clustering partition by fusing view-specific partitions obtained from multiple views. An alternate updating algorithm with validated convergence is developed to solve the resultant optimization problem. Extensive experiments on several benchmark datasets are conducted to illustrate the effectiveness of the proposed method when compared with other state-of-the-art methods. The demo code of this work is publicly available at https://github.com/tangchuan2000/AGLLFA.


Predicting Survival for Patients With Metastatic Disease.
This prospective study aimed to determine the accuracy of radiation oncologists in predicting the survival of patients with metastatic disease receiving radiation therapy and to understand factors associated with their accuracy. This single-institution study surveyed 22 attending radiation oncologists to estimate patient survival. Survival predictions were defined as accurate if the observed survival (OS) was within the correct survival prediction category (0-6 months, >6-12 months, >12-24 months, and >24 months). The physicians made survival estimates for each course of radiation, yielding 877 analyzable predictions for 689 unique patients. Data analysis included Stuart's Tau C, logistic regression models, ordinal logistic regression models, and stepwise selection to examine variable interactions. Of the 877 radiation oncologists' predictions, 39.7% were accurate, 26.5% were underestimations, and 33.9% were overestimations. Stuart's Tau C showed low correlation between OS and survival estimates (0.3499), consistent with the inaccuracy reported in the literature. However, results showed less systematic overprediction than reported in the literature. Karnofsky performance status was the most significant predictor of accuracy, with greater accuracy for patients with shorter OS. Estimates were also more accurate for patients with lower Karnofsky performance status. Accuracy by patient age varied by primary site and race. Physician years of experience did not correlate with accuracy. The sampled radiation oncologists have a 40% accuracy in predicting patient survival. Future investigation should explore how survival estimates influence treatment decisions and how to improve survival prediction accuracy.


Mammographic breast density as a risk factor for breast cancer: awareness in a recently screened clinical sample.
Breast density is an established, independent risk factor for breast cancer. Despite this, density has not been included in standard risk models or routinely disclosed to patients. However, this is changing in the face of legal mandates and advocacy efforts. Little information exists regarding women's awareness of density as a risk factor, their personal risk, and risk management options. We assessed awareness of density as a risk factor and whether sociodemographic variables, breast cancer risk factors. and perceived breast cancer risk were associated with awareness in 344 women with a recent screening mammogram at a tertiary care center. Overall, 62% of women had heard about density as a risk factor and 33% had spoken to a provider about breast density. Of the sample, 18% reported that their provider indicated that they had high breast density. Awareness of density as a risk factor was greater among White women and those with other breast cancer risk factors. Our results suggest that although a growing number of women are aware of breast density as a risk factor, this awareness varies. Growing mandates for disclosure suggest the need for patient education interventions for women at increased risk for the disease and to ensure all women are equally aware of their risks.


Dosimetric characteristics of a 6 MV photon beam from a linear accelerator with asymmetric collimator jaws.
Dosimetric measurements have been made of a 6 MV photon beam from a linear accelerator equipped with asymmetric jaws. The field size factors for asymmetrically set fields are compared to those for symmetrically set fields. The change of beam quality has been measured as a function of off-axis position of the asymmetric fields to assess its effect on depth dose. Additional measurements include beam penumbra and shape of isodose curves for open and wedge fields as the field opening is moved asymmetrically from the central ray.


Transcriptional regulation of corticotrophin releasing factor gene by furocoumarins isolated from seeds of Psoralea corylifolia.
Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system plays a causal role in the development and course of depression. Clinically effective antidepressant drugs normalize the disturbed activity of the HPA axis by inhibition of corticotrophin releasing factor gene promoter activity. Furocoumarins from Psoralea corylifolia have been demonstrated to possess potent antidepressant properties. In order to ascertain whether these coumarin components directly regulate corticotrophin releasing factor (CRF) gene transcription, we studied their effect on CRF promoter activity using the luciferase reporter assay in Neuro-2A cells. CRF promoter was cloned into firefly luciferase reporter vector and co-transfected into Neuro-2A cells with Renilla luciferase plasmid as internal control. CRF promoter transcription activity was induced by forskolin. We found that one of the components of P. corylifolia, psoralidin, strongly inhibited forskolin-induced CRF promoter activity. We further confirmed that psoralidin suppressed CRF gene transcription by quantitative reverse transcription polymerase chain reaction. Hence, down-regulation of CRF gene transcription by psoralidin may be involved in the molecular mechanism underlying its potent antidepressant effect.


ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P.
Nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) in response to elevated endoplasmic reticulum (ER) stress. Whereas the onset of simple steatosis requires elevated de novo lipogenesis, progression to NASH is triggered by accumulation of hepatocyte-free cholesterol. We now show that caspase-2, whose expression is ER-stress inducible and elevated in human and mouse NASH, controls the buildup of hepatic-free cholesterol and triglycerides by activating sterol regulatory element-binding proteins (SREBP) in a manner refractory to feedback inhibition. Caspase-2 colocalizes with site 1 protease (S1P) and cleaves it to generate a soluble active fragment that initiates SCAP-independent SREBP1/2 activation in the ER. Caspase-2 ablation or pharmacological inhibition prevents diet-induced steatosis and NASH progression in ER-stress-prone mice. Caspase-2 inhibition offers a specific and effective strategy for preventing or treating stress-driven fatty liver diseases, whereas caspase-2-generated S1P proteolytic fragments, which enter the secretory pathway, are potential NASH biomarkers.


DNA ploidy pattern and S-phase characteristics of metastatic melanoma.
Samples of 130 metastatic melanomas from 92 patients were analyzed by DNA flow cytometry. DNA aneuploidy was observed in 67% of the patients. DNA indices were evenly distributed from 0.6 to 2.6 Tumors originating from primary lesions in the lower extremities were more frequently DNA aneuploid than those of other sites. S-phase fraction (SPF) was evaluable from 73 tumors. DNA aneuploid tumors had a significantly higher SPF than diploid tumors, and females had a higher SPF than males. Furthermore, distant metastases had a higher SPF than metastases in regional lymph nodes and in transit metastases, probably indicating a higher growth potential in metastases spreading to distant sites.


Correction to: Genetic diversity and evolutionary history of Korean isolates of severe fever with thrombocytopenia syndrome virus from 2013-2016.
Authors would like to correct the 4th author name from "Ju-Yeon Lee" to the correct version "Joo-Yeon Lee".


Postoperative radiotherapy and concomitant temozolomide for elderly patients with glioblastoma.
The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GB) when compared to postoperative RT alone in patients up to 65 years of age. In older patients, RT alone has remained the standard of care because there is concern that radiochemotherapy causes excess toxicity and is less efficacious in this population, but no randomized trials have been reported. We retrospectively assessed feasibility, toxicity and outcome in elderly patients treated at a single institution with RT and concomitant TMZ. Between 04/1999 and 9/2009, 51 patients ≥65 years (median age 70 years, range 65-84) with GB were treated by RT (total dose 60 Gy in 30 fractions) and concomitant TMZ (75 mg/m(2)/day throughout RT). Biopsy only had been performed in 23 patients (45.1%), 15 patients (29.4%) had undergone partial resection, and 13 patients (25.5%) macroscopically complete resection. Adjuvant TMZ was applied in 10 of 51 patients. Median overall survival (OS) and progression-free survival (PFS) were 11.5 (95% CI, 6.7-16.3) and 5.5 months (95% CI, 3.7-7.3 months), respectively, in the total cohort. After complete resection, partial resection and biopsy, median OS was 27.4, 15.5 and 7.9 months (p=0.002), respectively. In multivariate Cox proportional hazards regression models extent of resection (p<0.0001) and Karnofsky's performance score (p=0.002) were significant independent prognostic factors for OS. RT with concomitant TMZ was well tolerated in the majority of patients and could be completed as scheduled in 30 patients (59%). Five patients (10%) discontinued RT because of disease progression (n=4) or toxicity (pneumonia, n=1). Another 16 patients interrupted concomitant chemotherapy (cytopenia: 9; pneumonia: 2; transaminase elevation: 2; rash: 3). RT with concomitant TMZ is a feasible regimen with acceptable toxicity in elderly patients. The promising outcome in patients with good performance status and patients with gross total resections are notable.


Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6.
Dickkopf1 (DKK1) was originally identified as an antagonist of Wnt signaling that binds to and induces the clathrin-mediated endocytosis of the Wnt coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6). DKK1 also binds to cytoskeleton-associated protein 4 (CKAP4), which was originally identified as an endoplasmic reticulum (ER) protein but also functions at the plasma membrane as a receptor for various ligands. The DKK1-CKAP4 pathway is activated in several human cancers and promotes cell proliferation by activating signaling through the kinases PI3K and AKT. We found that both CKAP4 and LRP6 primarily localized to detergent-resistant membrane (DRM) fractions of the plasma membrane in a palmitoylation-dependent manner and that palmitoylation of CKAP4 was required for it to promote cell proliferation. DKK1 induced the depalmitoylation of both CKAP4 and LRP6 by acylprotein thioesterases (APTs), resulting in their translocation to the non-DRM fractions. Moreover, DKK1-dependent depalmitoylation of both receptors required activation of the PI3K-AKT pathway. DKK1 simultaneously bound CKAP4 and LRP6, resulting in the formation of a ternary complex. LRP5/6 knockdown decreased DKK1-dependent AKT activation and cancer cell proliferation through CKAP4, whereas CKAP4 knockdown did not affect DKK1-dependent inhibition of Wnt signaling through LRP5/6. These results indicate that the palmitoylation states of CKAP4 and LRP6 play important roles in their signaling and that LRP5/6 enhance DKK1-CKAP4 signaling.


Why won't you change your mind? Knowledge of operational patterns hinders learning and performance on equations.
This study examined whether knowledge of arithmetic contributes to difficulties with equations. In Experiment 1, children (ages 7-11) completed tasks to assess their adherence to 3 operational patterns prevalent in arithmetic: (a) the strategy of performing all given operations on all given numbers, (b) the "operations = answer" problem structure, and (c) the concept that the equal sign means "the total." Next, children received a lesson on equations; then, they solved a set of equations. There was a negative relationship between adherence to the operational patterns and learning. In Experiment 2, undergraduates' knowledge of the operational patterns was activated or not. Students whose knowledge was activated did not perform as well on equations. Results suggest that early-learned patterns constrain future learning and performance.


[A perspective of the development of medical metrology].
This paper summarized the internal and external development of medical metrology, posed its main problem and studied its development trend.


Nanoscale membrane activity of surfactins: influence of geometry, charge and hydrophobicity.
We used real-time atomic force microscopy (AFM) to visualize the interactions between supported lipid membranes and well-defined surfactin analogs, with the aim to understand the influence of geometry, charge and hydrophobicity. AFM images of mixed dioleoylphosphatidylcholine/dipalmitoylphosphatidylcholine (DOPC/DPPC) bilayers recorded after injection of cyclic surfactin at 1 mM, i.e. well-above the critical micelle concentration, revealed a complete solubilization of the bilayers within 30 min. A linear analog having the same charge and acyl chains was able to solubilize DOPC, but not DPPC, and to promote redeposition leading eventually to a new bilayer. Increasing the charge of the polar head or the length of the acyl chains of the analogs lead to the complete solubilization of both DOPC and DPPC, thus to a stronger membrane activity. Lastly, we found that at low surfactin concentrations (40 microM), DPPC domains were always resistant to solubilization. These data demonstrate the crucial role played by geometry, charge and hydrophobicity in modulating the membrane activity (solubilization, redeposition) of surfactin. Also, this study suggests that synthetic analogs are excellent candidates for developing new surfactants with tunable, well-defined properties for medical and biotechnological applications.


Leaf-individual calibration for a double stack multileaf collimator in photon radiotherapy.
In online adaptive stereotactic body radiotherapy treatments, linear accelerator delivery accuracy is essential. Recently introduced double stack multileaf collimators (MLCs) have new facets in their calibration. We established a radiation-based leaf-individual calibration (LIMCA) method for double stack MLCs. MLC leaf positions were evaluated from four cardinal angles with test patterns at measurement positions throughout the radiation field on EBT3 radiochromic film for each single stack. The accuracy of the method and repeatability of the results were assessed. The effect of MLC positioning errors was characterized for a measured output factor curve and a clinical patient plan. All positions in the motor step - position calibration file were optimized in the established LIMCA method. The resulting double stack mean accuracy for all angles was 0.2 ± 0.1 mm for X1 (left bank) and 0.2 ± 0.2 mm for X2 (right bank). The accuracy of the leaf position evaluation was 0.2 mm (95% confidence level). The MLC calibration remained stable over four months. Small MLC leaf position errors (e.g. 1.2 mm field size reduction) resulted in important dose errors (-5.8 %) for small quadratic fields of 0.83 × 0.83 cm2. Single stack position accuracy was essential for highly modulated treatment plans. LIMCA is a new double stack MLC calibration method that increases treatment accuracy from four angles and for all moving leaves.


[Depression and psoriasis].
Psychiatric co-morbidity is very frequently associated with psoriasis. Depression is observed in numerous patients with psoriasis. Early detection and treatment are very important. There is a vicious circle psoriasis- alteration of quality of life- depression, but psoriasis improvement is not always followed by an improvement of depression. A contrario, it is obvious that a depressive patient has a bad observance of treatment. Links between psoriasis and depression are not only psychopathological. Biological factors, such as increase of blood amounts of substance P and TNF or decrease of serotonine could also explain this association.


Prognostic Value of Global Longitudinal Strain in Patients With Heart Failure With Improved Ejection Fraction.
The authors sought to determine whether global longitudinal strain (GLS) is independently associated with the natural history of patients with heart failure (HF) with improved ejection fraction (HFimpEF). Left ventricular (LV) ejection fraction (EF) often improves in patients with reduced EF. The clinical course of patients with HFimpEF, however, is quite variable. GLS, a sensitive indicator of LV systolic function, could help predict risk of future events in this population. Retrospective analysis of HF patients with LVEF >40% on index echocardiogram who had LVEF <40% on initial study and improvement of ≥10%. GLS was assessed by 2-dimensional speckle-tracking software on index echocardiography. Primary outcome was time to first occurrence of cardiovascular mortality or HF hospitalization/emergency treatment. Of the 289 patients with HFimpEF, median absolute values of GLS (aGLS) and LVEF from index echocardiography were 12.7% (IQR: 10.8%-14.7%) and 52% (IQR: 46%-58%), respectively. Over 53 months following index echocardiography, the primary endpoint occurred less frequently in patients with aGLS above the median than below it (21% vs 34%; P = 0.014); HR of 0.51; 95% CI: 0.33-0.81; P = 0.004. When assessed as a continuous variable, each 1% increase in aGLS on index echocardiogram was associated with a lower likelihood of the composite endpoint; HR of 0.86; 95% CI: 0.79-0.93; P < 0.001, an association that persisted after multivariable adjustment; HR 0.90; 95% CI: 0.82-0.97; P = 0.01. Lower aGLS was associated with increased likelihood of deterioration in LVEF. In patients with HFimpEF, GLS is a strong predictor for future HF events and deterioration in cardiac function.


Network analysis of an arterial tree.
The arterial tree of a Sprague-Dawley rat was casted and carefully mapped with the aim of comparing its network characteristics with those suggested by the classical model of an arterial tree. It is shown that if the tree is to be measured accurately, the concept of 'whole vessels' on which the classical model is based must be abandoned since such vessels do not actually exist in the network, nor can they be accurately defined. The concept of 'vessel segments' is proposed instead and its use is demonstrated. A total of 1313 vessel segments in the arterial tree of the rat are mapped and divided into well defined 'levels'. The length and diameter of each segment are measured and the distribution and averages of these at different levels are presented as indicators of the branching characteristics of the tree.


The eye in renal disease.
This article summarizes the ocular pathology that can be seen in conjunction with renal disease. Both the eye and the kidney can be the target of systemic disease processes, but the eye can also be affected as a consequence of either renal disease or its treatment.