Chondroprotective effects of palmatine on osteoarthritis in vivo and in vitro: A possible mechanism of inhibiting the Wnt/β-catenin and Hedgehog signaling pathways.
The present study aimed to investigate the effect of palmatine (Pal) in a rabbit osteoarthritis (OA) model in vivo and rabbit interleukin-1β (IL-1β)-stimulated chondrocytes in vitro. Appropriate concentrations of Pal were identified by the MTT assay and used to preincubate IL-1β-induced chondrocytes, as well as an activator or inhibitor of Wnt and Hedgehog signaling pathways. Matrix metalloproteinase (MMP)-1, 3, and 13; tissue inhibitor of metalloproteinase (TIMP)-1; collagenase II; aggrecan; and the related molecules of the Wnt/β-catenin and Hedgehog signaling pathways were investigated. Protein expression was detected by Western blot analysis and messenger RNA (mRNA) expression was examined by PCR analysis. Pal (0.3 mL, 100 mg/L) was injected into rabbit knee joints and histological examination, immunohistochemistry, and Mankin scoring of the articular cartilage were performed. Pal (10-100 mg/L) had no effect on chondrocyte viability, decreased the expression of the MMPs, and increased the synthesis of TIMP-1whereas collagenase II and aggrecan were inhibited by IL-1β. When the activator (Licl) and inhibitor (DKK-1) of the Wnt/β-catenin signaling pathway as well as the inhibitor (cyclopamine) of the Hedgehog signaling pathway were added, the Wnt/β-catenin signaling pathway was less inhibited by Pal, and a similar inhibitory effect of cyclopamine on the Hedgehog signaling pathway was evident. Additionally, Pal enhanced the effect of cyclopamine. The histological examination, immunohistochemistry and Mankin scoring also demonstrated the protective effect of Pal, and the inhibition of the Wnt and Hedgehog signaling pathways by Pal. Pal may be useful in the treatment of OA, in which its effect is likely mediated via the Wnt/β-catenin and Hedgehog signaling pathways.


Adsorption chromatography on cellulose. IV. Separation of D- and L-tryptophan and D- and L-methyltryptophan on cellulose with aqueous solvents.
Differences in RF values between D- and L-tryptophan on cellulose paper, developed with water, were observed already in 1954 and now several variables of this separation, such as modifications to the tryptophan molecule, the temperature and salting-out have been examined. Differences were found in the mechanism of the process compared with the systems described by Yuasa et al. [Chromatographia, 21 (1986) 79], who separated amino acid enantiomers on cellulose with pyridine-ethanol-water mixtures.


A Survival Analysis of Hypopharyngeal Cancer Patients: A Hospital-Cancer registry Based Study.
To study the survival in patients affected with hypopharyngeal cancer among treatment groups and different stages. Data of hypopharyngeal cancer patients diagnosed from 1st January 2010 to 31st December 2010 was used in the present study. The cases were analyzed for gender, age group distribution, sub-sites at presentation, stage at diagnosis and the type of treatments. Survival from the date of first diagnosis was estimated and hazard ratios were calculated. Survival probability and hazards ratios (HR) were calculated by Kaplan-Meier method and Cox-proportional regression analysis respectively. Censoring of patient who survived longer than 5 years was done. Active follow-up was done for the survival analysis. The study cohort included 217 patients and treatment compliance was observed in 46.9% of cases. The median age at diagnosis was 57 years (range 24-90), 86.2% of cases were locally advanced cases (stage III and IV), pyriform sinus was major sub-site (96%), radiotherapy was main treatment modality alone in 84.8% of cases, median survival was 31 months and 5-year overall survival was 36.9%, and HR for stage IV was 1.9 (P = 0.03, 95% CI - 1.04 to 3.7). In developing setting of North East India, radiotherapy was the main modality of treatment for hypopharyngeal cancer patients, and understanding the clinical parameters and survival of this group of cancers is crucial for its control.


Cingulo-opercular and frontoparietal control network connectivity and executive functioning in older adults.
Executive function is a cognitive domain that typically declines in non-pathological aging. Two cognitive control networks that are vulnerable to aging-the cingulo-opercular (CON) and fronto-parietal control (FPCN) networks-play a role in various aspects of executive functioning. However, it is unclear how communication within these networks at rest relates to executive function subcomponents in older adults. This study examines the associations between CON and FPCN connectivity and executive function performance in 274 older adults across working memory, inhibition, and set-shifting tasks. Average CON connectivity was associated with better working memory, inhibition, and set-shifting performance, while average FPCN connectivity was associated solely with working memory. CON region of interest analyses revealed significant connections with classical hub regions (i.e., anterior cingulate and anterior insula) for each task, language regions for verbal working memory, right hemisphere dominance for inhibitory control, and widespread network connections for set-shifting. FPCN region of interest analyses revealed largely right hemisphere fronto-parietal connections important for working memory and a few temporal lobe connections for set-shifting. These findings characterize differential brain-behavior relationships between cognitive control networks and executive function in aging. Future research should target these networks for intervention to potentially attenuate executive function decline in older adults.


The utility of banana peel extract agar in the presumptive identification of Cryptococcus neoformans.
We prepared a newer growth medium, banana peel extract agar (BPEA) containing the extracts of chopped banana peels for the selective cultivation of Cryptococcus neoformans. Over the medium, the growth resulted in the development of light to the dark brown coloured colonies indicating the chromogenic potential of the BPEA. The organism grown over BPEA was subsequently confirmed as C. neoformans by phenotypic as well as by molecular method. This medium, being cost-effective, may be used in resource-poor settings of the developing or underdeveloped countries for selective isolation of C. neoformans.


Early stage breast cancer conserving treatment: high dose rate brachytherapy boost to the tumour bed.
The dose administered to the tumour bed is a risk-factor for local recurrence in localised breast cancer following breast-conserving surgery. All patients (n=94) received 50 Gy external beam radiotherapy and one application of 700 cGy at 85% isodose with high dose rate brachytherapy. Of the cases, 84% were infiltrating ductal carcinoma; 31.2% were G3; 28% were intraductal component > 25%; 54% had margin < 1 cm or unknown. With a mean follow-up of 65 months (range: 36-107 months), the overall actuarial survival at 5 and 8 years was 93.2% and 84.2%, respectively; disease-free survival was 88.3% and 84.6%, respectively; local control was 92.2% and 88.75%, respectively. Local recurrence rate was 5.3%, and distant dissemination rate was 8.5%. Among the risk-factors analysed, only the presence of 4 or more lymph node involvement implied a higher risk for local recurrence (p =0.0001). For distant dissemination, the risk-factors were: 4 or more lymph nodes involved (p = 0.0001),G3 (p =0.029), tumour >3 cm (p = 0.001), irradiation volume with external beam radiotherapy (p =0.0001), and presence of local recurrence (p = 0.001). High dose rate brachytherapy is an effective method for reducing local recurrence, and increasing local control.


Association of the Q121 variant of ENPP1 gene with decreased kidney function among patients with type 2 diabetes.
Insulin resistance has a role in diabetic kidney complications. The K121Q (lysine to glutamine substitution at amino acid 121, encoded by single-nucleotide polymorphism rs1044498) variant of the ectonucleotide pyrophosphatase/phosphodiesterase gene (ENPP1) has been associated with insulin resistance and related vascular complications in patients with type 2 diabetes (T2D) in many, although not all, studies. This study investigated whether the ENPP1 Q121 variant modulates the risk of decreased glomerular filtration rate (GFR) in patients with T2D. Cross-sectional study. 2 diabetes units from Italy (in Gargano and Padua) and 1 from the United States (Boston, MA) recruited a total of 1,392 patients with T2D. The ENPP1 Q121 variant. Estimated GFR from serum creatinine, urinary albumin excretion, blood pressure, hemoglobin A(1c), triglycerides, total cholesterol, and high-density lipoprotein cholesterol. Decreased GFRs (ie, estimated GFR <60 mL/min/1.73 m(2)). In the Gargano and Boston populations, according to the dominant model of inheritance, Q121 carriers (ie, individual with either KQ or QQ alleles) had an increased risk of decreased GFR: odds ratios (ORs) of 1.69 (95% confidence interval [CI], 1.1 to 2.6) and 1.50 (95% CI, 1.0 to 2.2), respectively. In the Padua set, the association was in the same direction, but did not reach formal statistical significance (OR, 1.77; 95% CI, 0.7 to 4.5). When the 3 studies were pooled, Q121 carriers showed an increased risk of decreased GFR (OR, 1.58; 95% CI, 1.2 to 2.1; P = 0.002). Also, pooled mean differences in absolute GFRs were different across genotype groups, with Q121 carriers showing lower GFRs compared with KK individuals (P = 0.04). P values not approaching a genome-wide level of significance. Our data suggest that patients with T2D carrying the ENPP1 Q121 variant are at increased risk of decreased GFR.


Induction of benign prostatic hypertrophy in baboons.
Hormonal manipulation of intact male baboons has produced prostatic features resembling benign prostatic hypertrophy (BPH) in man. Long-acting androgen, testosterone enanthate (TE), given weekly (200 mg i.m.) for up to six months, caused significant gravimetric and volumetric increases in the prostate; a definite glandular and marked stromal hyperplasia with fibrosis developed in the caudal lobe (CD). After twenty weeks of TE treatment, there were dysplastic (atypical) changes in the glandular lining epithelium in the CD, causing pseudostratification of the lining cells with nuclear hyperchromatism. By the twenty-eighth week, there was an increase of stromal tissue with papillary ingrowth or invagination of glandular epithelium in the CD. Serum levels of testosterone and dihydrotestosterone were significantly elevated from 10 nm/ml and 2-3 ng/ml to 30-40 ng/ml and 5-6 ng/ml, respectively. There was a 3 to 4-fold increase in androstenedione levels and an increase in estradiol-17 beta from 20 pg/ml to 80-90 pg/ml. These steroidal levels may have played a direct role in the induction of early BPH in the baboons. Cytoplasmic and nuclear androgen receptor levels were higher in the CD compared to those of the cranial lobe (CR); AR concentration was increased in the cytosol and decreased in the nuclei of both lobes in TE treated animals. Scanning and transmission electron microscopy revealed heavy deposition of collagen fibers (fibrosis) in the central and periurethral regions of the CD after the administration of TE. Glandular as well as epithelial hyperplasia was most notable in the peripheral zone of the CD. These findings are similar to observations established in human BPH, indicating that the baboon prostate may be a useful model for studying various parameters of BPH.


Teamwork and Surgical Team-Based Training.
Effective teamwork, both in and out of the operating room, is an essential component of safe and efficient surgical performance. There are multiple available assessment tools for evaluating teamwork and important contributors to teamwork such as safety culture and nontechnical skills. Multiple types of interventions exist to improve and train providers on teamwork, and many have been demonstrated to improve not only teamwork but also patient outcomes. Teamwork strategies can be adapted to different contexts, based on provider needs and resources.


Painful, swollen, oozing right great toe.
We initially suspected septic arthritis or osteomyelitis in this patient. Further investigation proved it was neither.


The proposed modification of TNM staging and therapeutic strategy for skip metastasis in papillary thyroid carcinoma: A multicenter retrospective cohort study.
Skip metastasis is a special type of lateral lymph node metastasis, which is not classified definitely by the eighth edition of the AJCC TNM staging system. The aim of the research was to study the prognosis of skip metastasis in PTC patients, and carry out a more appropriate N staging for skip metastasis. Study subjects were 3167 patients with papillary thyroid carcinoma (PTC), who underwent thyroidectomy at three clinical centers from 2016 to 2019. We identified two well-balanced cohorts matched on the basis of propensity score. During a median follow-up of 42 months, recurrence occurred in 68 (4.3%) patients with lymph node metastasis. 34 cases recurred in 1120 patients with central lymph node metastasis (N1a), and 34 recurred in 461 patients with lateral lymph node metastasis (N1b), among which 73 patients were diagnosis with skip metastasis. The RFS of N1a was significantly lower than that of N1b (p < 0.001). After propensity-score matching, recurrence rate was significantly lower in the skip metastasis group than in the LLNM group (p = 0.039), whereas the rate was similar in the skip metastasis groups and the CLNM group (p = 0.29). In conclusion, our study indicated that, among patients with LLNM, those with positive skip metastasis showed significantly lower recurrence, exhibiting a similar rucurrence tendency as patients with CLNM. Thus, skip metastasis could be categorized into N1a stage rather than N1b stage based on the AJCC TNM staging system. The downstaging of skip metastasis may reveal more conservative treatment strategy.


Aldosterone on sodium transport of rat distal colon in long-term adrenalectomy during acute and chronic substitution.
1. The influence of aldosterone upon water and sodium transport properties of the distal colon was studied in long-term adrenalectomy (11-29 days).2. Six groups of rats were used: I, normal (control); II, adrenalectomized; III, adrenalectomized, acutely substituted with aldosterone (200 mug/kg 4 h); IV, adrenalectomized rats receiving aldosterone simultaneously with the specific inhibitor spironolactone (40 mg/kg within 4 h); V, adrenalectomized, substituted chronically with aldosterone (2 x 75 mug/kg day); VI, adrenalectomized, substituted chronically with dexamethasone (120 mug/kg day).3. Distal colon segments were perfused in vivo with isotonic Ringer solution. In addition, a hypotonic electrolyte solution (Na(+) 111 mM) was used in groups I and II.4. In adrenalectomy (group II), net water absorption (J(v)) was significantly decreased from (normal) 54.4 mul/h cm(2)+/-10.5 (n = 9) to 41.2 mul/h cm(2)+/-7.3 (n = 4), and net Na(+) absorption (J(Na)) was decreased from 13.6 mumol/h cm(2)+3.5 to 8.5 mumol/h cm(2)+/-0.9 (isotonic perfusate). Similarly, J(v) was decreased from 54.0 mul/h cm(2)+/-8.3 (n = 4) to 37.3 mul/h cm(2)+/-4.2 (n = 7), and J(Na) from 8.6 mumol/h cm(2)+/-2.1 to 4.2 mumol/h cm(2)+/-2.1 (hypotonic perfusate).5. Acute aldosterone substitution in adrenalectomy (III) had no effect upon J(v) (37.1 mul/h cm(2)+/-10.3; n = 5) but increased J(Na) to 10.3 mumol/h cm(2)+/-0.3.6. The luminal Na(+) steady-state concentration was higher in group II (11.2 mmol l(-1)+/-3.6; n = 6) than in group I (3.3 mmol l(-1)+/-1.4; n = 29). Acute aldosterone substitution restored this value to normal (3.0 mmol l(-1)+/-1.2; n = 4). The aldosterone effect was partly blocked by spironolactone: the Na(+) steady-state concentration was 6.4 mmol/l+/-0.6 (n = 3) in group IV.7. At the steady-state luminal Na(+) concentration, the osmotically driven net water fluxes were not different in groups I and II, indicating that the hydraulic permeability coefficient is not altered in adrenalectomy.8. In group V, J(v) (54.9 mul/h cm(2)+/-10.9; n = 7) and J(Na) (11.9 mumol/h cm(2)+/-1.7; n = 6) were not significantly different from normal.9. In group VI, J(v) (37.3 mul/h cm(2)+/-6.0; n = 5) and J(Na) (8.0 mumol/h cm(2)+/-1.4) were not significantly different from group II.10. The mineralocorticoid effects of aldosterone in long-term adrenalectomy appear to represent the principal determining factors of colonic J(v) and J(Na).


Addressing systematic inconsistencies between in vitro and in vivo transcriptomic mode of action signatures.
Because of their broad biological coverage and increasing affordability transcriptomic technologies have increased our ability to evaluate cellular response to chemical stressors, providing a potential means of evaluating chemical response while decreasing dependence on apical endpoints derived from traditional long-term animal studies. It has recently been suggested that dose-response modeling of transcriptomic data may be incorporated into risk assessment frameworks as a means of approximating chemical hazard. However, identification of mode of action from transcriptomics lacks a similar systematic framework. To this end, we developed a web-based interactive browser-MoAviz-that allows visualization of perturbed pathways. We populated this browser with expression data from a large public toxicogenomic database (TG-GATEs). We evaluated the extent to which gene expression changes from in-life exposures could be associated with mode of action by developing a novel similarity index-the Modified Jaccard Index (MJI)-that provides a quantitative description of genomic pathway similarity (rather than gene level comparison). While typical compound-compound similarity is low (median MJI = 0.026), clustering of the TG-GATES compounds identifies groups of similar chemistries. Some clusters aggregated compounds with known similar modes of action, including PPARa agonists (median MJI = 0.315) and NSAIDs (median MJI = 0.322). Analysis of paired in vitro (hepatocyte)-in vivo (liver) experiments revealed systematic patterns in the responses of model systems to chemical stress. Accounting for these model-specific, but chemical-independent, differences improved pathway concordance by 36% between in vivo and in vitro models.


Risk assessment of amorphous silicon dioxide nanoparticles in a glass cleaner formulation.
Since nanomaterials are a heterogeneous group of substances used in various applications, risk assessment needs to be done on a case-by-case basis. Here the authors assess the risk (hazard and exposure) of a glass cleaner with synthetic amorphous silicon dioxide (SAS) nanoparticles during production and consumer use (spray application). As the colloidal material used is similar to previously investigated SAS, the hazard profile was considered to be comparable. Overall, SAS has a low toxicity. Worker exposure was analysed to be well controlled. The particle size distribution indicated that the aerosol droplets were in a size range not expected to reach the alveoli. Predictive modelling was used to approximate external exposure concentrations. Consumer and environmental exposure were estimated conservatively and were not of concern. It was concluded based on the available weight-of-evidence that the production and application of the glass cleaner is safe for humans and the environment under intended use conditions.


Bioassay-based Corchorus capsularis L. leaf-derived β-sitosterol exerts antileishmanial effects against Leishmania donovani by targeting trypanothione reductase.
Leishmaniasis, a major neglected tropical disease, affects millions of individuals worldwide. Among the various clinical forms, visceral leishmaniasis (VL) is the deadliest. Current antileishmanial drugs exhibit toxicity- and resistance-related issues. Therefore, advanced chemotherapeutic alternatives are in demand, and currently, plant sources are considered preferable choices. Our previous report has shown that the chloroform extract of Corchorus capsularis L. leaves exhibits a significant effect against Leishmania donovani promastigotes. In the current study, bioassay-guided fractionation results for Corchorus capsularis L. leaf-derived β-sitosterol (β-sitosterolCCL) were observed by spectroscopic analysis (FTIR, 1H NMR, 13C NMR and GC-MS). The inhibitory efficacy of this β-sitosterolCCL against L. donovani promastigotes was measured (IC50 = 17.7 ± 0.43 µg/ml). β-SitosterolCCL significantly disrupts the redox balance via intracellular ROS production, which triggers various apoptotic events, such as structural alteration, increased storage of lipid bodies, mitochondrial membrane depolarization, externalization of phosphatidylserine and non-protein thiol depletion, in promastigotes. Additionally, the antileishmanial activity of β-sitosterolCCL was validated by enzyme inhibition and an in silico study in which β-sitosterolCCL was found to inhibit Leishmania donovani trypanothione reductase (LdTryR). Overall, β-sitosterolCCL appears to be a novel inhibitor of LdTryR and might represent a successful approach for treatment of VL in the future.


Heart failure patients' descriptions of participation in structured home care.
To strengthen the patient's position in health care, patient participation has been decreed in policy documents and legalizations. For patients suffering from heart failure, self-care is an important part of disease management and participation is crucial to succeed with this. To examine how heart failure patients receiving structured home care described participation in the care. Qualitative study. Thirteen men and six women, aged between 63 and 90 years, were interviewed. The informants received structured home care at four home care units in Sweden. The interviews were analysed using qualitative content analysis. Five categories with associated subcategories describing participation in care were identified: communication between patients and health-care professionals (HCPs) including time and space for dialogue and exchange of care-related information, accessibility to care through awareness of the plan for home visits or feasibility to initiate home visits, active involvement in care by engaging in self-care and collaboration with HCPs, trustful relation with HCPs, with confidence in competence and individually adapted care, options for decision making, by making decisions or entrusting decisions. Patient participation could be strengthened through structured home care. Participation was facilitated when there was a balance between the patient's own preferences to influence care and the health-care professional's actions and values and the organization of care. Barriers to participation could depend on the health-care organization, lack of continuity and confidence in HCPs.


The Arabidopsis NLP7-HB52/54-VAR2 pathway modulates energy utilization in diverse light and nitrogen conditions.
In plants, nitrate is the dominant nitrogen (N) source and a critical nutrient signal regulating various physiological and developmental processes.1,2,3,4 Nitrate-responsive gene regulatory networks are widely believed to control growth, development, and life cycle in addition to N acquisition and utilization,1,2,3,4 and NIN-LIKE PROTEIN (NLP) transcriptional activators have been identified as the master regulators governing the networks.5,6,7 However, it remains to be elucidated how nitrate signaling regulates respective physiological and developmental processes. Here, we have identified a new nitrate-activated transcriptional cascade involved in chloroplast development and the maintenance of chloroplast function in Arabidopsis. This cascade consisting of NLP7 and two homeodomain-leucine zipper (HD-Zip) class I transcription factors, HOMEOBOX PROTEIN52 (HB52) and HB54,8,9 was responsible for nitrate- and light-dependent expression of VAR2 encoding the FtsH2 subunit of the chloroplast FtsH protease involved in the quality control of photodamaged thylakoid membrane proteins.10,11 Consistently, the nitrate-activated NLP7-HB52/54-VAR2 pathway underpinned photosynthetic light energy utilization, especially in high light environments. Furthermore, genetically enhancing the NLP7-HB52/54-VAR2 pathway resulted in improved light energy utilization under high light and low N conditions, a superior agronomic trait. These findings shed light on a new role of nitrate signaling and a novel mechanism for integrating information on N nutrient and light environments, providing a hint for enhancing the light energy utilization of plants in low N environments.


Danish singles have a twofold risk of acute coronary syndrome: data from a cohort of 138 290 persons.
Atherosclerosis of the coronary and other arteries is an important health problem in virtually all countries of the world, and thus there is a persisting need for the development of preventive programmes including population risk group identification. The aim of the study was to identify sociodemographic population risk indicators of an initial episode of acute coronary syndrome (ACS), including unstable angina pectoris (UAP), myocardial infarction (MI), and sudden cardiac death (SCD). Cohort study of 138 290 residents of the municipality of Aarhus, Denmark, aged 30-69 years. Information on population members' individual age, sex, social background, and eventual death was obtained from Danish Population Registers. University hospital. The study prospectively identified 646 victims of ACS from 1 April 2000 to 31 March 2002. Based on multiple logistic regression, age and single living were found to be positively associated with incident ACS in both sexes. Women >60 years living alone and men >50 years living alone were at especially high risk. They constituted only 5.4% and 7.7% of the source population, respectively, but they accounted for 34.3% and 62.4% of ACS patients dying within 30 days. Single living is associated with an increased risk of ACS. Thus, risk groups identified by use of information on their age and family structure may be targets for future more focused and cost effective preventive strategies. In Western populations, such high risk groups will constitute comparatively limited parts of the population, and in Denmark they are easily identifiable in routine population registers.


Simultaneous determination of reducing monosaccharides by capillary zone electrophoresis as the borate complexes of N-2-pyridylglycamines.
Reducing monosaccharides were derivatized to N-2-pyridylglycamines and separated as their borate complexes by capillary zone electrophoresis, using a capillary tube (50 microns i.d., 65 cm) of fused silica containing 200 mM borate buffer (pH 10.5) as carrier. The derivatives of 12 saccharides were completely separated in ca. 25 min, with high resolution, at an applied potential of 15 kV. On-column uv monitoring allowed detection of these derivatives at the 10-pmol level, and quantification by the relative peak area method allowed reproducible determination of these saccharides at least in the concentration range of 10-100 mM in reaction solutions. This method was applied to the determination of the monosaccharide compositions of various carbohydrate materials to demonstrate its usefulness.


Covalent anionic copolymer coatings with tunable electroosmotic flow for optimization of capillary electrophoretic separations.
We present a method for finely adjustable electroosmotic flow (EOF) velocity in cathodic direction for the optimization of separations in capillary electrophoresis. To this end, we use surface modification of the separation fused silica capillary by the covalently attached copolymer of acrylamide (AM) and 2-acrylamido-2-methyl-1-propanesulfonate (AMPS), that is, poly(AM-co-AMPS) or PAMAMPS. Coatings were formed by the in-capillary polymerization of a mixture of the neutral AM and anionic AMPS monomers premixed in various ratios in order to control the charge density of the copolymer. EOF mobility varies in the 0 to ∼40 × 10-9 m2 V-1 s-1 interval for PAMAMPS coatings ranging from 0 to 60 mol.% of charged AMPS monomer. For EOF in PAMAMPS-treated capillaries, we observed (i) a negligible dependence on pH in the 2-10 interval, (ii) a minor variance among background electrolytes (BGEs) in function of their components and (iii) its standard decrease with increasing ionic strength of the BGE. Interest in variable cathodic EOF was demonstrated by the amelioration of separation of two kinds of isomeric anionic analytes, that is, monosaccharides phosphates and helquat enantiomers, in counter-EOF mode.


The influence of KRAS and BRAF mutations on the efficacy of cetuximab-based first-line therapy of metastatic colorectal cancer: an analysis of the AIO KRK-0104-trial.
Our study investigated the impact of specific KRAS mutations and BRAF mutation on progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated within the AIO KRK-0104-trial as first-line therapy. In total, 146 (of 185) patients were included in this analysis. Seventy-nine patients presented with KRAS/BRAF wild-type (wt), 41 patients with a KRAS codon 12 and nine patients with a KRAS codon 13 mutation. Seventeen patients presented a BRAF-mutated tumor. The patients of our study were treated with CAPIRI/CAPOX plus cetuximab. Major differences regarding PFS and OS were observed depending on the mutation of the tumor. PFS was 8 months in patients with wt-tumors, 5.8 months with codon 12-mutated, 9.9 months with codon 13-mutated and 4.2 months with BRAF-mutated tumors. OS was 23.5 months in patients with wt-tumors, 18.9 months with codon 12-mutated, 26.2 months with codon 13-mutated and 13.0 months with BRAF-mutated tumors. Although the conventional separation of patients with KRAS wild-type versus KRAS mutant tumors did not have a significant impact on outcome parameters in the AIO KRK 0104-trial, this analysis demonstrates that markedly differing results are obtained when subtypes of KRAS and BRAF mutation are taken into account.


Cigarette smoking and smoking cessation in relation to risk of rheumatoid arthritis in women.
Whereas the overall association between smoking and rheumatoid arthritis (RA) must be regarded as established, considerably less is known about how much smoking is needed to increase the risk of RA, that is, the effect of smoking intensity, duration and cessation. The Swedish Mammography Cohort, including 34,101 women aged 54 to 89 years, was followed up from January 1, 2003 through December 31, 2010 (219 RA cases identified). Relative risks (RR) and their 95% confidence intervals (CI) were estimated as rate ratios using Cox proportional hazards model. There was a statistically significant association between smoking intensity (RR comparing 1 to 7 cigarettes/day vs never smoking 2.31 (95% CI: 1.59, 3.36)) as well as duration of smoking (comparing 1 to 25 years vs never smoking RR = 1.60 (95% CI: 1.07, 2.38)) and risk of RA. Compared to never smokers, the risk was still significantly elevated 15 years after smoking cessation (RR = 1.99 (95% CI: 1.23, 3.20)). However, among former smokers, the risk of RA seemed to be decreasing over time since stopping smoking: women who stopped smoking 15 years before the start of the follow-up had 30% lower risk of RA compared to those who stopped only a year before start of the follow-up (RR = 0.70 (95% CI: 0.24,2.02)). This prospective study highlights that even light cigarette smoking is associated with increased risk of RA in women and that smoking cessation may reduce, though not remove, this risk.


Interactions between beta2-adrenoreceptor agonist and NO donors in the relaxation of guinea pig trachea in vitro.
The effects of interaction between the beta2-adrenoreceptor agonist, salbutamol, and the nitric oxide donors, sodium nitroprusside and 3-morpholinosydnonimine (SIN-1), on guinea pig trachea contraction were studied. Cumulatively increased concentrations (0.1-10 nM) of salbutamol together with a single concentration of SNP (0.33 microM) or with SIN-1 (1 microM) showed significant (p < 0.001) synergy for the inhibition of 1 microM metacholine-induced contraction. Significant synergy (p < 0.05) was also found for the inhibition of this contraction by cumulatively increased concentrations (0.1-33 microM) of SNP and a single concentration (1 nM) of salbutamol. No synergistic effect was found on the 40 mM KC1-induced contraction. We suggest that the combination of NO donors with salbutamol has a synergistic effect on metacholine contraction.


The implications of cognitive psychology for computer-assisted instruction.
An information processing model is used to describe the learning process. The implications of some of these cognitive concepts are examined in the context of computer-assisted instruction.


Surgical treatment of unruptured cerebral aneurysms in the elderly.
We retrospectively analyzed the prevalence and surgical outcomes of unruptured cerebral aneurysms in the elderly for the past five years. Between 1998 and 2002, we collected data from 575 subjects with unruptured aneurysms who had no history of subarachnoid hemorrhage (SAH). One hundred and eighty-two of these patients (31.7%) were aged > or = 70 years and they had 233 aneurysms. The proportion of older patients among all subjects increased significantly from 21.4% in 1998 to 40.3% in 2002. Unruptured aneurysms found in the elderly had a predominance of female, higher frequency of multiple aneurysms, and lower frequency of anterior communicating artery aneurysms when compared with those in the younger patients. The majority of intradural aneurysms detected in the elderly were less than 10 mm in diameter (84.8%). One hundred and eleven out of 224 intradural aneurysms in the elderly were treated (49.6%); most aneurysms were directly clipped, while only 13 aneurysms including six basilar artery aneurysms were coiled endovascularly. Among the 83 elderly subjects who underwent direct surgery, perioperative complication appeared in seven subjects (morbidity 8.4%, mortality 1.2%). No SAH occurred postoperatively and conservatively during 1-5 years of follow-up. Since the rupture rate of small unruptured aneurysms without SAH history is reported to be low, surgical indication should be considered with care particularly in the elderly.


Review of evolution of the public long-term care insurance (LTCI) system in different countries: influence and challenge.
The growing demand for LTC (Long-term care) services for disabled elderly has become a daunting task for countries worldwide, especially China, where population aging is particularly severe. According to CSY (China Statistical Yearbook,2019), the elderly aged 65 or above has reached 167 million in 2018, and the number of disabled elderly is as high as 54%. Germany and other countries have alleviated the crisis by promoting the public LTCI (Long-Term Care Insurance) system since the 1990s, while China's public LTCI system formal pilot only started in 2016. Therefore, the development of the public LTCI system has gradually become a hot topic for scholars in various countries, including China. This review has been systematically sorted the existing related literature to discuss the development of public LTCI (Long-Term Care Insurance)system form four aspects, namely, the comparison of public LTCI systems in different countries, the influence of public LTCI, challenge of public LTCI, and the relationship between public LTCI and private LTCI. We searched some databases including Web of Science Core Collection, Medline, SCOPUS, EBSCO, EMBASE, ProQuest and PubMed from January 2008 to September 2020. The quality of 38 quantitative and 21 qualitative articles was evaluated using the CASP(Critical Appraisal Skills Programme) critical evaluation checklist. The review systematically examines the development of public LTCI system from four aspects, namely, the comparison of public LTCI systems in different countries, the influence of public LTCI, the challenge of public LTCI, and the relationship between public LTCI and private LTCI. For example, LTCI has a positive effect on the health and life quality of the disabled elderly. However, the role of LTCI in alleviating the financial burden on families with the disabled elderly may be limited. Some policy implications on the future development of China's LTCI system can be obtained. For example, the government should fully consider the constraints such as price rise, the elderly disability rate, and the substantial economic burden. It also can strengthen the effective combination of public LTCI and private LTCI. It does not only help to expand the space for its theoretical research but also to learn the experiences in the practice of the LTCI system in various countries around the world. It will significantly help the smooth development and further promote the in-depth reform of the LTCI system in China.


Understanding changing public transit travel patterns of urban visitors during COVID-19: A multi-stage study.
COVID-19 has caused huge disruptions to urban travel and mobility. As a critical transportation mode in cities, public transit was hit hardest. In this study, we analyze public transit usage of urban visitors with a nearly two-year smart card dataset collected in Jeju, South Korea - a major tourism city in the Asia Pacific. The dataset captures transit usage behavior of millions of domestic visitors who traveled to Jeju between January 1, 2019 and September 30, 2020. By identifying a few key pandemic stages based on COVID-19 timeline, we employ ridge regression models to investigate the impact of pandemic severity on transit ridership. We then derive a set of mobility indicators - from perspectives of trip frequency, spatial diversity, and travel range - to quantify how individual visitors used the transit system during their stay in Jeju. By further employing time series decomposition, we extract the trend component for each mobility indicator to study long-term dynamics of visitors' mobility behavior. According to the regression analysis, the pandemic had a dampening effect on public transit ridership. The overall ridership was jointly affected by national and local pandemic situations. The time series decomposition result reveals a long-term decay of individual transit usage, hinting that visitors in Jeju tended to use the transit system more conservatively as the pandemic endured. The study provides critical insights into urban visitors' transit usage behavior during the pandemic and sheds light on how to restore tourism, public transit usage, and overall urban vibrancy with some policy suggestions.


Transcription factors GATA/ELT-2 and forkhead/HNF-3/PHA-4 regulate the tropomyosin gene expression in the pharynx and intestine of Caenorhabditis elegans.
Gene regulation during development is an important biological activity that leads to synthesis of biomolecules at specific locations and specific times. The single tropomyosin gene of Caenorhabditis elegans, tmy-1/lev-11, produces four isoforms of protein: two from the external promoter and two from the internal promoter. We investigated the internal promoter of tropomyosin to identify sequences that regulate expression of tmy-1 in the pharynx and intestine. By promoter deletion of tmy-1 reporters as well as by database analyses, a 100-bp fragment that contained binding sequences for a GATA factor, for a chicken CdxA homolog, and for a forkhead factor was identified. Both the forkhead and CdxA binding sequences contributed to pharyngeal and intestinal expression. In addition, the GATA site also influenced intestinal expression of tmy-1 reporter. We showed that ELT-2 and PHA-4 proteins interact directly with the GATA and forkhead binding sequences, respectively, in gel mobility shift assays. RNA interference knockdown of elt-2 diminished tmy-1::gfp expression in the intestine. In contrast to RNA interference knockdown of pha-4, expression of tmy-1::gfp in pha-4;smg-1 mutants was slightly weaker than that of the wild type. Ectopic expression of PHA-4 and ELT-2 by heat shock was sufficient to elicit widespread expression of tmy-1::lacZ reporter in embryos. We found no indication of a synergistic relation between ELT-2 and PHA-4. Based on our data, PHA-4 and CdxA function as general transcription factors for pharyngeal and intestinal regulation of tmy-1. We present models by which ELT-2, PHA-4, and CdxA orchestrate expression from the internal promoter of tmy-1.


Secular stability and reliability of measurements of the percentage of dense tissue on mammograms.
Elevated mammographic density is associated with increased risk of breast cancer. We conducted a reliability study on mammographic density assessments to determine their potential usefulness for projecting individual breast cancer risk. We used baseline screening mammograms from 7251 women in the Breast Cancer Detection Demonstration Project (BCDDP). Repeated measurements from the same images were used to assess measurement variability by an experienced evaluator. Intraclass correlations of assessments over time usually exceeded 0.9, indicating usefulness for prospective applications. Data also indicated it may be reasonable to include cases identified in the first year of screening together with other cases in developing a risk model. Older ages and increased weight were associated with decreased mammographic density. The density of the right breast slightly exceeded that of the left. Among women who developed breast cancer, the baseline mammographic density of the ipsilateral (diseased) breast was 0.53 (95% confidence interval (CI) 0.20-0.86) percentage units higher than in the contralateral breast.


Progressive Dysregulation of Tau Phosphorylation in an Animal Model of Temporal Lobe Epilepsy.
Tau is an intracellular protein known to undergo hyperphosphorylation and subsequent neuro-toxic aggregation in Alzheimer's disease (AD). Here, tau expression and phosphorylation at three canonical loci known to be hyperphosphorylated in AD (S202/T205, T181, and T231) were studied in the rat pilocarpine status epilepticus (SE) model of temporal lobe epilepsy (TLE). We measured tau expression at two time points of chronic epilepsy: two months and four months post-SE. Both time points parallel human TLE of at least several years. In the whole hippocampal formation at two months post-SE, we observed modestly reduced total tau levels compared to naïve controls, but no significant reduction in S202/T205 phosphorylation levels. In the whole hippocampal formation from four month post-SE rats, total tau expression had reverted to normal, but there was a significant reduction in S202/T205 tau phosphorylation levels that was also seen in CA1 and CA3. No change in phosphorylation was seen at the T181 and T231 tau loci. In somatosensory cortex, outside of the seizure onset zone, no changes in tau expression or phosphorylation were seen at the later time point. We conclude that total tau expression and phosphorylation in an animal model of TLE do not show hyperphosphorylation at the three AD canonical tau loci. Instead, the S202/T205 locus showed progressive dephosphorylation. This suggests that changes in tau expression may play a different role in epilepsy than in AD. Further study is needed to understand how these changes in tau may impact neuronal excitability in chronic epilepsy.


Cancer-on-a-Chip: Models for Studying Metastasis.
The microfluidic-based cancer-on-a-chip models work as a powerful tool to study the tumor microenvironment and its role in metastasis. The models recapitulate and systematically simplify the in vitro tumor microenvironment. This enables the study of a metastatic process in unprecedented detail. This review examines the development of cancer-on-a-chip microfluidic platforms at the invasion/intravasation, extravasation, and angiogenesis steps over the last three years. The on-chip modeling of mechanical cues involved in the metastasis cascade are also discussed. Finally, the popular design of microfluidic chip models for each step are discussed along with the challenges and perspectives of cancer-on-a-chip models.


Control of developmental timing by small temporal RNAs: a paradigm for RNA-mediated regulation of gene expression.
Heterochronic genes control the timing of developmental programs. In C. elegans, two key genes in the heterochronic pathway, lin-4 and let-7, encode small temporally expressed RNAs (stRNAs) that are not translated into protein. These stRNAs exert negative post-transcriptional regulation by binding to complementary sequences in the 3' untranslated regions of their target genes. stRNAs are transcribed as longer precursor RNAs that are processed by the RNase Dicer/DCR-1 and members of the RDE-1/AGO1 family of proteins, which are better known for their roles in RNA interference (RNAi). However, stRNA function appears unrelated to RNAi. Both sequence and temporal regulation of let-7 stRNA is conserved in other animal species suggesting that this is an evolutionarily ancient gene. Indeed, C. elegans, Drosophila and humans encode at least 86 other RNAs with similar structural features to lin-4 and let-7. We postulate that other small non-coding RNAs may function as stRNAs to control temporal identity during development in C. elegans and other organisms.


In vitro and in vivo anti-tumor activity of recombinant mouse tumor necrosis factor (TNF) in a mouse bladder tumor (MBT-2).
Tumor necrosis factor (TNF) has confirmed anti-tumor activity. When used in combination with interferon gamma (IFNG) or chemotherapeutic drugs targeted at DNA topoisomerase II, synergistic cytotoxicity has been observed. Investigations of the anti-tumor activity of recombinant mouse TNF in a mouse bladder tumor model (MBT-2) were performed. The cytotoxicity of TNF and low dose actinomycin-D (AMD) against MBT-2 in vitro was examined alone and following preincubation with IFNG. The activity of TNF/AMD in vivo utilizing an intravesical implantation mode (MBT-2) was also evaluated. TNF alone had no cytotoxic effect in vitro. TNF/AMD was cytotoxic for MBT-2 growth in vitro. Maximum cytotoxicity (86%) occurred at one microgram./ml. TNF/one microgram./ml. AMD with 50% cytotoxicity at .64 micrograms./ml. TNF/one/microgram./ml. AMD. A two hour preincubation with IFNG markedly increased the cytotoxicity of TNF/AMD whereas longer incubations did not enhance cytotoxic activity. TNF alone and in combination with AMD did not significantly reduce the percentage of intravesical tumor outgrowth in vivo compared to controls. This study demonstrated that TNF/AMD exhibits cytotoxicity for MBT-2 cells in vitro but is ineffective in reducing implantation of intravesical tumors in vivo. The in vitro data suggest brief exposure of MBT-2 cells to IFNG augments the subsequent anti-tumor activity of TNF/AMD.


Rapid and sensitive detection of Mycoplasma hyopneumoniae by recombinase polymerase amplification assay.
Mycoplasma hyopneumoniae is the etiological agent of swine enzootic pneumonia, which is associated with high economic losses in swine production worldwide. In this study, recombinase polymerase amplification assays using real-time fluorescence detection (real-time RPA) and lateral flow strip detection (LFS RPA) were developed to detect M. hyopneumoniae based on the conserved region of the mhp165 gene. Real-time RPA was performed in Genie III at 39 °C for 20 min, while the LFS RPA was performed in an incubator block at 39 °C for 15 min, and the products were visible on the LFS inspected by the naked eyes within 2 min. Both assays were specific for M. hyopneumoniae, as there were no cross-reactions with other pathogens tested. The limit of detection of both RPA assay was 5.0 × 102 fg of M. hyopneumoniae DNA, which was the same as that of a real-time PCR assay. Of the 146 clinical samples, M. hyopneumoniae DNA was identified in 41, 42, and 47 samples by the real-time RPA, LFS RPA and real-time PCR, respectively. Compared to real-time PCR, the real-time RPA and LFS RPA assays showed diagnostic specificity of 100%, a diagnostic sensitivity of 87.23% and 89.36%, and a kappa value of 0.903 and 0.909, respectively. These results have demonstrated that the developed RPA assays are suitable for rapid and reliable detection of M. hyopneumoniae in diagnostic laboratory and at point-of-need facility.


Bioavailability of trace metals to aquatic organisms--a review.
The physiological characteristics of the environmental interface of organisms determine the metal forms of highest bioavailability. Studies of metal uptake from solution by aquatic organisms verify the high availability of free metal ions. Metals also are accumulated from food by many aquatic organisms, as indicated by both laboratory and field studies. The quantitative importance of the food vector depends upon biological availability, which differs with the specific type of food being ingested. Uptake from both food and solute vectors may be influenced by interactions among cations, pH, redox, temperature and physiological variables. Separating their relative importance through a basic understanding of these processes will be a necessary prerequisite to understanding metal impacts in natural systems.


Twenty cases of persistent sore nipples: collaboration between lactation consultant and dermatologist.
The nipple and surrounding area, like other areas of skin, are subject to irritation, inflammation, and infection. Twenty women with persistent sore nipples were first seen by a lactation consultant and later referred to a dermatologist. The dermatologist successfully treated 18 of the 20 mothers. A lactation consultant should be able to identify those women who will benefit from evaluation and treatment by a dermatologist.


Long-term experience of general ultrasound screening in pregnancy.
Since January 1, 1974, 43,000 routine ultrasound examinations have been performed on 22,400 pregnant women in the Department of Obstetrics and Gynecology, Malmö General Hospital. At the present time, one examination is performed in the seventeenth week of pregnancy and one in thirty-third week. At the first examination, the number of fetuses, fetal anatomy, cardiac activity, and placental site are indicated. Fetometry is performed. Gestational age is adjusted according to the value of the biparietal diameter. The second ultrasound examination is aimed at detecting fetal growth deviations and malformations. In 15% of all pregnancies, ultrasound corrected gestational age by more than 14 days. Ultrasound appeared to be superior to the clinical assessment in 88% of these discrepant pregnancies in predicting date of delivery. The early examination detected 98% of the twin pregnancies, with no false positive results. If an ultrasound examination had been performed within 3 weeks of delivery, 92% of the fetuses with growth retardation were detected. Altogether, the program detected 60% of the growth-retarded fetuses. In 0.4% of the examinations, malformations were detected (0.6% during the last 2 years). A cost-benefit analysis suggested that large economical gains are to be realized by screening. However, organizational and educational problems must be properly solved before general screening is offered to a healthy pregnant population.


[Adjuvant radiotherapy after radical cystectomy for muscle-invasive bladder cancer].
Locoregional relapse (LRR) after cystectomy is a common early event associated with poor prognosis. The role of radiotherapy as an adjunct to radical cystectomy is not well-defined. The aim of this critical literature review is to provide an overview of the elements in favor of adjuvant radiation for patients treated for muscle-invasive bladder cancer. An exhaustive review of the literature was carried out using the Pubmed search tool with the following keywords: "radiotherapy" [Mesh], "adjuvant" [Mesh], "local recurrence" [Mesh], "Bladder cancer" [Mesh]. Several recent publications have led to the development of a nomogram that predicts the risk of LRR, in order to identify patients for which adjuvant radiotherapy could be beneficial. Several randomized trials seem to suggest a benefit of radiotherapy, in particular when combined with chemotherapy, in terms of reducing LRR, and may even improve overall survival, with good safety profile. However, there are many biases and the interest of adjuvant radiotherapy in urothelial carcinomas remains debated. Prospective trials evaluating adjuvant radiotherapy with current techniques should be undertaken.


Flexion and extension laxity after medial, mobile-bearing unicompartmental knee arthroplasty: a comparison between a spacer- and a tension-guided technique.
In a mobile-bearing unicompartmental knee arthroplasty (UKA), stability is of utmost importance to promote knee function and to prevent dislocation of the insert. Gap balancing can be guided by the use of spacers or a tensioner. The goal of this study is to compare laxity of a tension-guided implantation technique versus a spacer-guided technique for medial UKA with a mobile bearing. Also clinical function was compared between the groups. The tension-guided UKA system (BalanSys™, Mathys Ltd, Bettlach, Switzerland) was compared with a retrospective group with a spacer-guided system (Oxford, Biomet Ltd, Bridgend, UK). A total of 30 tension-guided medial UKAs were implanted and compared with 35 spacer-guided medial prostheses. In both groups, valgus laxity was measured at least 4 months postoperatively in extension and 70° flexion using stress radiographs. Knee Society Scores (KSS) were obtained at the 6-month follow-up. Valgus laxity in flexion was significantly higher in the tension-guided group compared with the spacer-guided group: 3.9° (SD 1.8°) versus 2.4° (SD 1.2°), respectively, P < 0.001). In extension, valgus laxity was significantly different: 1.8° (SD 1.0°) in the tension-guided group compared with 2.7° (SD 0.9°) in the spacer-guided group (P < 0.001). There was no significant difference between the KSS for the two groups (n.s.). The tensor-guided system resulted in significantly more valgus laxity in flexion compared with the spacer-guided system. However, in extension, the situation was reversed: the tension-guided system resulted in less valgus laxity than the spacer-guided system. Clinically, there were no differences between the groups. The valgus laxity found with the spacer-guided system better approximates the valgus laxity values of the healthy elderly.


Retraction: Influencing factors of early cognitive deficits after ambulatory anesthesia.
[This retracts the article on p. 123 in vol. 15, PMID: 34188628.].


Revealing novel synergistic defense and acid tolerant performance of Escherichia coli in response to organic acid stimulation.
Escherichia coli is an important producer of mono- and di-acids, such as D-lactic acid, itaconic acid, and succinic acid. However, E. coli has limited acid tolerance and requires neutralizers in large-scale fermentation, which leads to increased production costs. Mutagenesis breeding has been shown to be inefficient in improving the acid tolerance of strains. Therefore, it is crucial to analyze the acid resistance mechanism of E. coli. To this end, important regulatory genes and metabolic pathways in the highly evolved acid-resistant E. coli were identified based on transcriptome sequencing. By analyzing the overlap of the genes with significantly different expression levels in the four groups, a synergistic membrane-centric defense mechanism for E. coli against organic acid stress was identified. The mechanism includes four modules: signal perception, energy countermeasures, input conditioning, and envelope reinforcement. In addition, genes related to the ABC transporter pathway, polyketide metabolism, pyrimidine metabolism, and dual-arginine translocation system pathways were found for the first time to be potentially resistant to organic acid stress after overexpression. A new antacid ingredient, RffG, increases the survival rate of E. coli by 4509.6 times. This study provides new clues for improving the performance of acid-tolerant cells and reducing the production cost of industrial organic acid fermentation. KEY POINTS: • Systematic analysis of the mechanism of membrane protein partitioning in E. coli to resist organic acids • TAT system transports correctly folded hydrogenase accessory proteins to resist D-lactic acid stress • Enhanced PG synthesis and weakened hydrolysis to reduce acid penetration into cells • Overexpression of RffG in the polyketide synthesis pathway enhances acid tolerance.


Is growth hormone a feasible adjuvant in the treatment of children after small bowel resection?
The aim of our study was to assess the metabolic consequences of short-term administration of growth hormone in children after gut resection and influence on polyamine production in red blood cells (RBC). Twelve children aged 4-60 months were studied. All children remained on parenteral nutrition and 11 also received oral feeding. Total non-protein energy intake was 429 +/- 86 kJ/kg body weight (BW)/day. Recombinant growth hormone (GH) was administered subcutaneously at a dose of 0.3 IU/kg BW/day for 10 days. Resting energy expenditure (REE; kJ/kg BW/day) was: 316.07 +/- 54.08 before and 346.04 +/- 54.40 during GH administration (P < 0.02), but daily weight gain before GH administration was significantly lower than during treatment. A significant increase of polyamine concentrations was observed in the RBC (spermidine: 30.1 +/- 15.1 and 43.8 +/- 24.9 nmol/ml packed RBC, P < 0.003; spermine: 15.6 +/- 5.1 and 19.6 +/- 10.6 nmol/ml packed RBC, P < 0.02) and in jejunal mucosa (spermidine: 172.10 +/- 142.35 nmol/g tissue and 193.92 +/- 108.15 nmol/g tissue). The authors concluded that increased polyamine concentrations in the RBC and jejunal mucosa reflect a cellular response to GH administration. The anabolic effect of GH results in higher weight gain, although increased REE may indicate increased energy requirements during GH treatment.


Molecular cloning of a chloride channel that is regulated by dehydration and expressed predominantly in kidney medulla.
Complementary DNA encoding a rat kidney chloride channel (CIC-K1) was isolated by a polymerase chain reaction (PCR) cloning strategy. We designed degenerate primers, based on the regions where previously cloned chloride channels (CIC-0, -1, and -2) possess significant amino acid identity, and performed reverse transcription PCR with whole kidney mRNA. The 686-amino acid protein encoded by CIC-K1 is about 40% identical to the previously cloned chloride channels and has a similar hydropathy profile. Expression of CIC-K1 in Xenopus oocytes induced Cl- currents that activate instantaneously upon hyperpolarization and depolarization, and displayed a slightly outwardly rectifying current-voltage relationship. The message for CIC-K1 was 2.4 kilobases and was found predominantly in kidney, especially in the inner medulla. Reverse transcription PCR technique using micro-dissected nephron segments revealed that the main site of expression in kidney was the thin ascending limb of Henle's loop, which has the highest Cl- permeability among the nephron segments and is thought to be involved in a counter-current system for urine concentration in the inner medulla. The abundance of CIC-K1 mRNA in kidney increased about 4-fold as rats became dehydrated by deprivation of water for 5 days. The site of expression and the regulation by dehydration suggest that CIC-K1 function may be important in urinary concentrating mechanisms.


Mic10, a Core Subunit of the Mitochondrial Contact Site and Cristae Organizing System, Interacts with the Dimeric F1Fo-ATP Synthase.
The mitochondrial contact site and cristae organizing system (MICOS) is crucial for maintaining the architecture of the mitochondrial inner membrane. MICOS is enriched at crista junctions that connect the two inner membrane domains: inner boundary membrane and cristae membrane. MICOS promotes the formation of crista junctions, whereas the oligomeric F1Fo-ATP synthase is crucial for shaping cristae rims, indicating antagonistic functions of these machineries in organizing inner membrane architecture. We report that the MICOS core subunit Mic10, but not Mic60, binds to the F1Fo-ATP synthase. Mic10 selectively associates with the dimeric form of the ATP synthase and supports the formation of ATP synthase oligomers. Our results suggest that Mic10 plays a dual role in mitochondrial inner membrane architecture. In addition to its central function in sculpting crista junctions, a fraction of Mic10 molecules interact with the cristae rim-forming F1Fo-ATP synthase.


Hip-shelf procedure in the treatment of osteonecrosis of the transpositioned acetabulum after rotational acetabular osteotomy.
Necrosis of the transpositioned acetabulum after rotational acetabular osteotomy (RAO) is a major complication characteristic of this procedure. This complication, although rare, has been thought difficult to treat. We report a patient with acetabular osteonecrosis and subsequent collapse after RAO that was effectively treated with a shelf operation, providing satisfactory remodeling of the hip joint. A 16-year-old female had undergone RAO for the treatment of developmental acetabular dysplasia. Postoperative radiography showed that the osteotomized acetabular fragment was unusually thin, and that the osteotome entered the hip joint during the surgery. Five months after the RAO, X-rays revealed significant collapse of the transpositioned acetabulum, and femoral head subluxation caused by postoperative osteonecrosis. Seven months after the RAO, the patient underwent a hip-shelf procedure. The remaining acetabular fragment was used in this procedure, according to the Spitzy method. Seven years after the second operation, favorable remodeling of the hip joint was observed; however, early osteoarthritic changes, including slight joint space narrowing, bone sclerosis of the new acetabulum, and bone cysts within the femoral head, were seen.


Effects of seed aerosols on the growth of secondary organic aerosols from the photooxidation of toluene.
Hydroxyl radical (.OH)-initiated photooxidation reaction of toluene was carried out in a self-made smog chamber. Four individual seed aerosols such as ammonium sulfate, ammonium nitrate, sodium silicate and calcium chloride, were introduced into the chamber to assess their influence on the growth of secondary organic aerosols (SOA). It was found that the low concentration of seed aerosols might lead to high concentration of SOA particles. Seed aerosols would promote rates of SOA formation at the start of the reaction and inhibit its formation rate with prolonging the reaction time. In the case of ca. 9000 pt/cm3 seed aerosol load, the addition of sodium silicate induced a same effect on the SOA formation as ammonium nitrate. The influence of the four individual seed aerosols on the generation of SOA decreased in the order of calcium chloride>sodium silicate and ammonium nitrate>ammonium sulfate.


Prolactin and ergocryptine effects on mucus glycoproteins of the rat ileum.
The present work reports observations from a first study on the effect of prolactin on mucous cells of the mammalian ileum. Sprague-Dawley rats were treated with prolactin or with the prolactin-inhibitor ergocryptine. Light microscopic histochemical study revealed that ergocryptine increased the number both of Alcian Blue-positive mucous cells and of the total number of mucous cells in the ileal crypts. Prolactin treatment apparently decreased the number of Alcian Blue pH 1.0-positive (sulphated glycoprotein-containing) mucous cells on the villi but was without effect on crypt cells. The implications of these observations are discussed.


A prospective study of Epstein-Barr virus load in 85 hematopoietic stem cell transplants.
EBV viral load (EBV-VL) in PBMC was prospectively determined by semi-quantitative PCR in 85 stem cell transplants (40 genoidentical, 45 non-genoidentical) in order to characterize the kinetics of EBV-VL and to assess the ability of this measure to predict the development of EBV-induced lymphoproliferative disease (EBV-LPD). PCR was performed prior to and after transplantation. An EBV-VL >300 copies/microg DNA was chosen as the threshold for risk of developing an EBV-LPD. Two hundred and fifty-eight EBV-VL measures were evaluable. Five patients (5.9%) developed an EBV-LPD. All had an elevated EBV DNA peak level before EBV-LPD. Fifteen out of 80 recipients (18.7%) without EBV-LPD had EBV levels over 300 copies/microg DNA at least once during the follow-up. Overall, the manifestation of at least one EBV-VL over 300 copies/microg DNA during the entire follow-up demonstrated a sensitivity, specificity, positive and negative predictive value for the diagnosis of EBV-LPD of 100%, 81%, 25% and 100%, respectively. In patients without EBV-LPD, HLA incompatibility, grade > or = II acute GVHD and use of an unmanipulated graft were significantly associated with an EBV-VL >300 copies/microg DNA. This strategy appears sensitive for the diagnosis of EBV-LPD but its positive predictive value has to be improved in order to guide pre-emptive therapy.


Morphological study of surgically induced open neural tube defect in old (14 and 21 days) chick embryos.
As an experimental model for the research of open neural tube defect (NTD), the surgical model has several advantages over others, in spite of the fact that the pathogenetic mechanism is not compatible with the human intrauterine events. To make reproducible NTDs by surgery and to compare the surgically induced lesions with the human myeloschisis morphologically, we opened the neural tube for a length of 9-11 somites in Hamburger and Hamilton stage 16-19 chick embryos. Embryos which survived until the late in ovo life (total age 14 and 21 days) showed relatively reproducible open NTDs. Morphologically they are similar to human myeloschisis. This study suggests that the surgical model can be suitable for studies of open NTDs.


Does the Incidence of Treatment-Related Toxicity Plateau After Radiation Therapy: The Long-Term Impact of Integral Dose in Hodgkin's Lymphoma Survivors.
Conventional radiation therapy (RT) has produced unprecedented cure rates in patients with Hodgkin's lymphoma (HL) but exposed large volumes of nontargeted tissue to radiation (integral dose). Our goal was to report the effects of integral radiation dose on health outcomes in patients with at least 20 years of potential follow-up time. We reviewed the medical records of 365 patients who were treated with RT for HL between 1965 and 1995. All patients were confirmed to have received primary RT with curative intent at our institution for de novo HL. Serious adverse events were classified as HL progression or death, grade ≥3 treatment- or staging-related acute or late effects, second malignancies, or cardiovascular events. The minimum potential follow-up time was 20 years, and the actual median follow-up time 22 years (range, <1-49 years) for all patients and 27 years (range, 5-49 years) for surviving patients. The overall survival rates at 5, 10, 20, 30, and 40 years were 86%, 76%, 64%, 44%, and 27%, respectively. The observed-to-expected ratio for second malignancy was 3.6 (95% confidence interval, 2.9-4.4). Grade ≥3 cardiovascular events occurred in 31% of all patients (n = 112). At the time of the most recent follow up, serious adverse events occurred in 70% of the entire cohort (n = 256) and 58% (n = 103), 77% (n = 103), and 93% (n = 50) among those with a potential 20, 30, and 40 years of follow up, respectively. With increased survivorship, the long-term impact of the integral radiation dose may result in clinically significant adverse events, which suggests the importance of surveillance and affirms advances in both chemotherapy and RT that minimize the integral dose in future patients with HL.


Unconventional Myosin ID is Involved in Remyelination After Cuprizone-Induced Demyelination.
Myelin, which is a multilamellar structure that sheathes the axon, is essential for normal neuronal function. In the central nervous system (CNS), myelin is produced by oligodendrocytes (OLs), which wrap their plasma membrane around axons. The dynamic membrane trafficking system, which relies on motor proteins, is required for myelin formation and maintenance. Previously, we reported that myosin ID (Myo1d) is distributed in rat CNS myelin and is especially enriched in the outer and inner cytoplasm-containing loops. Further, small interfering RNA (siRNA) treatment highlighted the involvement of Myo1d in the formation and maintenance of myelin in cultured OLs. Myo1d is one of the unconventional myosins, which may contribute to membrane dynamics, either in the wrapping process or transport of myelin membrane proteins during myelination. However, the function of Myo1d in myelin formation in vivo remains unclear. In the current study, to clarify the function of Myo1d in vivo, we surgically injected siRNA in the corpus callosum of a cuprizone-treated demyelination mouse model via stereotaxy. Knockdown of Myo1d expression in vivo decreased the intensities of myelin basic protein and myelin proteolipid protein immunofluorescence staining. However, neural/glial antigen 2-positive signals and adenomatous polyposis coli (APC/CC1)-positive cell numbers were unchanged by siRNA treatment. Furthermore, Myo1d knockdown treatment increased pro-inflammatory microglia and astrocytes during remyelination. In contrast, anti-inflammatory microglia were decreased. The percentage of caspase 3-positive cells in total CC1-positive OLs were also increased by Myo1d knockdown. These results indicated that Myo1d plays an important role during the regeneration process after demyelination.


Transferrin receptor expression of AML blasts is related to their proliferative potential.
Expression of the transferrin receptor (TfR) was studied on peripheral blood blast cells from 11 patients with acute myeloid leukaemia (AML). Using a monoclonal anti-TfR antibody (OKT9) and a polyclonal antibody against surface membrane-bound transferrin, a proportion of blasts from all the patients was found to express receptors for transferrin. Further analysis of OKT9 expression using a fluorescent activated cell sorter (FACS) showed that the TfR was heterogeneously distributed in the blast cell population. In five out of six samples studied, stimulation of DNA synthesis following short-term culture induced a several-fold increase in TfR display as analysed by flow cytometry using OKT9 or FITC-conjugated transferrin. Blasts from seven patients stained with OKT9 were separated on the FACS into positive and negative or weakly positive fractions. Culture of the TfR negative population in a blast cell colony assay produced no colonies in either of two patients. In a further five patients the colony forming cells were predominantly associated with the TfR strongly positive fraction (52 +/- 25 colonies/10(4) cells) rather than the TfR weakly positive fraction (12 +/- 11 colonies/10(4) cells). Analysis of colony size showed that clones derived from the weakly positive fraction were smaller than clones from the TfR strongly positive fraction. These results suggest that TfR display by AML blasts is related to their proliferative capacity and is expressed by the leukaemic stem cell fraction.


A new terpenoid glycoside from Nauclea diderrichii bark.
A new terpenoid glycoside, marounoside [1], was isolated from the bark of Nauclea diderrichii and characterized by 1D and 2D nmr spectroscopy. The aglycone, a terpene with an unusual carbon skeleton, is linked to glucose, which, in turn, is connected to an apiofuranose residue.


Exploratory analysis of diffusion tensor imaging in children with attention deficit hyperactivity disorder: evidence of abnormal white matter structure.
Abnormalities in the white matter microstructure of the attentional system have been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Diffusion tensor imaging (DTI) is a promising magnetic resonance imaging (MRI) technology that has increasingly been used in studies of white matter microstructure in the brain. The main objective of this work was to perform an exploratory analysis of white matter tracts in a sample of children with ADHD versus typically developing children (TDC). For this purpose, 13 drug-naive children with ADHD of both genders underwent MRI using DTI acquisition methodology and tract-based spatial statistics. The results were compared to those of a sample of 14 age- and gender-matched TDC. Lower fractional anisotropy was observed in the splenium of the corpus callosum, right superior longitudinal fasciculus, bilateral retrolenticular part of the internal capsule, bilateral inferior fronto-occipital fasciculus, left external capsule and posterior thalamic radiation (including right optic radiation). We conclude that white matter tracts in attentional and motor control systems exhibited signs of abnormal microstructure in this sample of drug-naive children with ADHD.


Investigation on the differences of accumulating Escherichia coli in three types of shellfish species, involving in the environmental factors.
This study investigated accumulation of Escherichia coli and aerobic colony count in three types of shellfish species. The results indicated that the capability of accumulating E. coli and aerobic colony count for Sinonovacula constricta was stronger than that for Meretrix meretrix and Tegillarca granosa, and capability of accumulating E. coli for M. meretrix was slightly stronger than that for T. granosa. However, no significant difference was observed in the capability of accumulating aerobic colony count between M. meretrix and T. granosa. Moreover, accumulation of E. coli in S. constricta is affected by contaminated seawater and E. coli were accumulated much faster and more in S. constricta when the seawater contaminated more serious. Meanwhile, the results suggested that the populations of E. coli in S. constricta changed in accordance with the weather. This is the first study to investigate the differences of accumulating E. coli in three types of shellfish species.


A left-handed fern twiner in a Permian swamp forest.
The twining habit is a climbing strategy that helps slender plants grow upward by using circumnutation around other plants. In geological history, climbing may have already been present in the first Middle Devonian forests, as indicated by possible climbers among aneurophytalean progymnosperms [1] and lycopsids [2]. By the late Carboniferous, climbing was both more common and diverse - preserved in swamp forests with modes of attachment ranging from aerial roots to appendages modified into hooks and tendrils on the leaves [3]. However, all of these diagnoses of a climbing habit are based upon either indirect morphological characteristics of the purported climber or on direct physical contact with a host plant, but without direct preservation of twining [3,4]. Permineralized epiphytes have been preserved in the Carboniferous [5], but the interpretation of scars purported to have been caused by twiners that have been found on trunk compressions of potential host-plants has been questioned [5] (see Supplemental Information). Direct preservation of a climber engaged in true twining around a host has only been documented in the Miocene Shanwang Formation of Eastern China, albeit with the identity of the twiner difficult to establish and likely to be a self-twiner [6]. Here, we report a climbing fern engaged in left-handed twining around a seed plant from the early Permian Wuda Tuff fossil Lagerstätte of Inner Mongolia, China [7]. Moreover, the host plant is likely to also be a climber based on its overall form. Such a climber-climbing-a-climber phenomenon signals the potential ecological complexity of late Paleozoic forests.


Structure-function coupling in white matter uncovers the abnormal brain connectivity in Schizophrenia.
Schizophrenia is characterized by dysconnectivity syndrome. Evidence of widespread impairment of structural and functional integration has been demonstrated in schizophrenia. Although white matter (WM) microstructural abnormalities have been commonly reported in schizophrenia, the dysfunction of WM as well as the relationship between structure and function in WM remains uncertain. In this study, we proposed a novel structure-function coupling measurement to reflect neuronal information transfer, which combined spatial-temporal correlations of functional signals with diffusion tensor orientations in the WM circuit from functional and diffusion magnetic resonance images (MRI). By analyzing MRI data from 75 individuals with schizophrenia (SZ) and 89 healthy volunteers (HV), the associations between structure and function in WM regions in schizophrenia were examined. Randomized validation of the measurement was performed in the HV group to confirm the capacity of the neural signal transferring along the WM tracts, referring to quantifying the association between structure and function. Compared to HV, SZ showed a widespread decrease in the structure-function coupling within WM regions, involving the corticospinal tract and the superior longitudinal fasciculus. Additionally, the structure-function coupling in the WM tracts was found to be significantly correlated with psychotic symptoms and illness duration in schizophrenia, suggesting that abnormal signal transfer of neuronal fiber pathways could be a potential mechanism of the neuropathology of schizophrenia. This work supports the dysconnectivity hypothesis of schizophrenia from the aspect of circuit function, and highlights the critical role of WM networks in the pathophysiology of schizophrenia.


Comparison of Substance Use Typologies as Predictors of Sexual Risk Outcomes in African American Adolescent Females.
African American female adolescents have a disproportionate risk of sexually transmitted infections (STIs) and other adverse sexual health outcomes. Both alcohol and marijuana use have been shown to predict sexual risk among young African American women. However, no studies have attempted to differentiate alcohol and marijuana typologies use as predictors of sexual risk outcomes exclusively among adolescents who use these substances. This study compared recent alcohol and/or marijuana use as predictors of sexual risk outcomes over 18 months among 182 African American female adolescents. African American females (14-20 years) completed interviews at baseline, 6-, 12-, and 18-months. At each assessment, pregnancy testing was conducted and self-collected vaginal swab specimens were assayed for Trichomonas vaginalis, Chlamydia trachomatis, and Neisseria gonorrhoeae using DNA amplification. Logistic subject-specific random-intercept models compared sexual risk outcomes during follow-up among adolescents who reported recent use of alcohol only (AO), marijuana only (MO) or both substances (A + M) at the baseline assessment. Relative to baseline AO use, baseline MO use predicted condom non-use at last sex. Relative to AO use, A + M use predicted pregnancy. Relative to MO use, A + M use predicted pregnancy and acquisition of T. vaginalis and any STI. The results suggest that African American female adolescents who use A + M may represent a priority population for STI, HIV, and pregnancy prevention efforts.


Medicaid expansion and provision of prescription contraception to Medicaid beneficiaries.
Medicaid expansion increased access to care, but longitudinal patterns of contraception use after the Medicaid expansion have not been described. We evaluated the effects of Medicaid expansion on the amount and type of contraceptive prescriptions using the Medicaid State Utilization Dataset. Overall long-acting reversible contraception (LARC) use increased in both expansion and non-expansion states. In a difference-in-differences analysis, states that expanded Medicaid had no appreciable increase in per-capita prescription rates of LARC (p = 0.26) or short-acting hormonal contraception (p = 0.09) when compared to nonexpansion states. The Medicaid expansion was not associated with a change in per-capita LARC or short-acting hormonal contraception use.


Adaptive replanning using cone beam CT for deformation of original CT simulation.
During a course of radiation therapy, anatomical changes such as a decrease in tumour size or weight loss can trigger the need for repeating a computed tomography (CT) simulation scan in order to generate a new treatment plan. This adaptive approach requires a separate appointment for an additional CT scan which generates additional burden, cost, and radiation exposure for patients. Here, we present a case of a head and neck cancer patient who required palliative radiation for a large neck mass. During treatment, he had a remarkable response which required a replan due to rapid tumour downsizing. In this case, we used a novel technique to avoid repeating the planning CT simulation by using a mid-treatment high-quality cone beam CT (CBCT) to deform the secondary image (plan CT) of the original planning CT and generate a new adapted treatment plan. This is the first report to our knowledge using a Halcyon CBCT to deform the original planning CT in order to generate a new radiation treatment plan, and this novel technique represents a new potential method of adaptive replanning for select patients.


[Speech recognition: impact on workflow and report availability].
With ongoing technical refinements speech recognition systems (SRS) are becoming an increasingly attractive alternative to traditional methods of preparing and transcribing medical reports. The two main components of any SRS are the acoustic model and the language model. Features of modern SRS with continuous speech recognition are macros with individually definable texts and report templates as well as the option to navigate in a text or to control SRS or RIS functions by speech recognition. The best benefit from SRS can be obtained if it is integrated into a RIS/RIS-PACS installation. Report availability and time efficiency of the reporting process (related to recognition rate, time expenditure for editing and correcting a report) are the principal determinants of the clinical performance of any SRS. For practical purposes the recognition rate is estimated by the error rate (unit "word"). Error rates range from 4 to 28%. Roughly 20% of them are errors in the vocabulary which may result in clinically relevant misinterpretation. It is thus mandatory to thoroughly correct any transcribed text as well as to continuously train and adapt the SRS vocabulary. The implementation of SRS dramatically improves report availability. This is most pronounced for CT and CR. However, the individual time expenditure for (SRS-based) reporting increased by 20-25% (CR) and according to literature data there is an increase by 30% for CT and MRI. The extent to which the transcription staff profits from SRS depends largely on its qualification. Online dictation implies a workload shift from the transcription staff to the reporting radiologist.


Metastatic islet cell carcinoma to the umbilicus: diagnosis by fine-needle aspiration.
Internal malignancies rarely metastasize to the umbilical region. The gastrointestinal tract and female genital tract are the most common primary sites. Although the pancreas is frequently involved, the majority of these metastases are adenocarcinoma. Here, we present a case of umbilical metastasis from an islet cell carcinoma diagnosed by fine-needle aspiration in a young woman 2 yr after distal pancreatectomy. This finding led to further radiological studies and surgical intervention, which revealed intraabdominal tumor spread. Neuroendocrine tumors represent a rare tumor type that can give rise to umbilical metastases. Only two cases of carcinoid tumor metastasizing to the umbilicus have been reported.


Explicit encoding vs. fast mapping of novel spoken words: Electrophysiological and behavioural evidence of diverging mechanisms.
It has been claimed that two major neurocognitive mechanisms - instruction-based explicit encoding (EE) and inference-driven fast mapping (FM) may be involved in rapid acquisition of novel words, but their exact neural underpinnings remain poorly understood. To address this, we trained 36 adult participants with 20 novel spoken words in an audio-visual task, carefully balanced between the EE and FM conditions for physical, psycholinguistic and pragmatic properties as well as the overall task setup. To assess the neural dynamics associated with novel word acquisition, we recorded event-related potentials (ERPs) elicited by these words before and after training, and analysed their relationship with the behavioural learning outcomes, measured in a semantic matching task. Both learning regimes led to successful acquisition, which was somewhat more efficient for EE than FM, as indicated by higher accuracy in the behavioural task. We also found that, whereas words learnt via both EE and FM protocols elicited most pronounced ERP peaks at ∼196 and ∼280 ms, these two phases of activity diverged with respect to the learning type. Multiple linear regression and correlation analyses indicated that the learning-induced amplitude dynamics in the earlier peak was significantly related to behavioural performance for FM-learned items, which may possibly be explained by FM's stronger reliance on early automatic mechanisms of word processing. Performance on EE words was, in turn, significantly linked to the amplitude of the second peak only, potentially due to the involvement of later, top-down controlled processes in this type of word acquisition. Grand-average ERP-based source analysis indicated a left-lateralised activity in the anterior-temporal lobe for FM learning, and a bilateral activation for EE. The results confirm the existence of partially diverging neurocognitive systems for word acquisition and suggest that the configuration of newly established word memory circuits depends on the mode of their acquisition.


Infundibular localization of vasopressin, oxytocin and neurophysins in the rat; its relationships with corticotrope function.
The distribution of vasopressin (VP), oxytocin (OXY) and neurophysins 1 and 2 (N1, N2) has been studied in the median eminence (ME) of normal, heterozygous (HDI) and Brattleboro (DI) rats. Numerous thin periportal VP and N2 fibres exist in the normal and HD1 rats; they have never been observed in the DI rats. N1 and OXY fibres in the external layer of the median eminence are rare. Adrenalectomy increases periportal VP and N2 loading in normal and HDI rats; it does not modify the appearance of the DI median eminence. Dexamethasone prevents external VP and N2 overloading in adrenalectomized rats injected during the whole postoperative period. Injections of vasopressin indicated that it had a negative feedback effect during a short time (3 days) but not during a longer period (7 days). The suprachiasmatic neurons are stained only by anti-VP and anti-N2 antibodies. Their overstaining induced by adrenalectomy disappears with dexamethasone, aldosterone or vasopressin treatment. This central effect of hormones is not necessarily associated with disappearance of overloading in the external layer of the ME. The hypothalamo-infundibular tract carrying VP and N2 is involved in regulatory mechanisms of the corticotrope axis. Its relationships with suprachiasmatic neurons are discussed.


Cellular events during arthritis-induced hyperalgesia are mediated by interleukin-6 and p38 MAPK and their effects on the expression of spinal mu-opioid receptors.
Activation of mitogen-activated protein kinase (MAPK) enzymes in nociceptive plasticity has been extensively studied. P38 MAPK enzyme, which can be activated by cytokines, acts as a crucial intracellular regulator of environmental changes. The aim of this study was to elucidate the cellular events during arthritis-induced hyperalgesia that are mediated by interleukin-6 and p38 MAPK, and their effects on the expression of spinal mu-opioid receptors (MORs), in different stages of arthritis in male Wistar rats. Complete Freund's adjuvant (CFA)-induced arthritis (AA) was caused by subcutaneous injection of CFA into the rats' hindpaw. Anti-IL-6 antibody and p38 MAPK phosphorylation inhibitor were administered during 21 days of study. Spinal MOR, p38, and phosphorylated-p38 (pp38) proteins expressions were detected by Western blotting. Daily treatment with anti-IL-6 antibody and p38 MAPK phosphorylation inhibitor, SB203580, significantly decreased paw edema in AA group. Daily anti-IL-6 and SB203580 administration caused a significant reduction in hyperalgesia in the first week of the study, but increased hyperalgesia in the next 2 weeks in experimental groups compared to the AA control group. Expression of pp38 MAPK protein significantly decreased on the 3, 7, 14, and 21 days in AA+SB203580 and AA+anti-IL6 groups compared to AA group. Additionally, daily treatment with anti-IL6 antibody and SB203580 in AA group caused significantly decrease in spinal MOR expression compared to AA control group. The results of our study can confirm that activated spinal p38 MAPK enzyme may play an important role in cellular IL-6 signaling pathways in hyperalgesia variation during different stages of AA inflammation. Also, it can be suggested that at least a part of p38 MAPK effects on hyperalgesia is mediated by spinal MOR expression variation.


The biochemical composition of tympanosclerotic deposits.
We have studied the quantitative analysis of calcium, phosphate and cholesterol in the tympanosclerotic plaques removed from 25 patients. Our findings confirm that tympanosclerosis has a partly calcified organic matrix, in which the calcification process is probably similar in its qualitative chemical structure to that occurring in other calcified pathological tissues. The degree of calcification varies from one case to another and is even different in various locations of the same sampling. However, calcium levels are usually lower than in other pathological tissues which are calcified. The average quantity of calcium in our studies was 2 mg in 100 mg tissue or 12 mg in 100 mg protein. The average molar ratio between calcium and phosphate was 3, corresponding to the hydroxyapatite ratio. The average total quantity of cholesterol present was only 15 micrograms in 100 mg protein.


Participatory medicine and patient empowerment towards personalized healthcare in multiple sclerosis.
The current understanding that the key for successful healthcare is an integrated approach, involving predictive, preventive, personalized and participatory medicine, is leading major changes. These are: a shift from medical decisions based on 'trial and error' to informed therapeutics based on diagnostics (theranostics); a shift from a 'disease-centered' to a 'patient-centered' approach; and a shift from a 'reactive' to 'proactive' medical approach. It is essential that not only the physician, but also the patient, becomes proactive. Therefore, beyond the integration of genomic medicine and predictive biomarkers into practice, patient empowerment and participatory medicine are gaining increasing attention. This requires, besides appropriate sharing of information between patients and healthcare providers, new insights in patient involvement, such as patient-reported outcomes, both at the clinical trial stage of drug development and during post-marketing follow-up assessments. Patient empowerment and participatory medicine, as part of predictive, preventive, personalized and participatory medicine, are especially crucial in paving the way towards optimized healthcare in complex and chronic neurological diseases, such as multiple sclerosis.


The effects of roundabouts on traffic safety for bicyclists: an observational study.
A before-and-after study was carried out of injury accidents involving bicyclists on 91 roundabouts in Flanders-Belgium. The study design accounted for the effects of general safety trends and regression-to-the-mean, but could not take into account the possibility of specific changes in traffic volume at roundabouts. The conversion of intersections into roundabouts produces a significant 27% increase in the number of injury accidents involving bicyclists on or nearby the roundabouts. The increase is even higher for accidents involving fatal or serious injuries (41-46%). Compared to the proven favourable effects of roundabouts on safety in general, this result is unexpectedly poor. However, the effects of roundabouts on bicycle accidents differ depending on whether these roundabouts are built inside or outside built-up areas. When inside built-up areas, the construction of roundabouts increased the number of injury accidents involving bicyclists by 48%. For accidents causing fatal or serious injuries inside built-up areas, an average increase of 77% was found. However, outside built-up areas the zero-hypothesis of 'no safety effect for bicyclists' cannot be rejected (best estimate: +1% accidents, not significant). Roundabouts that replace traffic signals perform worse when compared to roundabouts at other types of intersections.


Massively parallel, computationally guided design of a proenzyme.
Confining the activity of a designed protein to a specific microenvironment would have broad-ranging applications, such as enabling cell type-specific therapeutic action by enzymes while avoiding off-target effects. While many natural enzymes are synthesized as inactive zymogens that can be activated by proteolysis, it has been challenging to redesign any chosen enzyme to be similarly stimulus responsive. Here, we develop a massively parallel computational design, screening, and next-generation sequencing-based approach for proenzyme design. For a model system, we employ carboxypeptidase G2 (CPG2), a clinically approved enzyme that has applications in both the treatment of cancer and controlling drug toxicity. Detailed kinetic characterization of the most effectively designed variants shows that they are inhibited by ∼80% compared to the unmodified protein, and their activity is fully restored following incubation with site-specific proteases. Introducing disulfide bonds between the pro- and catalytic domains based on the design models increases the degree of inhibition to 98% but decreases the degree of restoration of activity by proteolysis. A selected disulfide-containing proenzyme exhibits significantly lower activity relative to the fully activated enzyme when evaluated in cell culture. Structural and thermodynamic characterization provides detailed insights into the prodomain binding and inhibition mechanisms. The described methodology is general and could enable the design of a variety of proproteins with precise spatial regulation.


Predictive power of portal pressure gradient remeasured shortly after transjugular intrahepatic portosystemic shunt.
The portal pressure gradient (PPG) measured at the time of transjugular intrahepatic portosystemic shunt (TIPS) completion (immediate PPG) is easily disturbed by many factors. This study aimed to assess the diagnostic value of PPG remeasured 2-4 days after TIPS (delayed PPG) by comparison with immediate PPG. We retrospectively analyzed cirrhotic patients aged 18-75 years who received TIPS for preventing variceal rebleeding and pressure measurements at different time points. Of 154 eligible patients, 60 (39.0%), 62 (40.3%), and 32 (20.8%) were categorized into group LL (both immediate and delayed PPG < 12 mmHg), LH (immediate PPG < but delayed PPG ≥ 12 mmHg) and HH (both immediate and delayed PPG ≥ 12 mmHg), respectively. Mean immediate and delayed PPG were 9.2 mmHg and 12.8 mmHg (p < 0.001). During a median follow-up of 22 months, the 1-year probability of variceal rebleeding was significantly lower in group LL (1.7%) compared to LH (9.8%, absolute risk difference [ARD]: - 8.2%, p = 0.028) and HH (12.6%, ARD: - 11.1%, p = 0.014), but was not significantly different between groups LH and HH (ARD: - 2.9%, p = 0.671). Delayed PPG (p < 0.001) was identified as an independent predictor of variceal rebleeding in multivariable Cox regression analysis. The area under curves of delayed and immediate PPG in predicting variceal rebleeding were 0.837 and 0.693 for all patients (p = 0.031), and 0.936 and 0.694 for patients without shunt dysfunction (p < 0.001). In cirrhotic patients with variceal bleeding, delayed PPG has higher predictive power for variceal rebleeding than immediate PPG.


The first six-month clinical outcomes and risk factors associated with high on-treatment platelet reactivity of clopidogrel in patients undergoing coronary interventions.
This study attempted to fill the gaps in evidence related to response to clopidogrel treatment in the Turkish population. The study aimed to determine the prevalence, associated risk factors, and clinical outcomes of high on-treatment platelet reactivity (HTPR) of clopidogrel in patients undergoing percutaneous coronary intervention (PCI) in a tertiary cardiovascular hospital in Turkey. In this prospective studied a total of 1.238 patients undergoing PCI were included in the present study. Blood samples were analyzed using a Multiplate analyzer. All patients were examined in the outpatient clinics at the end of the first and sixth months for recording drug therapy compliance and study endpoints. Among the study population, 324 (30.2%) patients were found to have HTPR (mean age 58.03±11.88 years, 71.7% men). The incidence of HTPR was higher amongst females than amongst males (38.3% vs. 27%, p=0.010). Hypertension and diabetes mellitus were more frequently observed in the HTPR group (57.7% vs. 48.7%, p=0.004; 35% vs. 29.1%, p=0.040, respectively). When the recorded data were analyzed using multinomial regression analysis, hypertension, hemoglobin level, platelet, lymphocyte, and eosinophil count were independently associated with HTPR. On the basis of the results obtained from our study, we conclude that 30.2% of the Turkish population has HTPR. Our results also led us to believe that hypertension is an associated risk factor and decreased hemoglobin level as well as increased platelet counts are laboratory parameters that are strongly associated with the presence of HTPR. However, no differences were observed with regard to cardiovascular mortality and stent thrombosis.


Patterns of alcohol and multiple drug use among rural white and American Indian adolescents.
This study examined the attitudes and practices of sample of White (N=667) and American Indian (N=280) adolescents in regard to the use of alcohol and other drugs. The findings lend general support to the hypothesis of Whitehead et al. that users of any one drug will show increased probability to use another drug when compared to those not using that drug. Additionally, it was found that rural Indian youth are somewhat more likely than rural White youth to be involved with alcohol, marijuana, and hard drugs.