Protein turnover and proliferation. Failure of SV-3T3 cells to increase lysosomal proteinases, increase protein degradation and cease net protein accumulation.
The contrasting control of lysosomal proteinases, protein turnover and proliferation was studied in 3T3 and SV-3T3 (SV-40-virus-transformed 3T3) cells. 1. In 3T3 cells, net protein accumulation proceeded from 5%/h (doubling time, T(d)=14h) in growing cells to 0%/h as cells became quiescent. SV-3T3 cells never ceased to gain protein, but rather decreased their protein accumulation rate from 6-7%/h (T(d)=10-12h) to 2%/h (T(d)=35-40h) just before culture death in unchanged medium. 2. In both cell types the rates of protein synthesis per unit of protein (a) were proportional to the initial serum concentration from 0 to 6%, and (b) declined under progressive depletion of undefined serum growth factors. In depleted growth medium, leucine incorporation per unit of protein in 3T3 and SV-3T3 cells declined to almost equal synthetic rates while the 3T3 cell existed in a steady state of zero net gain, and the SV-3T3 cell continued to gain protein at a rate of 2%/h. 3. Whereas a large fraction of the control of 3T3-cell net protein accumulation can be accounted for by an increase in degradation from 1%/h to 3%/h, the SV-3T3 cell did not exhibit a growth-related increase in degradation appreciably above 1%/h. 4. Thus, by using first-order kinetics, the continued net protein accumulation of the transformed cell can be accounted for by a failure to increase protein degradation, whereas fractional synthesis can be made to decline to a rate similar to that in the quiescent non-transformed cell. 5. Upon acute serum deprivation, both cell types similarly exhibited small rapid increases in proteolysis independent of cell growth state or lysosomal enzyme status. 6. The 3T3 cell increased its lysosomal proteinase activity in conjunction with increase in the growth-state-dependent proteolytic mechanism; however, the SV-3T3 cell failed to increase lysosomal proteinases or the growth-state-dependent proteolytic mechanism.


[Transmission of F'lac plasmid from Escherichia coli K-12 to bacteria of the genus Erwinia].
The F'lac plasmid was transferred by conjugation from Escherichia coli K-12 W1655 to 21 lac- strains of Erwinia spp. (5.2 . 10(-6) to 6.8 . 10(-2) lac+ exconjugants per donor cell). Erw. herbicola and Erw. chrysanthemi were the better recipients than others. The degree of the stability of lac+ genes in Erwinia exconjugants depends on the strains. Stable exconjugants of Erwinia, which harbored F'lac plasmid, were able to utilize lactose, to transfer lac genes by conjugation to Erwinia spp. and E. coli, and were sensitive to the F-specific phages f1, f2, Qbeta. The F'lac plasmid was eliminated from the exconjugants by the treatment with acridine orange, which indicates that this genetic element is not integrated into the Erwinia chromosome.


A critical GxxxA motif in the gamma6 calcium channel subunit mediates its inhibitory effect on Cav3.1 calcium current.
The eight members of the calcium channel gamma subunit family are integral membrane proteins that regulate the expression and behaviour of voltage and ligand gated ion channels. While a subgroup consisting of gamma(2), gamma(3), gamma(4) and gamma(8) (the TARPs) modulate AMPA receptor localization and function, the gamma(1) and gamma(6) subunits conform to the original description of these proteins as regulators of voltage gated calcium channels. We have previously shown that the gamma(6) subunit is highly expressed in atrial myocytes and that it is capable of acting as a negative modulator of low voltage activated calcium current. In this study we extend our understanding of gamma(6) subunit modulation of low voltage activated calcium current. Using engineered chimeric constructs, we demonstrate that the first transmembrane domain (TM1) of gamma(6) is necessary for its inhibitory effect on Cav3.1 current. Mutational analysis is then used to identify a unique GxxxA motif within TM1 that is required for the function of the subunit strongly suggesting the involvement of helix-helix interactions in its effects. Results from co-immunoprecipitation experiments confirm a physical association of gamma(6) with the Cav3.1 channel in both HEK cells and atrial myocytes. Single channel analysis reveals that binding of gamma(6) reduces channel availability for activation. Taken together, the results of this study provide both a molecular and a mechanistic framework for understanding the unique ability of the gamma(6) calcium channel subunit to modulate low voltage activated (Cav3.1) calcium current density.


A branch-heterogeneous model of protein evolution for efficient inference of ancestral sequences.
Most models of nucleotide or amino acid substitution used in phylogenetic studies assume that the evolutionary process has been homogeneous across lineages and that composition of nucleotides or amino acids has remained the same throughout the tree. These oversimplified assumptions are refuted by the observation that compositional variability characterizes extant biological sequences. Branch-heterogeneous models of protein evolution that account for compositional variability have been developed, but are not yet in common use because of the large number of parameters required, leading to high computational costs and potential overparameterization. Here, we present a new branch-nonhomogeneous and nonstationary model of protein evolution that captures more accurately the high complexity of sequence evolution. This model, henceforth called Correspondence and likelihood analysis (COaLA), makes use of a correspondence analysis to reduce the number of parameters to be optimized through maximum likelihood, focusing on most of the compositional variation observed in the data. The model was thoroughly tested on both simulated and biological data sets to show its high performance in terms of data fitting and CPU time. COaLA efficiently estimates ancestral amino acid frequencies and sequences, making it relevant for studies aiming at reconstructing and resurrecting ancestral amino acid sequences. Finally, we applied COaLA on a concatenate of universal amino acid sequences to confirm previous results obtained with a nonhomogeneous Bayesian model regarding the early pattern of adaptation to optimal growth temperature, supporting the mesophilic nature of the Last Universal Common Ancestor.


The incidence of pine pollen reactivity in an allergic atopic population.
In the past there has been controversy concerning the allergenicity of pine pollen. Most reports have suggested that pine pollen has not been a significant allergen due to its low antigenicity and relatively large size. While little investigation has been done, there are some older studies supporting pine pollen as an allergen and its use in individual cases for immunotherapy. To our knowledge, no extended testing or screening had been done. A total of 200 patients presenting with symptoms during the pine pollen season were tested to Pinus radiata. Five (3.2%) of the 155 pollen-sensitive patients exhibited skin test sensitivity to Pinus radiata. Based on this data it is concluded that the incidence of skin test reactivity to pine pollen is low.


MicroRNA let-7: an emerging next-generation cancer therapeutic.
In recent years, various RNA-based technologies have been under evaluation as potential next-generation cancer therapeutics. Micrornas (miRNAS), known to regulate the cell cycle and development, are deregulated in various cancers. Thus, they might serve as good targets or candidates in an exploration of anticancer therapeutics. One attractive candidate for this purpose is let-7 ("lethal-7"). Let-7 is underexpressed in various cancers, and restoration of its normal expression is found to inhibit cancer growth by targeting various oncogenes and inhibiting key regulators of several mitogenic pathways. In vivo, let-7 administration was found effective against mouse-model lung and breast cancers, and our computational prediction supports the possible effectiveness of let-7 in estrogen receptor (ER)-positive metastatic breast cancer. Data also suggest that let-7 regulates apoptosis and cancer stem cell (CSC) differentiation and can therefore be tested as a potential therapeutic in cancer treatment. However, the exact role of let-7 in cancer is not yet fully understood. There is a need to understand the causative molecular basis of let-7 alterations in cancer and to develop proper delivery systems before proceeding to therapeutic applications. This article attempts to highlight certain critical aspects of let-7's therapeutic potential in cancer.


Injection of basic fibroblast growth factor for unilateral vocal cord paralysis.
Unilateral vocal cord paralysis (UVCP) not only induces severe dysphonia, but aspiration as well. Although laryngeal framework surgery is usually performed to treat this condition, the procedure is not tolerated by some patients. In the previous study, basic fibroblast growth factor (bFGF) injections for vocal cord scarring and sulcus have been reported to provide favorable outcomes while being minimally invasive. In this study, the authors retrospectively investigated phonological outcomes after bFGF injection in patients with UVCP. This study was registered in University hospital Medical Information Network - Clinical Trials Registry (UMIN000019347). Nineteen patients with unilateral cord paralysis were treated with bFGF injection. The treatment regimen involved a single injection of 50 μg of bFGF into the muscle layer. More than six months after the injection, aerodynamic and acoustic outcomes were examined. The voice handicap index, maximum phonation time, mean airflow rate, and pitch range improved significantly after injection of bFGF. No sex-related differences were observed in any phonological parameter. bFGF injection, an easy method and suitable as an office procedure, significantly improved the hoarseness caused by UVCP. It is expected to be widely adopted and effective adjunctive drugs, and procedures are anticipated to be developed.


The 3D Genome: From Structure to Function.
The genome is the most functional part of a cell, and genomic contents are organized in a compact three-dimensional (3D) structure. The genome contains millions of nucleotide bases organized in its proper frame. Rapid development in genome sequencing and advanced microscopy techniques have enabled us to understand the 3D spatial organization of the genome. Chromosome capture methods using a ligation approach and the visualization tool of a 3D genome browser have facilitated detailed exploration of the genome. Topologically associated domains (TADs), lamin-associated domains, CCCTC-binding factor domains, cohesin, and chromatin structures are the prominent identified components that encode the 3D structure of the genome. Although TADs are the major contributors to 3D genome organization, they are absent in Arabidopsis. However, a few research groups have reported the presence of TAD-like structures in the plant kingdom.


High-resolution measurements of face-to-face contact patterns in a primary school.
Little quantitative information is available on the mixing patterns of children in school environments. Describing and understanding contacts between children at school would help quantify the transmission opportunities of respiratory infections and identify situations within schools where the risk of transmission is higher. We report on measurements carried out in a French school (6-12 years children), where we collected data on the time-resolved face-to-face proximity of children and teachers using a proximity-sensing infrastructure based on radio frequency identification devices. Data on face-to-face interactions were collected on Thursday, October 1(st) and Friday, October 2(nd) 2009. We recorded 77,602 contact events between 242 individuals (232 children and 10 teachers). In this setting, each child has on average 323 contacts per day with 47 other children, leading to an average daily interaction time of 176 minutes. Most contacts are brief, but long contacts are also observed. Contacts occur mostly within each class, and each child spends on average three times more time in contact with classmates than with children of other classes. We describe the temporal evolution of the contact network and the trajectories followed by the children in the school, which constrain the contact patterns. We determine an exposure matrix aimed at informing mathematical models. This matrix exhibits a class and age structure which is very different from the homogeneous mixing hypothesis. We report on important properties of the contact patterns between school children that are relevant for modeling the propagation of diseases and for evaluating control measures. We discuss public health implications related to the management of schools in case of epidemics and pandemics. Our results can help define a prioritization of control measures based on preventive measures, case isolation, classes and school closures, that could reduce the disruption to education during epidemics.


The 2017 Assisi Think Tank Meeting on rectal cancer: A positioning paper.
To describe current practice in the management of rectal cancer, to identify uncertainties that usually arise in the multidisciplinary team (MDT)'s discussions ('grey zones') and propose next generation studies which may provide answers to them. A questionnaire on the areas of controversy in managing T2, T3 and T4 rectal cancer was drawn up and distributed to the Rectal-Assisi Think Tank Meeting (ATTM) Expert European Board. Less than 70% agreement on a treatment option was indicated as uncertainty and selected as a 'grey zone'. Topics with large disagreement were selected by the task force group for discussion at the Rectal-ATTM. The controversial clinical issues that had been identified within cT2-cT3-cT4 needed further investigation. The discussions focused on the role of (1) neoadjuvant therapy and organ preservation on cT2-3a low-middle rectal cancer; (2) neoadjuvant therapy in cT3 low rectal cancer without high risk features; (3) total neoadjuvant therapy, radiotherapy boost and the best chemo-radiotherapy schedule in T4 tumors. A description of each area of investigation and trial proposals are reported. The meeting successfully identified 'grey zones' and, in the light of new evidence, proposed clinical trials for treatment of early, intermediate and advanced stage rectal cancer.


[Surgical and interventional treatment of liver metastases].
The liver is the most common target organ for metastatic disease. The majority of patients undergoing surgical treatment for liver metastases have colorectal primaries. Endocrine liver metastases, or metastases from other tumors such as mammary carcinoma, sarcomas, renal tumors or gastrointestinal stromal tumors (GIST) are appreciably less common for surgical treatment. The gold standard of treatment is resection of the metastatic lesions. In the meantime, advances in surgical techniques and improved perioperative patient management make it possible to perform extensive resections with acceptable morbidity and mortality rates. In the event of metastases that are not primarily resectable, various downstaging procedures are available, with the aid of which secondary resectability can be achieved. Among the interventional treatment options that should be applied only in palliative intent, radiofrequency ablation is in widespread use.


Adherence with infection prevention and control measures among Italian healthcare workers: Lessons from the COVID-19 pandemic to tackle future ones.
To tackle future health threats, the study aimed to assess healthcare workers' (HCWs) adherence to infection prevention and control (IPC) measures and to evaluate whether knowledge and concerns related to COVID-19 could be its potential predictors. A secondary aim was to explore how and how much healthcare facilities support HCWs to implement IPC practices. This cross-sectional study was conducted between June and September 2021 in Southern Italy using a self-administered questionnaire. Socio-demographic and professional characteristics, COVID-19 preparedness and response plan in the facilities, knowledge about COVID-19's transmission and non-pharmaceutical interventions (NPIs), concerns about the possibility of transmitting COVID-19 to family members and patients, adherence to IPC practices, and sources of information were investigated. Among the 492 enrolled HCWs, the overall knowledge median score was 6 out of a maximum score of 8 and predictors of good knowledge were practicing in a facility that organized training courses about IPC measures and having more years in practice. HCWs were more concerned about the possibility of transmitting the infection to their family members (64.4%) than to negative patients (38.9%). A sizable proportion claimed to take off the face mask by touching only the straps or ties (76.3%) and to replace the face mask when it was wet (70.7%). Only 26.2% never/rarely touched the face mask while wearing it. Good adherence to preventative practices was more likely in HCWs other than physicians and practicing in a facility that organized training courses about IPC measures and in regional hospitals compared with those practicing in district hospitals. The study findings produce information about what worked well and where gaps were identified during COVID-19 pandemic, along with data useful for hospitals and health systems in general to better prepare and put in place appropriate interventions in case of similar future events.


Dietary guar gum improves insulin sensitivity in streptozotocin-induced diabetic rats.
Although dietary recommendations for diabetics stress the need for increased carbohydrate and dietary fiber, the effectiveness of dietary fiber in improving insulin sensitivity remains controversial. The aim of this study was to compare the effects of a soluble fiber (guar gum) and an insoluble fiber (wheat bran) on insulin sensitivity in streptozotocin-induced (STZ) diabetic rats. Consequently, the rats were divided into two groups and one half were rendered diabetic with streptozotocin. The STZ diabetic and nondiabetic rats were further randomized and fed a diet containing dietary fiber (7 g/100 g diet) from either guar gum or wheat bran. The hyperinsulinemic clamp technique, combined with infusion of the glucose analog, 2-deoxyglucose (2DG), was utilized to examine insulin sensitivity. Bran-fed STZ diabetic rats were significantly (P < 0.001) hyperglycemic, which was ameliorated by guar gum. Insulin-mediated glucose disposal was increased by the guar diet compared with the bran diet in both the STZ diabetic rats [17.7 +/- 2.2 vs. 11.8 +/- 2.4 mL/(kg x min), P < 0.05] and the nondiabetic rats [20.5 +/- 2.8 vs. 15.5 +/- 1.5 mL/(kg x min), P < 0.05]. The accumulation of 2DG in peripheral muscles reflected the changes in insulin sensitivity with a trend for increased 2DG uptake in the majority of analyzed tissues in rats fed the guar diet, both nondiabetic and STZ diabetic, compared with the bran-fed rats. Accompanying these alterations in insulin sensitivity, guar gum suppressed food intake in the hyperphagic diabetic rats by 20% (P < 0.001). The present results demonstrate the effectiveness of guar gum in improving insulin sensitivity in STZ diabetic rats and suggest that reduced food intake may be an important mechanism of action of guar in hyperphagic diabetic rats.


Requirement for vascular endothelial growth factor in wound- and inflammation-related corneal neovascularization.
Vascular endothelial growth factor (VEGF) is required for vascular development and for ischemia-related tumor, iris, and retinal neovascularization. The role of VEGF in inflammatory corneal neovascularization is unknown and was investigated in these studies. A rat model was used in which removal of the corneal and limbal epithelium resulted in circumferential neovascularization. Corneal VEGF mRNA levels were quantified with ribonuclease protection assays, and VEGF protein was studied in situ using immunohistochemical analysis. Controlled-release pellets containing anti-VEGF antibodies were implanted into the corneal stroma and were used to determine the requirement for VEGF in corneal neovascularization. VEGF mRNA and protein were induced to high levels after corneal injury and were temporally and spatially correlated with inflammation and neovascularization. VEGF immunoreactivity was localized primarily to the inflammatory cells invading the wounded cornea. The specific inhibition of VEGF bioactivity with neutralizing antibodies potently suppressed corneal neovascularization. These data are the first to demonstrate that VEGF may be required for inflammatory neovascularization of the rat cornea and to identify VEGF as a functional endogenous corneal angiogenic factor.


Kinetics of the specific binding of a second RNA polymerase to the standard bacterial-transposon-Tn3 bla promoter complex.
It was shown previously, that at moderate excess of RNA polymerase (RNAP) relative to DNA, the complex of the bla promoter from bacterial transposon Tn3 with RNAP is locked in an inactive, heparin-resistant, isomeric state which is not that of the 'open' complex. This 1:1 isomer can accommodate a second RNAP, which becomes tightly and specifically bound just upstream of the first RNAP [Duval-Valentin & Reiss (1990) Mol. Microbiol. 4, 1465-1475]. Both the resulting 2:1 complex and its antecedent 1:1 complex formed at excess of RNAP are immediately and permanently inhibited for transcription initiation. Using the gel-retardation technique, we investigate here the kinetics of formation and decay of the 2:1 complex under various experimental conditions. The data are consistent with pseudo-first-order kinetics at moderate excess of RNAP. The salt-dependence of rate and equilibrium constants has been analysed within the framework of the theoretical model described by Lohman, Dehaseth & Record [(1978) Biophys. Chem. 8, 281-294]. It was found that the salt-dependence is consistent with the existence of a transient intermediate during formation of the 2:1 complex, which forms rapidly on the time scale of its isomerization to the final 2:1 complex. The intermediate is characterized by the release of about seven cations from the 1:1 complex, one additional cation being released upon its final isomerization. Formation of the 2:1 complex at high excess of RNAP becomes inhibited, probably as a result of a 'bumping' effect of the complex by the enzyme, also observed with several other promoters. We conclude that formation of the 2:1 complex closely mimics that of the standard 1:1 complex, except that the final isomerization step to an 'open' complex is lacking. A mechanism of the formation of the 2:1 complex and of its role in transcription regulation of constitutive promoter by RNAP is proposed.


[Evaluation criteria of medical and ecological situation based on the method of sigma deviations].
Comparative analysis of the existing criteria for assessment of health and environmental situation was produced. The approach to health assessment of the environmental situation, where sigma intervals are used as criteria of belonging population morbidity in certain administrative areas in the region to the background incidence rate was proposed. The suggested criteria will increase the objectivity of the assessment of environmental health situation in the environment and health monitoring and implementation of epidemiological research.


Hazard Ratio of 90-Day Mortality in ICU Patients with Abdominal Injuries Compared with Head Injuries.
Despite advances in the treatment of abdominal injuries in patients with trauma, it remains a major public health problem worldwide. Evaluation of hazard ratio (HR) of 90-day mortality in intensive care unit (ICU) patients with abdominal injuries compare with head injuries in trauma patients and non-trauma surgical ICU patients. This single-center, prospective cohort study was conducted on 400 patients admitted to the ICU between 2018 and 2019 due to trauma or surgery in Hamadan, Iran. The main outcome was mortality at 90-day after ICU admission. Cox proportional hazards models were used to determine the HR and 95% confidence interval (CI) for 90-day mortality. The 90-day mortality was 21.9% in abdominal injuries patients. According to multivariate Cox regression, the expected hazard mortality was 2.758 times higher in patients with abdominal injuries compared to non-trauma patients (HR: 2.758, 95% CI: 1.077-7.063, P=0.034). About more than 50% of all deaths in the abdominal and head trauma groups occurred within 20 days after admission. Mean time to death was 27.85±20.1, 30.27±18.22 and 31.43±26.24 days for abdominal-trauma, surgical-ICU, and head-trauma groups, respectively. Difficulty in accurate diagnosis due to the complex physiological variability of abdominal trauma, less obvious clinical symptoms in blunt abdominal injuries, multi-organ dysfunction in abdominal injuries, failure to provide timely acute care, as well as different treatment methods all account for the high 90-day mortality rate in abdominal-trauma patients. Therefore, these patients need a multidisciplinary team to care for them both in the ICU and afterwards in the general ward.


Incorporating local ancestry improves identification of ancestry-associated methylation signatures and meQTLs in African Americans.
Here we report three epigenome-wide association studies (EWAS) of DNA methylation on self-reported race, global genetic ancestry, and local genetic ancestry in admixed Americans from three sets of samples, including internal and external replications (Ntotal = 1224). Our EWAS on local ancestry (LA) identified the largest number of ancestry-associated DNA methylation sites and also featured the highest replication rate. Furthermore, by incorporating ancestry origins of genetic variations, we identified 36 methylation quantitative trait loci (meQTL) clumps for LA-associated CpGs that cannot be captured by a model that assumes identical genetic effects across ancestry origins. Lead SNPs at 152 meQTL clumps had significantly different genetic effects in the context of an African or European ancestry background. Local ancestry information enables superior capture of ancestry-associated methylation signatures and identification of ancestry-specific genetic effects on DNA methylation. These findings highlight the importance of incorporating local ancestry for EWAS in admixed samples from multi-ancestry cohorts.


Patterns of Care of Node-Positive Prostate Cancer Patients Across the United States: A National Cancer Data Base Analysis.
Twelve percent of newly diagnosed prostate cancers in the United States are node-positive. In a setting of disparate treatment guideline recommendations for node-positive disease, this study describes the treatment patterns for clinical node-positive (cN+) and pathologic node-positive (pN+) patients across the United States. MATERIALS AND METHODS: Using the National Cancer Data Base, men diagnosed with cN+ or pN+ disease were identified from 2006 to 2011. For each cohort, the proportion of patients who received radiotherapy (RT), androgen deprivation therapy (ADT), and other treatments was analyzed. Multivariable logistic regression models were used to examine patient and clinical factors associated with use of definitive treatment (RT or prostatectomy) in cN+ patients, and postprostatectomy RT in pN+ patients. A total of 8464 cN+ and 4890 pN+ patients were identified. For cN+ disease, ADT alone was the most common treatment used (3892 patients, 46.0%) followed by RT with or without ADT (2657 patients, 31.4%). Men with older age, higher prostate-specific antigen at diagnosis, or higher biopsy Gleason score were less likely to receive curative treatment (RT or prostatectomy), whereas those with higher clinical T stage were more likely. For pN+ disease, 2948 patients (60.3%) received no adjuvant treatment and 833 patients (17.0%) received RT following prostatectomy. Patients with older age, negative margin, and comorbidities were less likely to undergo RT after prostatectomy, whereas those with higher pathologic T-stage were more likely. Many patients with cN+ or pN+ prostate cancer do not receive RT, despite the possibility of long-term control and cure. Randomized trials are needed to guide treatment decisions in this patient population.


Up-regulation of DDX39 in human pancreatic cancer cells with acquired gemcitabine resistance compared to gemcitabine-sensitive parental cells.
Intrinsic or acquired resistance of pancreatic cancer to gemcitabine (2'-deoxy-2'-difluorodeoxycytidine) is an important factor in the failure of gemcitabine treatment. Proteomic analysis of gemcitabine-sensitive KLM1 pancreatic cancer cells and -resistant KLM1-R cells identified heat-shock protein-27(HSP27) as a biomarker protein which is involved in gemcitabine resistance. However, a knock-down experiment showed that HSP27 was not the only protein implicated with gemcitabine-resistance. Finding further candidate proteins is necessary for achieving effective gemcitabine therapy for patients with pancreatic cancer. DDX39 is an Asp-Glu-Ala-Asp (DEAD)-box RNA helicase reported to be overexpressed in tumor cells, such as lung squamous cell cancer, gastrointestinal stromal tumor, urinary bladder cancer and malignant pleural mesothelioma. In urinary bladder cancer cells, overexpression of this protein is intimately bound with tumorigenesis and poor prognosis. In the present study, the expression of DDX39 in gemcitabine-sensitive KLM1 and -resistant KLM1-R cells was compared. It was found that DDX39 was significantly up-regulated in gemcitabine-resistant KLM1-R cells compared to sensitive KLM1 cells. The ratio of expression of DDX39 to that of actin was significantly up-regulated in KLM1-R cells compared to KLM1 cells (p=0.0072 by Student's t-test). These results suggest that DDX39 is a possible candidate biomarker for predicting the response of patients with pancreatic cancer to treatment with gemcitabine.


The association of alcohol with circulating total fibrinogen and plasma clot density is mediated by fibrinogen and FXIII genotypes.
Alcohol consumption is associated with haemostasis and so may influence cardiovascular conditions. It is unknown whether the association of alcohol with total and γ' fibrinogen concentrations, as well as clot structure, are modulated by fibrinogen and factor (F) XIII single nucleotide polymorphisms (SNPs). Total fibrinogen, γ' fibrinogen and clot properties of 2010 healthy Africans residing in South Africa were measured in relation to alcohol intake as well as its markers - gamma-glutamyltransferase (GGT), percentage carbohydrate deficient transferrin (%CDT), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Fourteen fibrinogen and two SNPs in the FXIII gene were genotyped to determine their influence. Alcohol intake and its markers correlated negatively with fibrinogen and clot lysis time (CLT) as well as with most of the clot properties. Percentage γ' fibrinogen correlated positively with AST and negatively with alcohol intake. We then stratified for alcohol intake and found inverse associations between γ' fibrinogen and both %CDT and GGT-CDT in consumers, but the positive association with AST remained only in abstainers. Alcohol intake and its markers modulated the influence of fibrinogen SNPs on total fibrinogen concentrations and the fibrinogen SNPs as well as an FXIII SNP on clot density (all p < 0.004). We show for the first time that some individuals harbour certain genotypes that, in combination with alcohol consumption, might predispose or protect them from haemostatic factors that might lead to the development of cardiovascular disease. Studies are needed to clarify the mechanisms related to the interplay between alcohol and the gene variants observed here.


Structured analysis of histopathological characteristics of vulvar lichen sclerosus in a juvenile population.
Genital lichen sclerosus (LS), a chronic noninfectious dermatosis, is not rare in pediatric dermatology. The histopathological diagnosis in children and adults in both genital and nongenital LS is considered to be the same and encompasses a broad range of possible characteristics. Clinical manifestations and treatment options of genital LS in children are different depending on gender. The vast majority of boys are treated with circumcision, making for a larger amount of information on the histopathology of genital LS in boys, whereas substantial information on the histopathology of juvenile vulvar LS is lacking. In girls, vulvar LS almost always persists beyond puberty and, therefore, presents a particular challenge to clinicians and cause for concern for the patient. Vulvar LS in childhood and adolescence (juveniles) is underreported, and there are uncertainties with regard to the long-term course of the disease when it occurs at an age when the vulva is still developing. The present study investigates biopsies of 100 juvenile cases of vulvar LS and analyzes the presence or absence of the most salient histopathological characteristics of LS that are described in the literature. We found that the range of histopathological characteristics known for adult LS are also present in juvenile vulvar LS, even at very young ages, including histopathological features associated with autoimmune disease, in support of the idea of a similar pathogenesis.


Public understanding of food risks in four European countries: a qualitative study.
In the wake of the 'bovine spongiform encephalopathy (BSE) crisis' there was renewed interest in how those responsible for public health could take account of public views, both to 'democratize' policy making and to increase the likelihood of information about health risks resonating with public concerns. This study explored how members of the public in four European countries (Finland, Germany, Italy and the UK) understood food risks in general, and risks arising from BSE in particular. The aims were to identify the sources of knowledge used and trusted by the public and to explore how public views could be accessed for public health information policy. Thirty-six focus group interviews were held using a common protocol across the four countries, including people from four life-cycle stages. The study demonstrated the utility of using focus groups as a relatively efficient method for accessing public views, and the feasibility of cross-national qualitative research on public views. We found that public views of food risks are neither irrational nor naïve, but that they do need to be interpreted in the context of everyday food purchasing decisions, in which particular food risks are unlikely to have the same salience as they do for experts. Focus groups are a feasible method for accessing public knowledge on public health risks to inform information strategies.


Nitric oxide regulates energy metabolism and Bcl-2 expression in intestinal epithelial cells.
Nitric oxide (NO) inhibits the respiration of mitochondria and enteric bacteria, particularly under low O2 concentration, and induces apoptosis of various types of cells. To gain insight into the molecular role of NO in the intestine, we examined its effects on the respiration, Ca2+ status, and expression of Bcl-2 in cultured intestinal epithelial cells (IEC-6). NO reversibly inhibited the respiration of IEC-6 cells, especially under physiologically low O2 concentration. Although NO elevated cytosolic Ca2+ as determined by the fura 2 method, the cells were fairly resistant to NO. Kinetic analysis revealed that prolonged exposure to NO elevated the levels of Bcl-2 and suppressed the NO-induced changes in Ca2+ status of the cells. Because Bcl-2 possesses antiapoptotic function, toxic NO effects might appear minimally in enterocytes enriched with Bcl-2. Thus NO might effectively exhibit its antibacterial action in anaerobic intestinal lumen without inducing apoptosis of Bcl-2-enriched mucosal cells.


High-resolution studies of lysis-lysogeny decision-making in bacteriophage lambda.
Cellular decision-making guides complex development such as cell differentiation and disease progression. Much of our knowledge about decision-making is derived from simple models, such as bacteriophage lambda infection, in which lambda chooses between the vegetative lytic fate and the dormant lysogenic fate. This paradigmatic system is broadly understood but lacking mechanistic details, partly due to limited resolution of past studies. Here, we discuss how modern technologies have enabled high-resolution examination of lambda decision-making to provide new insights and exciting possibilities in studying this classical system. The advent of techniques for labeling specific DNA, RNA, and proteins in cells allows for molecular-level characterization of events in lambda development. These capabilities yield both new answers and new questions regarding how the isolated lambda genetic circuit acts, what biological events transpire among phages in their natural context, and how the synergy of simple phage macromolecules brings about complex behaviors.


Five new species of philometrid nematodes (Philometridae) from marine fishes off Java, Indonesia.
Based on light and scanning electron microscopical studies, the following five species of the Philometridae (Nematoda: Dracunculoidea) are described from female specimens collected from marine fishes off the southwestern coast of Java, Indonesia: Philometra lobotidis sp. n. from the abdominal cavity of the Atlantic tripletail Lobotes surinamensis (Bloch) (Lobotidae, Perciformes); Philometra javaensis sp. n. from the abdominal cavity of the immaculate puffer Arothron immaculatus (Bloch et Schneider) (Tetraodontidae, Tetraodontiformes); Philometra psettoditis sp. n. from the musculature of the Indian spiny turbot Psettodes erumei (Bloch et Schneider) (Psettodidae, Pleuronectiformes); Philometroides indonesiensis sp. n. from the musculature of the hound needlefish Tylosurus crocodilus crocodilus (Péron et Lesueur) (Belonidae, Beloniformes); and Philometroides trichiuri sp. n. from the dorsal fin of the largehead hairtail Trichiurus lepturus Linnaeus (type host) and the savalai hairtail Lepturacanthus savala (Cuvier) (both Trichiuridae, Perciformes). All these new species are distinguished from their congeners parasitizing marine fishes by morphological (mainly the shape and structure of the cephalic and caudal ends and of the oesophagus) and biometrical features. Besides previously known Philometra pellucida (Jägerskiöld, 1893) and Philometra ocularis Moravec, Ogawa, Suzuki, Miyazaki et Donai, 2002, they are the only nominal philometrid species recorded from Indonesian waters.


K-ras and p16 aberrations confer poor prognosis in human colorectal cancer.
Mutations in the K-ras gene are frequent in human cancer. ras activation in primary cells results in a cellular senescence phenotype that is precluded by inactivation of p16. At the clinical level, this may imply a differential behavior for tumors with alternative or cooperative activation of K-ras function and impairment of p16 pathways. We have determined the presence of mutations in the K-ras gene and the methylation status of p16 promoter in a series of 119 prospectively collected colorectal carcinomas. p53 mutations and p14 alternative reading frame methylation status were also assessed. Associations with survival were investigated. K-ras mutations were present in 44 (38%) of 115 cases, and p16 methylation was present in 42 (37%) of 113 cases. p53 mutations were detected in 50% (56 of 115) and p14 methylation in 29% (32 of 112) of cases. K-ras and p16 alterations were independent genetic events. Presence of K-ras or p16 genetic alterations (analyzed independently) was associated with shorter survival, although differences were not statistically significant. Cox analysis of the two variables combined showed a diminished survival as the results of an interaction between p16 and K-ras. Alternative alteration of K-ras and p16 genes was an independent prognostic factor in human colorectal cancer in univariate and multivariate analysis. Differences were maintained when cases undergoing radical surgery and without distant metastases were considered. These results suggest that the combined K-ras and p16 analyses may be of prognostic use in human colorectal cancer.


Accelerated neoadjuvant chemotherapy of non-small cell lung cancer (NSCLC).
Thirty patients with marginally resectable stage IIIA or stage IIIB NSCLC were treated with cisplatin (80 mg/ m(2)/i.v./dl), ifosfamide (4,000 mg/m(2)/i.v./dl) and vinorelbine (30 mg/m(2)/i.v./dl) plus G-CSF 300 mu g/s.c. on days 7-12 every 14 days for three cycles before surgery. In 26 evaluable patients, the radiographically assessed response rate to chemotherapy was 77% (8% complete). Three septic deaths (10%) occurred in spite of G-CSF and 1 patient refused to continue after the first cycle. Thoracothomy was performed in 23 patients including 19 complete resections. At 15 months median follow-up (range 10-22+), 11/19 (57%) completely resected patients relapsed. The overall median time to treatment failure was 11 months (range 0-17). Actuarial survival probability at 12, 18 and 24 months are 56%, 43% and 36%, respectively. In conclusion, the combination of cisplatin, ifosfamide and vinorelbine in full doses at a 14 day interval (accelerated chemotherapy) was very effective in neoadjuvant NSCLC setting. Nevertheless, relevant toxicity was demonstrated with a 10% death rate probably due to the overlapping toxicity of chemotherapy cycles, suggesting the need for a more intense supportive care or longer interval between cycles.


Children living in prison with a primary caregiver: a global mapping of age restrictions and duration of stay.
Women represent a growing proportion of the global prison population of 11·5 million people. No reliable estimates exist of the number of pregnant women or number of children born in or living in prison with a primary caregiver. Permitting a child to stay in prison with a primary caregiver for any duration has advantages and disadvantages for both the caregiver and the child. Global consensus on the age at which child confinement inhibits healthy development has not been reached. Human rights violations worldwide illustrate the failures of prison systems to consider the needs of children and ensure humane standards for children living in detention. In this Health Policy, we map the global variation in age restrictions and durations of stay in prison with a primary caregiver. We show a broad range of approaches and provisions for the placement of children in prison. Policy makers are advised to adopt provisions of Article 30 of the African Charter on the Rights and Welfare of the Child, as it is the only set of explicit guidelines regarding individualised qualitative judicial decision-making processes, consideration of relevant safeguarding factors, practical application of permissions to stay in prison regarding standards of paediatric care, and provisions of safety-net supports on prison exit. Training of staff and routine monitoring of paediatric standards of detention by national prison inspectorates and UN Human Rights Treaty Bodies are crucial. Future research agendas must focus on optimal child safeguarding and development during transfer and confinement, and on requisite prison-exit supports in various cultural contexts and settings.


Complete sequence and organization of Antheraea pernyi nucleopolyhedrovirus, a dr-rich baculovirus.
The completion and reporting of baculovirus genomes is extremely important as it advances our understanding of gene function and evolution. Due to the large number of viral genomes now sequenced it is very important that authors present significantly detailed analyses to advance the understanding of the viral genomes. However, there is no report of the Antheraea pernyi nucleopolyhedrovirus (AnpeNPV) genome. The genome of AnpeNPV, which infects Chinese tussah silkworm (Antheraea pernyi), was sequenced and analyzed. The genome was 126,629 bp in size. The G+C content of the genome, 53.4%, was higher than that of most of the sequenced baculoviruses. 147 open reading frames (ORFs) that putatively encode proteins of 50 or more amino acid residues with minimal overlap were determined. Of the 147 ORFs, 143 appeared to be homologous to other baculovirus genes, and 4 were unique to AnpeNPV. Furthermore, there are still 29 and 33 conserved genes present in all baculoviruses and all lepidopteran baculoviruses respectively. In addition, the total number of genes common to all lepidopteran NPVs is sill 74, however the 74 genes are somewhat different from the 74 genes identified before because of some new sequenced NPVs. Only 6 genes were found exclusively in all lepidopteran NPVs and 12 genes were found exclusively in all Group I NPVs. AnpeNPV encodes v-trex(Anpe115, a 3' to 5' repair exonuclease), which was observed only in CfMNPV and CfDEFNPV in Group I NPVs. This gene potentially originated by horizontal gene transfer from an ancestral host. In addition, AnpeNPV encodes two conotoxin-like gene homologues (ctls), ctl1 and ctl2, which were observed only in HycuNPV, OpMNPV and LdMNPV. Unlike other baculoviruses, only 3 typical homologous regions (hrs) were identified containing 2~9 repeats of a 30 bp-long palindromic core. However, 24 perfect or imperfect direct repeats (drs) with a high degree of AT content were found within the intergenic spacer regions that may function as non-hr, ori-like regions found in GrleGV, CpGV and AdorGV. 9 drs were also found in intragenic spacer regions of AnpeNPV. AnpeNPV belongs to Group I NPVs and is most similar to HycuNPV, EppoNPV, OpMNPV and CfMNPV based on gene content, genome arrangement, and amino acid identity. In addition, analysis of genes that flank hrs supported the argument that these regions are involved in the transfer of sequences between the virus and host.


Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events.
There is considerable evidence that remnants of triglyceride-rich lipoproteins may be particularly atherogenic. Levels of lipoprotein lipids and of apolipoprotein B in low-density lipoproteins were measured in 335 men and women enrolled in a study in which quantitative coronary angiography was carried out at 2-year intervals. Clinical events related to coronary disease occurred in 129 patients during the trial and in the subsequent follow-up period of 4 to 6 years. In multivariate analysis controlled for a number of nonlipid risk factors, high-density lipoprotein cholesterol was inversely related to the mean percentage increase in coronary artery stenosis in both men and women. Neither plasma triglycerides nor low-density lipoprotein cholesterol, triglycerides, or apolipoprotein B was related to change in stenosis, but a measure of remnants of triglyceride-rich lipoproteins, which included cholesterol in intermediate-density lipoproteins, was directly related to lesion progression. The same relations for these measures of plasma lipoprotein concentrations were found to hold for clinical events related to coronary artery atherosclerosis. In patients with established coronary heart disease, increased levels of remnants of triglyceride-rich lipoproteins and decreased levels of high-density lipoproteins appear to promote progression of coronary artery atherosclerosis, which in turn may lead to an untoward clinical event. No such relation could be shown for the level of components of low-density lipoproteins. These and other observations call for reevaluation of relations between particular species of lipoproteins containing apolipoprotein B and the pathogenesis of coronary artery atherosclerosis and coronary heart disease.


National, clinical cohort study of late effects among survivors of acute lymphoblastic leukaemia: the ALL-STAR study protocol.
More than 90% of patients diagnosed with childhood acute lymphoblastic leukaemia (ALL) today will survive. However, half of the survivors are expected to experience therapy-related chronic or late occurring adverse effects, reducing quality of life. Insight into underlying risk trajectories is warranted. The aim of this study is to establish a Nordic, national childhood ALL survivor cohort, to be investigated for the total somatic and psychosocial treatment-related burden as well as associated risk factors, allowing subsequent linkage to nation-wide public health registers. This population-based observational cohort study includes clinical follow-up of a retrospective childhood ALL survivor cohort (n=475), treated according to a common Nordic ALL protocol during 2008-2018 in Denmark. The study includes matched controls. Primary endpoints are the cumulative incidence and cumulative burden of 197 health conditions, assessed through self-report and proxy-report questionnaires, medical chart validation, and clinical examinations. Secondary endpoints include organ-specific outcome, including cardiovascular and pulmonary function, physical performance, neuropathy, metabolic disturbances, hepatic and pancreatic function, bone health, oral and dental health, kidney function, puberty and fertility, fatigue, and psychosocial outcome. Therapy exposure, acute toxicities, and host genome variants are explored as risk factors. The study is approved by the Regional Ethics Committee for the Capital Region in Denmark (H-18035090/H-20006359) and by the Danish Data Protection Agency (VD-2018-519). Results will be published in peer-reviewed journals and are expected to guide interventions that will ameliorate the burden of therapy without compromising the chance of cure.


River sequesters atmospheric carbon and limits the CO2 degassing in karst area, southwest China.
CO2 fluxes across water-air interfaces of river systems play important roles in regulating the regional and global carbon cycle. However, great uncertainty remains as to the contribution of these inland water bodies to the global carbon budget. Part of the uncertainty stems from limited understanding of the CO2 fluxes at diurnal and seasonal frequencies caused by aquatic metabolism. Here, we measured surface water characteristics (temperature, pH, and DO, DIC, Ca2+ concentrations) and CO2 fluxes across the air-water interface at two transects of Guijiang River, southwest China to assess the seasonal and diurnal dynamics of fluvial carbon cycling and its potential role in regional and global carbon budgets. The two transects had differing bedrock; DM transect is underlain by carbonate and detrital rock and PY is underlain by pure carbonate. Our results show that the river water both degasses CO2 to and absorbs CO2 from the atmosphere in both summer and winter, but the degassing and absorption varied between the two transects. Further, CO2 fluxes evolve through diurnal cycles. At DM, the river evaded CO2 from early morning through noon and absorbed CO2 from afternoon through early morning. At PY in summer, the CO2 evasion decreased during the daytime and increased at night while in winter at night, CO2 uptake increased in the morning and decreased in the afternoon but remained relatively stable at night. Although the river is a net source of carbon to the atmosphere (~15mMm-2day-1), the evasion rate is the smallest of all reported world's inland water bodies reflecting sequestration of atmospheric carbon through the carbonate dissolution and high primary productivity. These results emphasize the need of seasonal and diurnal monitoring of CO2 fluxes across water-air interface, particularly in highly productive rivers, to reduce uncertainty in current estimates of global riverine CO2 emission.


[Three-dimensional visualization of CT of the neck for surgical planning].
Surgical planning in ENT profits from computer assisted preoperative visualization and planning. The informative capability is to be improved by three-dimensional illustrating of the preoperative available data. The possibility of a 3-D-visualization of lymph nodes stands in the center of the interest. 16 CT data sets with a tumor-classification of T1N1 or higher were included. Altogether 720 pseudo-3-D-illustrations were provided with an average of 9.3 objects. Current algorithms were used for the segmentation and visualization and the results were divided in three classes. The average time requirement for visualization and segmenting amounted to 122 minutes, the minimum value is at 61 minutes per data set. Automatic segmenting succeeded only with structures with clear grey tone differences to the environment. In all other cases an additional manual interaction had to take place. 3-D-Visualising of CT of the neck represents a new quality in preoperative planning. A clear trend at increasing detail loyalty and information efficiency showed up in the groups of B and C. It is possible to make from these pictures a quantitative statement on surgery relevant infiltration. Likewise conceivable are the postoperative quality control or planning and process control of a postoperative radio-chemotherapy. The automatic algorithms can be estimated as reliable. Application is still far from a clinically efficient use. With the rising efficiency of the computing systems, the improved software and the imaging systems the problems mentioned are, however, solvable.


Thoracoscopic right apical segmentectomy for lung cancer with tracheal bronchus and variable pulmonary vein: a case report and literature review.
A 51-year-old woman visited our hospital with a chief complaint of an abnormal chest shadow in the right lung detected during a routine annual check-up. Chest computed tomography showed a 14-mm ground-glass opacity in the right upper lobe, suspicious for lung cancer. At the same time, a tracheal bronchus originating directly from the trachea was observed. In addition to the tracheal bronchus, a pulmonary vein variation running dorsal to the pulmonary artery was detected. She underwent thoracoscopic apical segmentectomy and mediastinal lymph node sampling. Her postoperative course was uneventful. Tracheal bronchus is a rare anomaly, with an incidence of 0.1% to 2%. However, tracheal bronchus is often accompanied by pulmonary vessel variations, and care should thus be taken when performing thoracoscopic lung resection.


Meanings of people's lived experiences of surviving an out-of-hospital cardiac arrest, 1 month after the event.
The out-of-hospital cardiac arrest (OHCA) survival rate has been poor and stable for a long time, but more recent studies describe its increase. However, there are few studies in which people narrate their experiences from surviving. The aim of this study was to elucidate meanings of people's lived experiences of surviving an OHCA with validated myocardial infarction (MI) etiology, 1 month after the event. A purposive sample of 2 women and 9 men was interviewed between February 2011 and May 2012. A phenomenological hermeneutical method was used for analysis, which involved 3 steps: naive reading and understanding, structural analysis, and comprehensive understanding. There were 2 themes, (1) returning to life and (2) revaluing life, and five subthemes, (1a) waking up and missing the whole picture, (1b) realizing it was not time to die, (2a) wondering why and seeking explanations, (2b) feeling ambiguous in relations, and (2c) wondering whether life will be the same. All were constructed from the analysis. Surviving an OHCA with validated MI etiology meant waking up and realizing that one had experienced a cardiac arrest and had been resuscitated. These survivors had memory loss and a need to know what had happened during the time they were dead/unconscious. They searched for a reason why they experienced an MI and cardiac arrest and had gone from being "heart-healthy" to having a lifelong illness. They all had the experience of passing from life to death and back to life again. For the participants, these differences led to a revaluation of what is important in life.


Ocular Perfusion Pressure and Pulsatile Ocular Blood Flow in Normal and Systemic Hypertensive Patients.
Glaucomatous neuropathy can be a consequence of insufficient blood supply, increase in intraocular pressure (IOP), or other risk factors that diminish the ocular blood flow. To determine the ocular perfusion pressure (OPP) in normal and systemic hypertensive patients. One hundred and twenty-one patients were enrolled in this prospective and comparative study and underwent a complete ophthalmologic examination including slit lamp examination, Goldmann applanation tonometry, stereoscopic fundus examination, and pulsatile ocular blood flow (POBF) measurements. The OPP was calculated as being the medium systemic arterial pressure (MAP) less the IOP. Only right eye values were considered for calculations using Student's t-test. The mean age of the patients was 57.5 years (36-78), and 68.5% were women. There was a statistically significant difference in the OPP of the normal and systemic hypertensive patients (p < 0.05). The difference in the OPP between these groups varied between 8.84 and 17.9 mm Hg. The results of this study suggest that although the systemic hypertensive patients have a higher OPP in comparison to normal patients, this increase does not mean that they also have a higher OBF (as measured by POBF tonograph). This may be caused by chronic changes in the vascular network and in the blood hemodynamics in patients with systemic hypertension. How to cite this article: Kanadani FN, Figueiredo CR, Miranda RM, Cunha PLT, Kanadani TCM, Dorairaj S. Ocular Perfusion Pressure and Pulsatile Ocular Blood Flow in Normal and Systemic Hypertensive Patients. J Curr Glaucoma Pract 2015;9(1):16-19.


The role of oxytocin receptor gene (OXTR) DNA methylation (DNAm) in human social and emotional functioning: a systematic narrative review.
The neuropeptide Oxytocin (OXT) plays a central role in birthing, mother-infant bonding and a broad range of related social behaviours in mammals. More recently, interest has extended to epigenetic programming of genes involved in oxytocinergic neurotransmission. This review brings together early findings in a rapidly developing field of research, examining relationships between DNA methylation (DNAm) of the Oxytocin Receptor Gene (OXTR) and social and emotional behaviour in human populations. A systematic search across Web of Knowledge/Science, Scopus, Medline and EMBASE captured all published studies prior to June 2017 examining the association between OXTR DNAm and human social and emotional outcomes. Search terms included 'oxytocin gene' or 'oxytocin receptor gene' and 'epigenetics' or 'DNA methylation'. Any article with a focus on social and emotional functioning was then identified from this set by manual review. Nineteen studies met eligibility criteria. There was considerable heterogeneity of study populations, tissue samples, instrumentation, measurement, and OXTR site foci. Only three studies examined functional consequences of OXTR DNAm on gene expression and protein synthesis. Increases in OXTR DNAm were associated with callous-unemotional traits in youth, social cognitive deficits in Autistic Spectrum Disorder (ASD), rigid thinking in anorexia nervosa, affect regulation problems, and problems with facial and emotional recognition. In contrast, reductions in DNAm were associated with perinatal stress, postnatal depression, social anxiety and autism in children. Consistent with an emerging field of inquiry, there is not yet sufficient evidence to draw conclusions about the role of OXTR DNAm in human social and emotional behaviour. However, taken together, findings point to increased OXTR DNAm in general impairments in social, cognitive and emotional functioning, and decreased OXTR DNAm in specific patterns of impairment related to mood and anxiety disorders (but not in all). Future progress in this field would be enhanced by adequately powered designs, greater phenotypic precision, and methodological improvements including longitudinal studies with multiple time-points to facilitate causal inference.


Peer mentorship to promote effective pain management in adolescents: study protocol for a randomised controlled trial.
This protocol is for a study of a new program to improve outcomes in children suffering from chronic pain disorders, such as fibromyalgia, recurrent headache, or recurrent abdominal pain. Although teaching active pain self-management skills through cognitive-behavioral therapy (CBT) or a complementary program such as hypnotherapy or yoga has been shown to improve pain and functioning, children with low expectations of skill-building programs may lack motivation to comply with therapists' recommendations. This study will develop and test a new manualized peer-mentorship program which will provide modeling and reinforcement by peers to other adolescents with chronic pain (the mentored participants). The mentorship program will encourage mentored participants to engage in therapies that promote the learning of pain self-management skills and to support the mentored participants' practice of these skills. The study will examine the feasibility of this intervention for both mentors and mentored participants, and will assess the preliminary effectiveness of this program on mentored participants' pain and functional disability. This protocol will recruit adolescents ages 12-17 with chronic pain and randomly assign them to either peer mentorship or a treatment-as-usual control group. Mentored participants will be matched with peer mentors of similar age (ages 14-18) who have actively participated in various treatment modalities through the UCLA Pediatric Pain Program and have learned to function successfully with a chronic pain disorder. The mentors will present information to mentored participants in a supervised and monitored telephone interaction for 2 months to encourage participation in skill-building programs. The control group will receive usual care but without the mentorship intervention. Mentored and control subjects' pain and functioning will be assessed at 2 months (end of intervention for mentored participants) and at 4 month follow-up to see if improvements persist. Measures of treatment adherence, pain, disability, and anxiety and depression will be assessed throughout study participation. Qualitative interviews for mentors, mentored participants, and control subjects will also be administered. ClinicalTrials.gov NCT01118988.


The importance of cancer prevention policies to inform and guide preventative and screening measures for people with intellectual disabilities: The COST project "Cancer- Understanding Prevention in Intellectual Disabilities".
Cancer is a global public health problem, but its exact prevalence in people with intellectual disabilities is still uncertain. This population, with limited health skills and complex health needs, faces many challenges in cancer prevention, screening, timely diagnosis and treatment. Furthermore, they are often underrepresented in general cancer prevention and screening policies across Europe, leading to widened disparities in health outcomes and premature mortality. Thus, unified national and local policies are needed to reduce inequalities and promoting a pan-European inclusion of people with intellectual disabilities. Our goal is to raise public awareness of this issue, including the involvement of people with intellectual disabilities, and promote engagement from relevant stakeholders. The COST Action 'Cancer- Understanding Prevention in Intellectual Disabilities' (CUPID) project will address health inequalities faced by people with intellectual disabilities in relation to cancer, and support the development of policy recommendations specifically tailored to their unique cognitive and healthcare needs, having a positive long-term impact on quality of life.


Quantification of Lyssavirus-Neutralizing Antibodies Using Vesicular Stomatitis Virus Pseudotype Particles.
Rabies is a highly fatal zoonotic disease which is primarily caused by rabies virus (RABV) although other members of the genus Lyssavirus can cause rabies as well. As yet, 14 serologically and genetically diverse lyssaviruses have been identified, mostly in bats. To assess the quality of rabies vaccines and immunoglobulin preparations, virus neutralization tests with live RABV are performed in accordance with enhanced biosafety standards. In the present work, a novel neutralization test is presented which takes advantage of a modified vesicular stomatitis virus (VSV) from which the glycoprotein G gene has been deleted and replaced by reporter genes. This single-cycle virus was trans-complemented with RABV envelope glycoprotein. Neutralization of this pseudotype virus with RABV reference serum or immune sera from vaccinated mice showed a strong correlation with the rapid fluorescent focus inhibition test (RFFIT). Importantly, pseudotype viruses containing the envelope glycoproteins of other lyssaviruses were neutralized by reference serum to a significantly lesser extent or were not neutralized at all. Taken together, a pseudotype virus system has been successfully developed which allows the safe, fast, and sensitive detection of neutralizing antibodies directed against different lyssaviruses.


An Improved VLSI Design of the ALU Based FIR Filter for Biomedical Image Filtering Application.
FIR filter is the most widely used device in DSP applications, which is also applicable to integrate with image processing approaches. The ALU based FIR structure is applicable for various devices to increase the performance. The ALU design operation includes accumulation, subtraction, shifting, multiplication and filtering. Existing methods are designed with various multipliers like Wallace tree multiplier, DADDA multiplier, Vedic multiplier and adders like carry select adder, and carry look-ahead adder. The main objective is to reduce the area, delay and power factors since optimum VLSI circuit is employed in this paper. By these adders and multipliers, operations are independently enabling main operations in DSP. The FIR filter is designed using a MAC unit with clock regenerative comparators. In the field of the VLSI industry, the low power, reduced time, and area-efficient designs are mostly preferred for various applications. Adders and multipliers play a vital role in VLSI circuit designs. The recent electronics industry uses a digital filter for various real-time applications. This utilizes Finite Impulse Response (FIR) and Infinite Impulse Response (IIR) filters, here the FIR filter is most stable than IIR filter. This FIR filter indicates the impulse signal into finite form and it is used mainly in DSP processors for getting high-speed. In these two ALU and FIR circuits, the adders and multiplier block's usage is increased, it consumes much power. The proposed research work uses the clock-gating technique for reducing power consumption. Here the latch-based clock gating technique provides an efficient result. XOR-based logic circuit reduces the design complexity and utilizes the less area. Carry save accumulator is a digital adder used for addition. It provides the two set of output, which is partial sum and carry output. The ripple carry adder uses a full adder circuit for its operation. It propagates the carry value in the last bit. In addition, the combination of CSA and RCA utilizes less area, high speed and provides the better throughput. In multiplier block, the booth multiplier algorithm is used with XOR-based logic. Here this proposed FIR filter is designed for performing image filtration of retina image. This process improves the better visualization approach inthe medical field. Thus, the proposed ALU based FIR filter with a latch-based clock gating technique is designed and analyzed with various parameters. Here the modified adders and multipliers are proposed for the efficiency of the system. The modified carry save adder is proposed with combining ripple carry adder logic for improving the adders' performance. The enhanced booth multiplier is designed using add and shift method for reducing the numberof stages to calculate the result. This process is applied to perform image processing of the retina image. After designing the ALU based FIR filter structure in the VLSI environment, the image is loaded on the MATLAB as the .png format, then it is converted into a hex file, which is read from the Xilinx to perform filtering the process. Then the 'dataout' is converted into a binary file to obtain the result of the filtering process. The enhanced booth multiplier reduces the delay by reducing the number of stages to calculate the result. Here the clock gating technique is proposed with the latch-based design for reducing the dynamic and clock power consumption. The number of adder's circuit in both ALU and FIR circuits is less since it improves the overall efficiency of the system. Thus, the proposed methodology concluded that the design and analysis of ALU based FIR filter for medical image processing give the efficient result on the way of achieving the factors such as power (Static & Dynamic), Delay (Path delay) area utilization, MSE and PSNR. Here the image processing of FIR results to MSE and PSNR values, which obtained a better result than the existing VLSI based image processing works. The latch-based clock gating circuit is connected with the proposed circuit, based on the gated clock signal, it optimizes the gated circuit of the whole design since it also reduces the error and provides the efficient power report. This proposed VLSI model is simulated using Xilinx ISE 14.5 and Modelsim synthesizes it; here with the help of MATLAB, with the adaptation of the 2018a tool, the image filtering was done.


Cerebrovascular Events During Treatment for Systemic Malignant Tumors in Patients with Moyamoya Disease.
With the increasing incidence of malignancies, the importance of cancer-associated stroke is emphasized. Although moyamoya disease is a leading cause of stroke, no reports have documented cancer-associated stroke in patients with this condition. We aimed to investigate cerebrovascular events during malignancy treatments in patients with moyamoya disease. A total of 405 patients with moyamoya disease who visited our hospital between January 2000 and March 2022 were retrospectively examined. We evaluated the management of moyamoya disease, presence of the ring finger protein 213 p.Arg4810Lys variant, treatments for malignant tumors, presence of cerebrovascular events during treatment, and follow-up periods and outcomes. Among the 405 patients, 17 patients with moyamoya disease (4.2%) were diagnosed with malignancies. Among patients aged 60 years and over, 7 out of 67 (10.4%) had malignancies. Of the 17 patients, 11 (64.7%) were symptomatic, and 7 (41.2%) had revascularization surgery. 9 patients were treated with oral antiplatelet drugs. There was no significant difference between the groups with and without malignancy regarding the presence of the ring finger protein 213 p.Arg4810Lys variant (80.0% vs. 62.7%, P = 0.33). All patients underwent surgical treatment, and 7 (41.2%) received chemotherapy. One death due to tumor progression was reported. No cerebrovascular event was observed during malignancy treatments and follow-up periods, which had a mean duration of 6 years. In our cohort, malignancy treatments in patients with moyamoya disease were safely conducted without cerebrovascular events. However, it is advisable to avoid hypotension, dehydration, hyperventilation, and long-term discontinuation of antiplatelet drugs during the treatment of malignant tumors.


Malic dehydrogenase patterns in different strains of Schistosoma japonicum and subspecies of Oncomelania hupensis.
Malic dehydrogenase (MDH) of the Formosan Philippine and Indonesian Strains of Schistosoma japonicum and 3 subspecies of snails, Oncomelania hupensis formosana, O. h. quadrasi, and O. h. lindoensis were identified by disc electrophoresis with 10.5% acrylamide gel columns using tris-malic buffer. Male worm extracts of S. japonicum demonstrated 3, 2, and 2 clear MDH patterns and female worm extracts showed patterns of 2, 1 and 1 for the Formosan, Philippine and Indonesian strains of the parasite, respectively. MDH patterns were the same for all 3 subspecies of snails; one major and one minor band being found in all.


Collagen matrix in decompressive hemicraniectomy.
Decompressive hemicraniectomy is an accepted treatment for otherwise untreatable intracranial hypertension. The aim of this prospective randomized study is to evaluate the benefit of application of collagen matrix as an onlay graft to reduce operating time during hemicraniectomy and to facilitate dural dissection during second-stage cranioplasty. Thirty-four consecutive patients were randomized to receive collagen matrix during hemicraniectomy or to undergo the conventional procedure. Specific time points were recorded during hemicraniectomy and cranioplasty. Intra- and postoperative complications, time course of Glasgow Coma Scale, Barthel's, and Early Rehabilitation Indices were monitored. The surgeon had to rate the convenience of the procedure if collagen matrix was used. Cost implications are discussed. The use of collagen matrix during hemicraniectomy resulted in a reduction of combined operating time for hemicraniectomy and cranioplasty by an average of 19.7%. The rate of cerebrospinal fluid effusion during cranioplasty was 13% when collagen was used and 58% in the control group. None of the patients who received collagen developed cerebrospinal fluid effusion persisting longer than 1 week, compared with 33% of patients in the control group. A total of 85% of the surgeons rated the use of collagen matrix as being easier than usual; the rest did not see a difference. The use of collagen matrix to cover the dural defect during hemicraniectomy reduces operating time in hemicraniectomy and cranioplasty. The complication rate (cerebrospinal fluid effusion), total treatment time, and time on intensive care unit can be reduced, giving a potential for cost reduction. There was no difference in the rehabilitative outcome.


Identification of a highly conserved module in E proteins required for in vivo helix-loop-helix dimerization.
Basic helix-loop-helix (bHLH) transcription factors often function as heterodimeric complexes consisting of a tissue-specific factor such as SCL/tal or MyoD bound to a broadly expressed E protein. bHLH dimerization therefore appears to represent a key regulatory step in cell lineage determination and oncogenesis. Previous functional and structural studies have indicated that the well defined HLH domain is both necessary and sufficient for dimerization. Most of these studies, however, have employed in vitro systems for analysis of HLH dimerization, and their implications for the requirements for in vivo dimerization remain unclear. Using multiple approaches, we have analyzed bHLH dimerization in intact, living cells and have identified a novel domain in E proteins, domain C, which is required for in vivo dimerization. Domain C, which lies just carboxyl-terminal to helix 2 of the HLH domain, represents the most highly conserved region within E proteins and appears to influence the in vivo conformation of the adjacent HLH domain. These results suggest that HLH dimerization in vivo may represent a complex, regulated process that is distinct from HLH dimerization in vitro.


[Pathogenesis and combined surgical treatment of the pyonecrotic diabetic foot].
Three hundred and fifteen patients with necrotic forms of diabetic foot were examined and treated. Neuropathic infected form of diabetic foot was diagnosed in 45.7% patients, neuro-ischemic form--in 54.3%. Mixed aerobic-anaerobic infection in foot's necrotic focus was detected in 87.6% diabetic patients, only aerobic--in 12.4%. High level of intoxication was seen in these patients. Algorithm of complex surgical treatment of different forms of diabetic foot is presented.


CASC21, a FOXP1 induced long non-coding RNA, promotes colorectal cancer growth by regulating CDK6.
Emerging studies indicate that long non-coding RNAs (lncRNAs) play crucial roles in colorectal cancer (CRC). Here, we reported lncRNA CASC21, which is induced by FOXP1, functions as an oncogene in CRC. We systematically elucidated its clinical significance and possible molecular mechanism in CRC. LncRNA expression in CRC was analyzed by RNA-sequencing data in TCGA. The expression level of CASC21 in tissues was determined by qRT-PCR. The functions of CASC21 was investigated by in vitro and in vivo assays (CCK8 assay, colony formation assay, EdU assay, xenograft model, flow cytometry assay, immunohistochemistry (IHC) and Western blot). Chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP) and luciferase reporter assays were utilized to demonstrate the potential mechanisms of CASC21. CASC21 is overexpressed in CRC and high CASC21 expression is associated with poor survival. Functional experiments revealed that CASC21 promotes CRC cell growth. Mechanistically, we found that CASC21 expressed predominantly in the cytoplasm. CASC21 could interact with miR-539-5p and regulate its target CDK6. Together, our study elucidated that CASC21 acted as an oncogene in CRC, which might serve as a novel target for CRC diagnosis and therapy.


Single-Shot Holographic Compression from the Area Law.
The area law conjecture states that the entanglement entropy of a region of space in the ground state of a gapped, local Hamiltonian only grows like the surface area of the region. We show that, for any state that fulfills an area law, the reduced quantum state of a region of space can be unitarily compressed into a thickened boundary of the region. If the interior of the region is lost after this compression, the full quantum state can be recovered to high precision by a quantum channel only acting on the thickened boundary. The thickness of the boundary scales inversely proportional to the error for arbitrary spin systems and logarithmically with the error for quasifree bosonic systems. Our results can be interpreted as a single-shot operational interpretation of the area law. The result for spin systems follows from a simple inequality showing that any probability distribution with entropy S can be approximated to error ϵ by a distribution with support of size exp(S/ϵ), which we believe to be of independent interest. We also discuss an emergent approximate correspondence between bulk and boundary operators and the relation of our results to tensor network states.


Relation of antioxidants and level of dietary lipid to epidermal lipid peroxidation and ultraviolet carcinogenesis.
It has become increasingly evident that both quantity and quality of dietary lipid can influence the developmental course of several major forms of cancer in experimental animals. Using the hairless mouse-ultraviolet (UV) model, we had previously demonstrated that unsaturated lipid compared to equivalent levels of hydrogenated lipid enhanced photocarcinogenesis with respect to both tumor latency and multiplicity. In the present study using the same model, we have examined the effect of unsaturated lipid level and antioxidants upon epidermal lipid peroxidation and UV carcinogenesis. Sixteen groups of 45 animals each were used in the study, representing all combinations of three design variables: (a) a semipurified diet containing 4, 2, or 0.75% corn oil or 4% soybean oil; (b) 2% (w/w) antioxidant supplement or no supplementation; and (c) an escalating regimen of UV radiation to a cumulative dose of 70 J/cm2 or no irradiation. The nonirradiated groups served as nutritional controls and as subjects for epidermal lipid peroxidation measurements. An approximate linear relationship between lipid level and tumor latency was observed, with 4% levels of unsaturated lipid producing maximum enhancement of photocarcinogenesis. Furthermore with increasing lipid level the numbers of tumors per animal increased. Antioxidants caused significant increases in tumor latency and decreases in tumor multiplicity but only at the highest lipid level used in these studies. Thiobarbituric acid values of epidermal homogenates also increased in relation to the level of dietary lipid intake. Epidermal thiobarbituric acid values from antioxidant supplemented animals were significantly lower regardless of lipid intake levels. From these data we conclude that (a) dietary lipid level has a direct effect upon the carcinogenic response to UV both in regard to tumor latency and tumor multiplicity; (b) antioxidants produce an inhibitory effect almost equal to the degree of exacerbation of carcinogenesis evoked by increasing lipid levels, at least for the range studied; and (c) dietarily administered antioxidants inhibit the formation of epidermal thiobarbituric acid reacting materials. These data strongly imply that free radical reactions, specifically lipid peroxidation, play a role in at least a part of the photocarcinogenic response.


In vitro differentiation of hepatic progenitor cells from mouse embryonic stem cells induced by sodium butyrate.
Recently it was shown that embryonic stem (ES) cells could differentiate into hepatocytes both in vitro and in vivo, however, prospective hepatic progenitor cells have not yet been isolated and characterized from ES cells. Here we presented a novel 4-step procedure for the differentiation of mouse ES cells into hepatic progenitor cells and then hepatocytes. The differentiated hepatocytes were identified by morphological, biochemical, and functional analyses. The hepatic progenitor cells were isolated from the cultures after the withdrawal of sodium butyrate, which was characterized by scant cytoplasm, ovoid nuclei, the ability of rapid proliferation, expression of a series of hepatic progenitor cell markers, and the potential of differentiation into hepatocytes and bile duct-like cells under the proper conditions that favor hepatocyte and bile epithelial differentiation. The differentiation of hepatocytes from hepatic progenitor cells was characterized by a number of hepatic cell markers including albumin secretion, upregulated transcription of glucose-6-phosphatase and tyrosine aminotransferase, and functional phenotypes such as glycogen storage. The results from our experiments demonstrated that ES cells could differentiate into a novel bipotential hepatic progenitor cell and mature into hepatocytes with typical morphological, phenotypic and functional characteristics, which provides an useful model for the studies of key events during early liver development and a potential source of transplantable cells for cell-replacement therapies.


A case report of recessive myotonia congenita and early onset cognitive impairment: Is it a causal or casual link?
Myotonia congenita (MC) is a non-dystrophic myotonia inherited either in dominant (Thomsen) or recessive (Becker) form. MC is due to an abnormal functioning of skeletal muscle voltage-gated chloride channel (CLCN1), but the genotype/phenotype correlation remains unclear. A 48-year-old man, from consanguineous parents, presented with a fixed muscle weakness, muscle atrophy, and a cognitive impairment. Notably, his brother presented the same mutation but with a different phenotype, mainly involving cognitive function. The patient was submitted to cognitive assessment, needle electromyography, brain and muscle MRI, and genetic analysis. The Milan Overall Dementia Assessment showed short-term memory, verbal fluency and verbal intelligence impairment. His genetic analysis showed a recessive splice-site mutation in the CLCN1 gene (IVS19+2T>A). Muscle MRI revealed a symmetric and bilateral fat infiltration of the tensor of fascia lata, gluteus medius, and gluteus maximus muscles, associated to mild atrophy. Recessive myotonia congenita was diagnosed. Further studies should establish if and to which extent the CLCN1 mutation is responsible for this c MC phenotype, taking into account a gene-gene and /or a gene-environment.


Wound botulism.
Botulism occurring in patients with wounds has been thought of as a rare disease. A patient with a lacerating wound of his hand and wrist and an avulsion of his fourth finger developed diplopia, dizziness, and slurred speech one week later, followed by generalized weakness and difficulty in swallowing. Repetitive nerve stimulation studies showed signs of neuromuscular block consistent with the diagnosis of botulism. Results of bacteriologic and immunologic tests were not revealing, but the subsequent course of progressing, and retrogressing, bulbar signs and symptoms with eventual nearcomplete recovery confirmed the diagnosis. Increasing awareness and employment of electrophysiologic studies are uncovering increasing numbers of cases.


Evaluation of Capiox FX05 oxygenator with an integrated arterial filter on trapping gaseous microemboli and pressure drop with open and closed purge line.
Gaseous microemboli (GME) remain a challenge for cardiopulmonary bypass (CPB) because there is a positive correlation between microemboli exposure during CPB and postoperative neurological injury. Thus, minimizing the number of GME delivered to pediatric patients undergoing CPB procedures would lead to better clinical outcomes. In this study, we used a simulated CPB model to evaluate the effectiveness of capturing GME and the degree of membrane pressure drop for a new membrane oxygenator, Capiox Baby FX05 (Terumo Corporation,Tokyo, Japan), which has an integrated arterial filter with open and closed purge line.We used identical components in this study as our clinical CPB circuit. Three emboli detection and classification quantifier transducers were placed at prepump, preoxygenator, and postoxygenator sites in the circuit.Two flow probes as well as three pressure transducers were placed upstream and downstream of the oxygenator. The system was primed with human blood titrated to 30% hematocrit with Lactated Ringer's solution.A bolus of air (1 mL) was injected in the prepump site under nonpulsatile perfusion mode at three flow rates (500,750, and 1000 mL/min) and with the purge line either open or closed. Six trials were performed for each unique set-up for a total of 36 trials.All trials were conducted at 35°C. The circuit pressure was kept constant at 100 mm Hg. Both the size and quantity of microemboli detected at postoxygenator site were recorded for 5 min postair injection. It was found that total counts of GME were significantly reduced with the purge line open when compared to keeping the purge line closed (P < 0.0001 at 1000 mL/min). At all flow rates, most of the GME were under 20 microns in size. In terms of microemboli greater than 40 microns, the counts were significantly higher with the purge line closed compared to keeping the purge line open at flow rates of 750 mL/min and 1000 mL/min (P < 0.01). At all flow rates,there is a tiny difference of less than 1 mmHg in membrane pressure drop between keeping the purge line open and closed, which is due to the small arteriovenous (A-V) shunt(P < 0.001). These results suggest that the integrated arterial filter of the Capiox FX05 oxygenator significantly improves the capturing of GME but has little impact on membrane pressure drop.


Actions that young people can take to prevent depression, anxiety and psychosis: beliefs of health professionals and young people.
Members of the public know about actions they can take to prevent major physical diseases, but there has been less attention to the public's capacity to take action to prevent mental disorders. Since mental disorders often have first onset during youth, young people's beliefs about prevention are of particular relevance. Young people's prevention beliefs were assessed by a national telephone survey of 3746 Australian youth aged 12-25 years. To allow a comparison with professional beliefs, postal surveys were carried out with 470 GPs, 591 psychiatrists, 736 psychologists and 522 mental health nurses. Respondents were asked to rate the helpfulness of 9 potential strategies in relation to the prevention of four disorders: depression, depression with alcohol misuse, social phobia and psychosis. Both young people and professionals believed that mental disorders could be prevented by physical activity, keeping contact with family and friends, avoiding use of substances, and making time for relaxing activities. However, professionals disagreed with young people about the benefits of avoiding stressful situations, particularly for social phobia. Professionals were also less optimistic about the prevention of psychosis than depression and anxiety. The surveys assessed beliefs, but not actual use of preventive strategies. Given the beliefs of young people and professionals that prevention is possible, there is fertile ground for health promotion in this area. However, young people need to be aware that avoiding stressful situations may not be helpful for anxiety.


In vivo paracrine interaction between urokinase and its receptor: effect on tumor cell invasion.
Numerous studies have linked the production of increased levels of urokinase type plasminogen activator (uPA) with the malignant phenotype. It has also been shown that a specific cell surface receptor can bind uPA through a domain distinct and distant from the proteolytic domain. In an in vivo model of invasion, consisting of experimentally modified chorioallantoic membrane (CAM) of a chick embryo, only cells that concurrently expressed both uPA and a receptor for uPA, and in which the receptor was saturated with uPA, were efficient in invasion. To test whether uPA produced by one cell can, in a paracrine fashion, affect the invasive capacity of a receptor-expressing cell, we transfected LB6 mouse cells with human uPA (LB6[uPA]), or human uPA-receptor cDNA (LB6[uPAR]). LB6(uPA) cells released into the medium 1-2 Ploug units of human uPA per 10(6) cells in 24 h. The LB6(uPAR) cells expressed on their surface approximately 12,000 high affinity (Kd 1.7 x 10(-10) M uPA binding sites per cell. Unlabeled LB6(uPA) and 125-IUdR-labeled LB6(uPAR) cells were coinoculated onto experimentally wounded and resealed CAMs and their invasion was compared to that of homologous mixtures of labeled and unlabeled LB6(uPAR) or LB6(uPA) cells. Concurrent presence of both cell types in the CAMs resulted in a 1.8-fold increase of invasion of the uPA-receptor expressing cells. A four-fold stimulation of invasion was observed when cells were cocultured in vitro, prior to in vivo inoculation. Enhancement of invasion was prevented in both sets of experiments by treatment with specific antihuman uPA antibodies, indicating that uPA was the main mediator of the invasion-enhancing, paracrine effect on the receptor-expressing cells.


Canine leishmaniosis and its relationship to human visceral leishmaniasis in Eastern Uzbekistan.
The Namangan Region in the Pap District, located in Eastern Uzbekistan is the main focus of visceral leishmaniasis (VL) in Uzbekistan. In total, 28 cases of human VL were registered during 2006-2008 in this region. A study on the epidemiology of VL in this area was carried out in 2007-2008 in the villages of Chodak, Oltinkan, Gulistan and Chorkesar located at elevations of 900-1200 above sea level. A total of 162 dogs were tested for Leishmania infection. Blood was drawn for serology and PCR. When clinical signs of the disease were present, aspirates from lymph nodes and the spleen were taken. Forty-two dogs (25.9%) had clinical signs suggestive of VL and 51 (31.5%) were sero-positive. ITS-1 PCR was performed for 135 dogs using blood and tissue samples and 40 (29.6%) of them were PCR-positive. Leishmanial parasites were cultured from lymph node or spleen aspirates from 10 dogs.Eight Leishmania strains isolated from dogs were typed by multi-locus microsatellite typing (MLMT) and by multilocus enzyme electrophoretic analysis (MLEE), using a 15 enzyme system. These analyses revealed that the strains belong to the most common zymodeme of L. infantum, i.e., MON-1, and form a unique group when compared to MON-1 strains from other geographical regions. The data obtained through this study confirm the existence of an active focus of VL in the Namangan region of Uzbekistan. The fact that L. infantum was the causative agent of canine infection with typical clinical signs, and also of human infection affecting only infants, suggests that a zoonotic form of VL similar in epidemiology to Mediterranean VL is present in Uzbekistan.


Mammographic screening for breast cancer. What cancers do we find?
The aim of this study was to compare lymph node involvement of breast cancer cases detected at mammography screening with clinically-detected cases. During a 3-year period, 273 primary breast cancers were detected in a population-based screening programme, and 149 primary breast cancers were diagnosed clinically. Lymph node involvement was evaluated in univariate and multivariate logistic regression models correcting for tumour size, histological grade, steroid receptor status and DNA-ploidy. Patients with screen-detected cancers had a low relative risk of having lymph node metastases (univariate, OR = 0.31; 95% confidence interval = 0.19-0.52). In the multivariate logistic regression model, the relative risk was halved (OR = 0.47; 0.28-0.78). The reduced risk was more pronounced for women younger than 50 years of age compared to older women. The risk for screen-detected cases of having lymph node metastases at diagnosis was statistically significantly lower than for clinically-detected cases. The marked reduction, even when correcting for tumour size, makes it less likely that factors such as detection of clinically innocent tumours, length bias sampling or clinical symptoms related to axillary metastases can explain the whole difference. The results indicate at least part of the effect may be explained by tumour progression in the late preclinical detectable phase.


Aortic valve replacement in a young patient with essential thrombocytosis.
Essential Thrombocythcythaemia (ET) is an uncommon type of myeloproliferative disorder, characterised by both thrombotic and haemorrhagic diathesis. No clear guidelines exist for the pre- and post-operative management of patients undergoing cardiac surgery in the haematological and surgical literature. This condition has profound implications in patients undergoing cardiac surgery with the use of cardiopulmonary bypass, where heparin is used for anti-coagulation. This dilemma is further compounded in the setting of a young patient undergoing aortic valve replacement (AVR), where insertion of a mechanical prosthesis would be the procedure of choice. This would require life-long anticoagulation with warfarin which can predispose these patients to catastrophic bleeding. Using a tissue valve will subject the patient to multiple redo operations in the patient's lifetime. We report a young patient with ET requiring AVR and discuss the dilemmas surrounding the choice of prosthesis in this patient.


Latex agglutination in the diagnosis of meningococcal meningitis.
Group-specific polysaccharides of Neisseria meningitidis groups A and C have been demonstrated by means of a rapid, sensitive slide agglutination test with latex particles coated with antibodies. In this manner, the diagnosis can be made from the cerebrospinal fluid of patients with meningococcal meningitis caused by serogroups A or C even when the culture is negative. The method appears to be more sensitive than countercurrent immunoelectrophoresis and less elaborate.


Overcoming the Crystallization Bottleneck: A Family of Gigantic Inorganic {Pdx }(L) (x=84, 72) Palladium Macrocycles Discovered using Solution Techniques.
The {Pd84 }(Ac) wheel, initially discovered serendipitously, is the only reported giant palladium macrocycle-a unique structure that spontaneously assembles from small building blocks. Analogues of this structure are elusive. A new modular route to {Pd84 }(Ac) is described, allowing incorporation of other ligands, and a new screening approach to cluster discovery. Structural assignments were made of new species from solution experiments, overcoming the need for crystallographic analysis. As a result, two new palladium macrocycles were discovered: a structural analogue of the existing {Pd84 }(Ac) wheel with glycolate ligands, {Pd84 }(Gly) , and the next in a magic number series for this cluster family-a new {Pd72 }(Prop) wheel decorated with propionate ligands. These findings confirm predictions of a magic number rule for the family of {Pdx } macrocycles. Furthermore, structures with variable fractions of functional ligands were obtained. Together these discoveries establish palladium clusters as a new class of tunable nanostructures. In facilitating the discovery of species that would not have been discovered by orthodox crystallization approaches, this work also demonstrates the value of solution-based screening and characterization in cluster chemistry, as a means to decouple cluster formation, discovery, and isolation.


[Surgical treatment of autoimmune thyroiditis].
The authors used combined modality therapy including clinical, laboratory, x-ray, radiological, immunological and histological methods to diagnose autoimmune thyroiditis. Enlargement of the thyroid up to the 3-4 th degree, signs of compression or shift of the trachea and esophagus, the presence of nodes, progressive goiter growth and suspected malignant transformation served as indications for surgical intervention. Subfascial extirpation of the thyroid can be an operation of choice in surgical treatment of Hoshimoto's thyroiditis. A question of the time of surgical intervention cannot be considered completely solved.