Zwitterlation mitigates protein bioactivity loss in vitro over PEGylation.
Conjugation with poly(ethylene glycol) (PEG) or PEGylation is a widely used tool to overcome the shortcomings of native proteins, such as poor stability, inadequate pharmacokinetic (PK) profiles, and immunogenicity. However, PEGylation is often accompanied by an unwanted detrimental effect on bioactivity, particularly, resulting from the amphiphilic nature of PEG. This is especially true for PEGylated proteins with large binding targets. Pegasys, a PEGylated interferon alpha-2a (IFN-α2a) bearing a 40 kDa branched PEG, is a typical example that displays only 7% in vitro activity of the unmodified IFN-α2a. In this work, by employing IFN-α2a as a model protein, we demonstrated that a protein conjugated with zwitterionic polymers (or zwitterlation) could significantly mitigate the antiproliferative bioactivity loss in vitro after polymer conjugation. The retained antiproliferative activity of zwitterlated IFN-α2a is 4.4-fold higher than that of the PEGylated IFN-α2a with the same polymer molecular weight, or 3-fold higher than that of the PEGylated IFN-α2a with a similar hydrodynamic size. It is hypothesized that nonspecific interactions between zwitterionic polymers and IFN-α2a/IFN-α2a receptors can be mitigated due to the super-hydrophilic nature of zwitterionic polymers. This, in turn, reduces the 'nonspecific blocking' between IFN-α2a and IFN-α2a receptors. In addition, we demonstrated that zwitterlated IFN-α2a showed a prolonged circulation time and a mitigated accelerated blood clearance after repeated injections in rats.


[Surveillance of communicable diseases in Europe; more than just a means of communication among national institutes].
The re-emergence of infectious diseases as a threat to the health of the public has led to the initiation of several surveillance programmes in the European community. The impact of these Europe-wide surveillance programmes, including the surveillance of antibiotic resistance, will depend on the ability of the epidemiologists involved to gather validated data that accurately reflect the trends in the occurrence of infectious diseases and of antibiotic resistances. The results of surveillance should be communicated not only between the national institutes but should also reach the medical communities and the public at large in the participating countries.


An ethical exploration of the narratives surrounding substance use and pain management at the end of life: a discussion paper.
This discussion article examines narrative positioning related to pain management for people who use substances at the end of life. We explore how dominant narrative genres associated with biomedicine, such as 'restitution' and narratives common within the context of drug services such as 'recovery' can hinder effective pain management within this population. We argue that these discourses can marginalise the ethical self-identity of patients who use substances at the end of life. It can also trouble health and social care professionals in supporting patients and generating counter-narratives that challenge those often associated with substance use. Stigma is a common experience for this population with stereotyping as 'junkies' and associated with criminality. They are positioned as drug-seeking, and this requires more surveillance at the end of life when opioid therapy is potentially more available and authorised. This can make it challenging to generate 'companion' stories that are positive and maintain moral adequacy. Dominant biomedical narrative genres often prevent the recognition of the fractured stories that people using substances can often present with. This can lead to narrative silencing and to the under treatment of pain. The person's self-identity is invested in narratives of recovery, and opioid use symbolises their addicted past because for practitioners, this population is at clinical risk with the potential for drug seeking behaviours. Whilst not requiring formal ethical review this discussion paper was constructed in accordance with good scientific practice with the work of other researchers respected and cited appropriately.


Altered Synchronizations among Neural Networks in Geriatric Depression.
Although major depression has been considered as a manifestation of discoordinated activity between affective and cognitive neural networks, only a few studies have examined the relationships among neural networks directly. Because of the known disconnection theory, geriatric depression could be a useful model in studying the interactions among different networks. In the present study, using independent component analysis to identify intrinsically connected neural networks, we investigated the alterations in synchronizations among neural networks in geriatric depression to better understand the underlying neural mechanisms. Resting-state fMRI data was collected from thirty-two patients with geriatric depression and thirty-two age-matched never-depressed controls. We compared the resting-state activities between the two groups in the default-mode, central executive, attention, salience, and affective networks as well as correlations among these networks. The depression group showed stronger activity than the controls in an affective network, specifically within the orbitofrontal region. However, unlike the never-depressed controls, geriatric depression group lacked synchronized/antisynchronized activity between the affective network and the other networks. Those depressed patients with lower executive function has greater synchronization between the salience network with the executive and affective networks. Our results demonstrate the effectiveness of the between-network analyses in examining neural models for geriatric depression.


Can notochordal cells promote bone marrow stromal cell potential for nucleus pulposus enrichment? A simplified in vitro system.
Bone marrow stromal cells (BMSCs) have shown promising potential to stop intervertebral disc degeneration in several animal models. In order to restore a healthy state, though, this potential should be further stimulated. Notochordal cells (NCs), influential in disc development, have been shown to stimulate BMSC differentiation, but it is unclear how this effect will translate in an environment where resident disc cells (nucleus pulposus cells [NPCs]) could also influence BMSCs. The goal of this study was, therefore, to evaluate the effects of NCs on BMSCs when cocultured with NPCs, in a simplified 3D in vitro system. Bovine BMSCs and NPCs were mixed (Mix) and seeded into alginate beads. Using culture inserts, the Mix was then cocultured with porcine NCs (alginate beads) and compared to coculture with empty beads or porcine skin fibroblasts (SFs, alginate beads). NPCs alone were also cocultured with NCs, and BMSCs alone cultured under chondrogenic conditions. The effects of coculture conditions on cell viability, matrix production (proteoglycan and collagen), and gene expression of disc markers (aggrecan, type II collagen, and SOX9) were assessed after 4 weeks of culture. The NC phenotype and gene expression profile were also analyzed. Coculture with NCs did not significantly influence cell viability, proteoglycan production, or disc marker gene expression of the Mix. When compared to NPCs, the Mix produced the same amount of proteoglycan and displayed a higher expression of disc marker, indicating a stimulation of the BMSCs (and/or NPCs) in the Mix. Additionally, during the 4 weeks of culture, the NC phenotype changed drastically (morphology, gene expression profile). These results show that NCs might not be as stimulatory for BMSCs in an NPC-rich environment, as believed from individual cultures. This absence of effects could be explained by a mild stimulation provided by (de)differentiating NCs and the costimulation of BMSCs and NPCs by each other.


A surgical technique to prevent tracheostomal stenosis after laryngectomy.
Tracheostomal stenosis after total laryngectomy is a frequently occurring nuisance to both the patient and the surgeon. Although many causes may contribute to the development of tracheostomal stenosis, operative technique seems to play a major role. The authors describe and explain their method of stomal construction. Over a 10-year period they have used the described method on 260 patients undergoing a total laryngectomy, with an incidence of tracheostomal stenosis of 6%.


Activation of beta-catenin by carcinogenic Helicobacter pylori.
Persistent gastritis induced by Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the distal stomach, yet only a fraction of colonized persons ever develop gastric cancer. The H. pylori cytotoxin-associated gene (cag) pathogenicity island encodes a type IV secretion system that delivers the bacterial effector CagA into host cells after bacterial attachment, and cag+ strains augment gastric cancer risk. A host effector that is aberrantly activated in gastric cancer precursor lesions is beta-catenin, and activation of beta-catenin leads to targeted transcriptional up-regulation of genes implicated in carcinogenesis. We report that in vivo adaptation endowed an H. pylori strain with the ability to rapidly and reproducibly induce gastric dysplasia and adenocarcinoma in a rodent model of gastritis. Compared with its parental noncarcinogenic isolate, the oncogenic H. pylori strain selectively activates beta-catenin in model gastric epithelia, which is dependent on translocation of CagA into host epithelial cells. Beta-catenin nuclear accumulation is increased in gastric epithelium harvested from gerbils infected with the H. pylori carcinogenic strain as well as from persons carrying cag+ vs. cag- strains or uninfected persons. These results indicate that H. pylori-induced dysregulation of beta-catenin-dependent pathways may explain in part the augmentation in the risk of gastric cancer conferred by this pathogen.


Midtrimester pregnancy termination for fetal malformations. Use of intravaginal prostaglandin E2.
To compare outcome differences and responses to treatment in pregnancies complicated by either major fetal malformations or previous fetal death in the second trimester. Data were analyzed from a computerized perinatal database and individual hospital records for singleton gestations between 14 and 23 weeks undergoing labor induction with prostaglandin E2 (PGE2) suppositories (20 mg intravaginally every three to five hours). Between January 1993 and June 1995, 65 pregnancies underwent induction of labor for either a lethal fetal malformation (38) or death (27). As compared with the fetal death group, the malformation group required more suppositories (median 4, range 1-10, versus median 3, range 1-6; P < .05) and needed a greater total dosage (77.5 +/- 38.5 mg versus 61.8 +/- 37.8 mg, P < .05). The mean time from initiation of treatment until delivery was two hours longer in the malformation group. There were no significant differences between the two treatment groups in incidence of maternal side effects or of retained placentas requiring operative intervention. Patients who undergo second-trimester induction of labor for major fetal malformations using intravaginal PGE2 should be counseled that the dosage of the drug is greater and that labor may last longer than in pregnancies complicated by a previous fetal death.


Association analysis of the Cadherin13 gene with schizophrenia in the Japanese population.
Cadherin13 (CDH13) is a glycosylphosphatidylinositol-anchored cell adhesion molecule that plays a crucial role in morphogenesis and the maintenance of neuronal circuitry. CDH13 has been implicated in the susceptibility to a variety of psychiatric diseases. A recent genome-wide association study using Danish samples showed, for the first time, the involvement of a single nucleotide polymorphism (SNP) of CDH13 (intronic SNP rs8057927) in schizophrenia. Here, we investigated the association between other SNPs of CDH13 and schizophrenia and tried to replicate the association for the SNP of rs8057927, in the Japanese population. Using TaqMan(®) SNP genotyping assays, five tag SNPs (rs12925602, rs7193788, rs736719, rs6565051, and rs7204454) in the promoter region of CDH13 were examined for their association with schizophrenia in two independent samples. The first sample comprised 665 patients and 760 controls, and the second sample comprised 677 patients and 667 controls. One tag SNP for rs8057927 was also examined for the association with schizophrenia in the first sample set. A GACAG haplotype of the five SNPs in the promoter region of CDH13 was significantly associated with schizophrenia in the first sample set (P=0.016 and corrected P=0.098). A combined analysis of the GACAG haplotype with the second sample set enhanced the significance (P=0.0026 and corrected P=0.021). We found no association between rs8057927 and schizophrenia in the first sample set. Our results suggest that CDH13 may contribute to the genetic risk of schizophrenia. Further replication on the association of CDH13 with schizophrenia and functional studies are required to confirm the current findings.


Liver Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells.
Liver cancer is the second most common cause of cancer-related death. The major forms of primary liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Both these tumors develop against a background of cirrhotic liver, non-alcoholic fatty liver disease, chronic liver damage and fibrosis. HCC is a heterogeneous disease which usually develops within liver cirrhosis related to various etiologies: hepatitis B virus (HBV) infection (frequent in Asia and Africa), hepatitis C virus (HCV), chronic alcohol abuse, or metabolic syndrome (frequent in Western countries). In cirrhosis, hepatocarcinogenesis is a multi-step process where pre-cancerous dysplastic macronodules transform progressively into HCC. The patterns of genomic alterations observed in these tumors were recently identified and were instrumental for the identification of potential targeted therapies that could improve patient care. Liver cancer stem cells are a small subset of undifferentiated liver tumor cells, responsible for cancer initiation, metastasis, relapse and chemoresistance, enriched and isolated according to immunophenotypic and functional properties: cell surface proteins (CD133, CD90, CD44, EpCAM, OV-6, CD13, CD24, DLK1, α2δ1, ICAM-1 and CD47); the functional markers corresponding to side population, high aldehyde dehydrogenase (ALDH) activity and autofluorescence. The identification and definition of liver cancer stem cells requires both immunophenotypic and functional properties.


Labour market income inequality and mortality in North American metropolitan areas.
To investigate relations between labour market income inequality and mortality in North American metropolitan areas. An ecological cross sectional study of relations between income inequality and working age (25-64 years) mortality in 53 Canadian (1991) and 282 US (1990) metropolitan areas using four measures of income inequality. Two labour market income concepts were used: labour market income for households with non-trivial attachment to the labour market and labour market income for all households, including those with zero and negative incomes. Relations were assessed with weighted and unweighted bivariate and multiple regression analyses. US metropolitan areas were more unequal than their Canadian counterparts, across inequality measures and income concepts. The association between labour market income inequality and working age mortality was robust in the US to both the inequality measure and income concept, but the association was inconsistent in Canada. Three of four inequality measures were significantly related to mortality in Canada when households with zero and negative incomes were included. In North American models, increases in earnings inequality were associated with hypothetical increases in working age mortality rates of between 23 and 33 deaths per 100 000, even after adjustment for median metropolitan incomes. This analysis of labour market inequality provides more evidence regarding the robust nature of the relation between income inequality and mortality in the US. It also provides a more refined understanding of the nature of the relation in Canada, pointing to the role of unemployment in generating Canadian metropolitan level health inequalities.


Urologic diseases in America project: urinary incontinence in males--demographics and economic burden.
We quantified and describe the demographics and economic burden of male urinary incontinence in the United States of America. The analytic methods used to generate these results have been described previously. Urinary incontinence (UI) affects men of all ages, including 17% of males older than 60 years in the United States, which is an estimated 3.4 million men. There is a strong trend toward an increasing prevalence of UI with increasing age as well as an increase in the prevalence of UI in males with time. Ethnicity has less of a role in prevalence estimates in men than in women. The largest impact of UI in elderly men is in physician office visits, followed by outpatient services and surgeries. Resource use is greatest in the nursing home setting, where more than half of men have UI and require assistance with toileting. The overall economic burden for male UI is estimated at 18.8 billion dollars in direct medical costs in 1998/1999 dollars. Medical expenditures for UI for male Medicare beneficiaries 65 years and older have doubled since 1992. Compared to persons without UI the presence of UI increases the annual expenditures per person yearly from 3,204 dollars to 7,702 dollars. The direct and indirect costs of male UI increased throughout the 1990s with annual expenditures per person yearly in men with UI more than double that in men without UI. Given the aging population and staggering impact of UI in nursing home settings, there is a compelling need for further research into effective prevention, treatment and management strategies.


Organization and activities of the International Radio Medical Centre (CIRM).
The International Radio Medical Centre (CIRM) was founded in 1935, to provide free medical assistance by radio to ships with no doctor on board and others who cannot be reached by a doctor. In 1950 CIRM was established as a non-profit-making foundation and has benefited since 1957 from an annual contribution from the Italian government. The results achieved by the Centre over 61 years include medical assistance to 42,935 patients on board ships (as well as on small islands and aircraft), with 375,264 medical messages received and transmitted. CIRM is organized into a medical service, a telecommunications service and a studies section. The 24-h continuous medical service is provided by doctors at the CIRM headquarters. The doctor on duty gives instructions for managing the case. If necessary the medical service will coordinate the patient's hospitalization at the nearest port with suitable medical facilities or arrange the patient's transfer to another ship with a doctor on board, or an airlift. The telecommunications service receives requests for assistance, locates the ship or whoever made the request, passes the call to the doctor on duty, and relays the doctor's response to those requesting assistance. The studies section, established in 1957-58, researches occupational pathologies of sailors and contributes to their prevention. This provides a scientific basis for improving medical assistance to sailors at sea.


Subjective and objective sleep in young people with borderline personality disorder features.
Characterising sleep in young people (aged 15-25 years) with borderline personality disorder (BPD) features is crucial given the association between BPD features and sleep disturbance, negative consequences of poor sleep, and normative developmental sleep changes that occur in this age group. The present study aimed to characterise the sleep profile of young people with BPD to determine whether this profile is non-normative and specific to BPD. Participants were 96 young people (40 with BPD features, 38 healthy individuals, and 18 young people seeking help for mental health difficulties without BPD). Sleep was measured subjectively (self-report questionnaires) and objectively (10 days of actigraphy). Young people with BPD features reported poorer subjective sleep quality, greater insomnia symptoms and later chronotype than same-age healthy and clinical comparison groups. Young people with BPD features also displayed irregular sleep timing, later rise times, greater time in bed and longer sleep durations than healthy young people. Those with BPD features had superior sleep quality (greater sleep efficiency, less wake after sleep onset) and longer sleep durations than the clinical comparison group. Sleep profiles were similar across young people with BPD features with and without co-occurring depression. Overall, the findings revealed a subjective-objective sleep discrepancy and suggest that sleep-improvement interventions might be beneficial to improve subjective sleep in young people with BPD features.


Antihypertensive treatment differentially affects vascular sphingolipid biology in spontaneously hypertensive rats.
We have previously shown that essential hypertension in humans and spontaneously hypertensive rats (SHR), is associated with increased levels of ceramide and marked alterations in sphingolipid biology. Pharmacological elevation of ceramide in isolated carotid arteries of SHR leads to vasoconstriction via a calcium-independent phospholipase A(2), cyclooxygenase-1 and thromboxane synthase-dependent release of thromboxane A(2). This phenomenon is almost absent in vessels from normotensive Wistar Kyoto (WKY) rats. Here we investigated whether lowering of blood pressure can reverse elevated ceramide levels and reduce ceramide-mediated contractions in SHR. For this purpose SHR were treated for 4 weeks with the angiotensin II type 1 receptor antagonist losartan or the vasodilator hydralazine. Both drugs decreased blood pressure equally (SBP untreated SHR: 191±7 mmHg, losartan: 125±5 mmHg and hydralazine: 113±14 mmHg). The blood pressure lowering was associated with a 20-25% reduction in vascular ceramide levels and improved endothelial function of isolated carotid arteries in both groups. Interestingly, losartan, but not hydralazine treatment, markedly reduced sphingomyelinase-induced contractions. While both drugs lowered cyclooxygenase-1 expression, only losartan and not hydralazine, reduced the endothelial expression of calcium-independent phospholipase A(2). The latter finding may explain the effect of losartan treatment on sphingomyelinase-induced vascular contraction. In summary, this study corroborates the importance of sphingolipid biology in blood pressure control and specifically shows that blood pressure lowering reduces vascular ceramide levels in SHR and that losartan treatment, but not blood pressure lowering per se, reduces ceramide-mediated arterial contractions.


The Vaginal Microbiome in U.S. Black Women: A Systematic Review.
Background: Advancements in next-generation sequencing have allowed for a more complete understanding of the vaginal microbiome and its role in health and disease. The role of race/ethnicity in the composition of the vaginal microbiome and what is deemed normal/healthy microbiome is conflicting. Thus, the purpose of this review is to synthesize research that investigated the vaginal microbiome in Black women in the United States by using advanced 16S analysis. Methods: Searches of Pubmed, Google Scholar, and relevant journals for publications between January 2008 and July 2018 were conducted. Eligibility criteria were that the study: (1) used a molecular technique for sequencing of the vaginal microbiome, (2) reported the microbiome by race/ethnicity that included Black women, and (3) was conducted in the United States. Results: Our review selected 18 manuscripts that met the inclusion criteria for full review. Three themes emerged: the vaginal microbiome in healthy women versus women with bacterial vaginosis (BV); vaginal microbiome considerations in HIV; and vaginal microbiome considerations in preterm labor/birth. Overall, our review found that a majority of Black women (including HIV-positive women) have a Lactobacillus dominant group. Specifically, Lactobacillus iners was the most frequently reported Lactobacillus species. Non-Lactobacillus dominant groups were also reported to be found in healthy asymptomatic Black women. The vaginal microbiome's influence on preterm labor and/or birth among Black women was inconclusive and warrants further investigation. Conclusions: The role that the microbiome plays in health and disease among Black women warrants further research to better elucidate the definition of a healthy versus pathogenic microbiome. The wide variability in methods for BV diagnostics and defining preterm labor/birth are significant limitations that should be considered when conducting comparative studies.


Synergistic role of ADP and Ca(2+) in diastolic myocardial stiffness.
Diastolic dysfunction in heart failure patients is evident from stiffening of the passive properties of the ventricular wall. Increased actomyosin interactions may significantly limit diastolic capacity, however, direct evidence is absent. From experiments at the cellular and whole organ level, in humans and rats, we show that actomyosin-related force development contributes significantly to high diastolic stiffness in environments where high ADP and increased diastolic [Ca(2+) ] are present, such as the failing myocardium. Our basal study provides a mechanical mechanism which may partly underlie diastolic dysfunction. Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca(2+) ] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca(2+) handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca(2+) ] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca(2+) in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca(2+) both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37°C in the presence of pathological levels of ADP and diastolic [Ca(2+) ] revealed a 76 ± 1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca(2+) overload. In isolated Langendorff-perfused rat hearts, CK inhibition increased ventricular stiffness only in the presence of diastolic [Ca(2+) ]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges, even at low Ca(2+) , and thereby increase myocardial stiffness.


Common cardiac arrhythmias.
The interpretation of cardiac arrhythmias plays an important role in the diagnosis of cardiac disorders. Helen Hand examines the physiology of the heart, the electrical conduction mechanism, cardiac rhythm disorders and cardiac monitoring.


Social isolation induces schizophrenia-like behavior potentially associated with HINT1, NMDA receptor 1, and dopamine receptor 2.
Both genetic factors and early life adversity play major roles in the etiology of schizophrenia. Our previous studies indicated that social isolation (SI) during early postnatal development leads to several lasting abnormal behavioral and pathophysiological features resembling the core symptoms of some human neuropsychiatric disorders in mice. The glutamate and dopamine hypotheses are tightly linked to the development of schizophrenia. The cross-talk between glutamate N-methyl-D-aspartate acid receptors and dopamine receptors is associated with histidine triad nucleotide binding protein 1 (HINT1), which is correlated with diverse psychiatric disorders. We examined the effects of SI on schizophrenia-like behavior and used enzyme-linked immunosorbent assays to investigate the expression levels of HINT1, the NR1 subunit of N-methyl-D-aspartate acid receptor, and dopamine type 2 receptor (D2R) in C57 mice. We found that SI leads to a series of schizophrenia-related deficits, such as social withdrawal, anxiety disorder, cognitive impairments, and sensorimotor gating disturbances. These abnormal phenotypes paralleled changes of HINT1, NR1, and D2R. SI may be considered a robust model of the effects of early life stress on the schizophrenia-related behaviors in mice. Potential interactions among HINT1, NR1, and D2R may underlie the behavioral deficits induced by SI.


The influence of dietary locust bean gum and live yeast on some digestive immunological parameters of piglets experimentally challenged with Escherichia coli.
Gums and yeast cells are natural mannose-rich products that can be used as subtracts for adhesion of gram-negative bacteria. The aim of the study was to investigate the role of dietary locust bean gum (LBG; Salmosan, ITPSA, Spain) or live yeast (Saccharomyces cerevisiae Sc47; Actisaf, Lesaffre, France) as immunological enhancers of the intestinal function of piglets. Treatments included a noninfected group fed with a control diet and 4 other groups orally challenged with 1x10(8) cfu of Escherichia coli K88. The challenged groups were fed the control or the control diet supplemented with colistin, LBG, or yeast. Twenty-five Landrace × Duroc piglets weaned at 4 wk were used. The animals were group housed, challenged on day 14, and euthanized 2 d later. Blood, bile, ileum, and mesenteric lymph node (MLN) samples were obtained for analysis of C-reactive protein (CRP), secretory immunoglobulin A (sIgA), and Toll-like receptors 2 (TLR2) and 4 (TLR4). Challenge increased the level of CRP of piglets fed the control diet, but this did not happen in the piglets fed the supplemented diets (P < 0.001). Challenge upregulated TLR2 in MLN and TLR4 in ileum and MLN (P < 0.05). This was prevented by yeast supplementation for the TLR2 in MLN and TLR4 in ileum. Pigs fed colistin and LBG diets showed intermediate but nonsignificant responses. In conclusion, the results suggest that colistin, live yeast, and LBG reduce the levels of CRP in blood of piglets challenged with E. coli, and yeast reduces the expression of Toll-like receptors in the intestine.


The Current Landscape of Antibody-based Therapies in Solid Malignancies.
Over the past three decades, monoclonal antibodies (mAbs) have revolutionized the landscape of cancer therapy. Still, this benefit remains restricted to a small proportion of patients due to moderate response rates and resistance emergence. The field has started to embrace better mAb-based formats with advancements in molecular and protein engineering technologies. The development of a therapeutic mAb with long-lasting clinical impact demands a prodigious understanding of target antigen, effective mechanism of action, gene engineering technologies, complex interplay between tumor and host immune system, and biomarkers for prediction of clinical response. This review discusses the various approaches used by mAbs for tumor targeting and mechanisms of therapeutic resistance that is not only caused by the heterogeneity of tumor antigen, but also the resistance imposed by tumor microenvironment (TME), including inefficient delivery to the tumor, alteration of effector functions in the TME, and Fc-gamma receptor expression diversity and polymorphism. Further, this article provides a perspective on potential strategies to overcome these barriers and how diagnostic and prognostic biomarkers are being used in predicting response to mAb-based therapies. Overall, understanding these interdependent parameters can improve the current mAb-based formulations and develop novel mAb-based therapeutics for achieving durable clinical outcomes in a large subset of patients.


Moving Toward Milestone-Based Assessment in Osteopathic Manipulative Medicine.
Osteopathic medicine is continuing to move toward competency-based education at undergraduate and graduate levels. Competencies and Entrustable Professional Activities (EPAs) have been implemented to guide educators on the skills and abilities that osteopathic medical students and residents should be able to perform as physicians. Unfortunately, many of these skills have not been well described, and the threshold of "competence" or "entrustability" for each of these tasks remains elusive. The author presents an approach to measuring competence in the domain of osteopathic manipulative medicine using a milestone rubric to assess skills related to osteopathic screening, diagnosis, technique, and explanation. This rubric can be applied to all levels of osteopathic training and across many diagnostic and treatment modalities. Clearly defining and assessing the individual skills composing competence in osteopathic manipulative medicine will be increasingly important as medical education continues to evolve and modernize.


A porous polymer scaffold for meniscal lesion repair--a study in dogs.
Meniscal lesions often occur in the avascular area of the meniscus with little chance of spontaneous repair. An access channel in the meniscal tissue can function as an entrance for ingrowing repair tissue from the vascular periphery of the meniscus to the lesion in the avascular zone which again induced healing of the lesion. Implantation of a porous polymer in a full-thickness access channel induced healing. However, a better integration between meniscal tissue and the implant might be achieved with the combination of the newly developed porous polymers and a modified surgical technique. This might improve meniscal lesion healing and the repair of the access channel with neo-meniscal tissue. Longitudinal lesions were created in the avascular part of 24 canine lateral menisci and a partial-thickness access channel was formed to connect the lesion with the meniscal periphery. In 12 menisci, the access channel was left empty (control group), while in the remaining 12 menisci the polymer implant was sutured into the access channel. Repair of the longitudinal lesions was achieved with and without polymer implantation in the partial-thickness access channel. Polymer implants induced fibrous ingrowth with cartilaginous areas, which resembled neo-meniscal tissue. Implantation did not prevent articular cartilage degeneration.


Responses to the region 5 NHEXAS time/activity diary. National Human Exposure Assessment Survey.
The time/activity diary developed for use in the National Human Exposure Assessment Survey (NHEXAS) was completed by 249 participants in the Research Triangle Institute/Environmental and Occupational Health Sciences Institute (RTI/EOHSI) NHEXAS population-based pilot project conducted in the upper Midwest (EPA Region 5). The majority of participants successfully completed the diary during the 6-day study period. Participant responses showed internal consistency between related questions within the diary and between instruments used within the study. Comparison of response rates with the National Human Activity Pattern Survey, a nationwide population-based study, found consistent results when the same questions were used in both studies. Several questions identified age-specific activities. The value of the 6-day diary over 1-day surveys was apparent in discriminating between episodic and regularly conducted activities and in identifying subpopulations whose behavior may contribute to exposure to environmental pollutants.


A novel tandem repeat sequence located on human chromosome 4p: isolation and characterization.
In an effort to analyze the genomic region of the distal half of human chromosome 4p, to where Huntington disease and other diseases have been mapped, we have isolated the cosmid clone (CRS447) that was likely to contain a region with specific repeat sequences. Clone CRS447 was subjected to detailed analysis, including chromosome mapping, restriction mapping, and DNA sequencing. Chromosome mapping by both a human-CHO hybrid cell panel and FISH revealed that CRS447 was predominantly located in the 4p15.1-15.3 region. CRS447 was shown to consist of tandem repeats of 4.7-kb units present on chromosome 4p. A single EcoRI unit was subcloned (pRS447), and the complete sequence was determined as 4752 nucleotides. When pRS447 was used as a probe, the number of copies of this repeat per haploid genome was estimated to be 50-70. Sequence analysis revealed that it contained two internal CA repeats and one putative ORF. Database search established that this sequence was unreported. However, two homologous STS markers were found in the database. We concluded that CRS447/pRS447 is a novel tandem repeat sequence that is mainly specific to human chromosome 4p.


[Peasant strategies for economic reproduction and malaria epidemiology in the ravines microregion of the Chiapas mountains, Mexico: a case study]
The goal of this investigation was to establish an initial correlation between farming activities and malaria and to define risk factors and prevalence of the latter through an analysis of the integration of farm production strategies by members of an indigenous peasant community in the Chiapas mountains in Mexico. Information was obtained on places of work, land use, coffee, corn, and bean farming, and number of family members involved in farming activities, wage labor, and handicrafts production. Migration of farm workers to warmer climates was also analyzed. The study compared families with and without cases of malaria from 1987 to 1993 in the town of Yibeljoj, Chenalhó county. The most outstanding characteristics of this analysis were the following: strategies involving greater risk and prevalence of malaria were those which combined corn farming and wage labor; on the other hand, strategies in which handicraft production was the activity of primary or secundary importance were associated with few or no cases of the disease.


Effects of ionizing radiation on locomotory behavior and mechanosensation in Caenorhabditis elegans.
Locomotory behavior (motility) and mechanosensation are of vital importance in animals. We examined the effects of ionizing radiation (IR) on locomotory behavior and mechanosensation using a model organism, the nematode Caenorhabditis elegans. Bacterial mechanosensation in C. elegans induces the dopamine-mediated slowing of locomotion in the presence of bacteria (food), known as the basal slowing response. We previously reported an IR-induced reduction of locomotory rate in the absence of food. In the present study, we observed a similar IR-induced reduction of locomotory rate in the cat-2 mutant, which is defective in bacterial mechanosensation. The dose response pattern of the locomotory rate in the presence of food was relatively flat in wild-type animals, but not in cat-2 mutants. This suggests that the dopamine system, which is related to bacterial mechanosensation in C. elegans, might have a dominant effect on locomotory rate in the presence of food, which masks the effects of other stimuli. Moreover, we found that the behavioral responses of hydrogen peroxide-exposed wild-type animals are similar to those of IR-exposed animals. Our findings suggest that the IR-induced reduction of locomotory rate in the absence of food is mediated by a different pathway from that for bacterial mechanosensation, at least partially through IR-produced hydrogen peroxide.


Proteome-wide detection of phospholipid-protein interactions in mitochondria by photocrosslinking and click chemistry.
Photoactivatable lipid analogues are uniquely suited for the detection of lipid-protein interactions in biological membranes. Based on photocrosslinking, new methodology has been developed for the proteome-wide detection of lipid-protein interactions. Bifunctional lipid analogues containing a tag for click chemistry in addition to the photoactivatable moiety enable the enrichment of the crosslinked proteins that is required for subsequent identification by mass spectrometry. In principle the phospholipid interaction-based membrane protein proteomics approach is applicable to any biomembrane and any lipid. Here, we review the background and the development of the new methodology. Results obtained with photocrosslinking in purified mitochondrial membranes from the yeast Saccharomyces cerevisiae are summarized and future perspectives discussed.


Cross-Sectional Evaluation of Open Science Practices at Imaging Journals: A Meta-Research Study.
Objective: To evaluate open science policies of imaging journals, and compliance to these policies in published articles. Methods: From imaging journals listed we extracted open science policy details: protocol registration, reporting guidelines, funding, ethics and conflicts of interest (COI), data sharing, and open access publishing. The 10 most recently published studies from each journal were assessed to determine adherence to these policies. We calculated the proportion of open science policies into an Open Science Score (OSS) for all journals and articles. We evaluated relationships between OSS and journal/article level variables. Results: 82 journals/820 articles were included. The OSS of journals and articles was 58.3% and 31.8%, respectively. Of the journals, 65.9% had registration and 78.1% had reporting guideline policies. 79.3% of journals were members of COPE, 81.7% had plagiarism policies, 100% required disclosure of funding, and 97.6% required disclosure of COI and ethics approval. 81.7% had data sharing policies and 15.9% were fully open access. 7.8% of articles had a registered protocol, 8.4% followed a reporting guideline, 77.4% disclosed funding, 88.7% disclosed COI, and 85.6% reported ethics approval. 12.3% of articles shared their data. 51% of articles were available through open access or as a preprint. OSS was higher for journal with DOAJ membership (80% vs 54.2%; P < .0001). Impact factor was not correlated with journal OSS. Knowledge synthesis articles has a higher OSS scores (44.5%) than prospective/retrospective studies (32.6%, 30.0%, P < .0001). Conclusion: Imaging journals endorsed just over half of open science practices considered; however, the application of these practices at the article level was lower.


Passive imaging with pulsed ultrasound insonations.
Previously, passive cavitation imaging has been described in the context of continuous-wave high-intensity focused ultrasound thermal ablation. However, the technique has potential use as a feedback mechanism for pulsed-wave therapies, such as ultrasound-mediated drug delivery. In this paper, results of experiments and simulations are reported to demonstrate the feasibility of passive cavitation imaging using pulsed ultrasound insonations and how the images depend on pulsed ultrasound parameters. The passive cavitation images were formed from channel data that was beamformed in the frequency domain. Experiments were performed in an invitro flow phantom with an experimental echo contrast agent, echogenic liposomes, as cavitation nuclei. It was found that the pulse duration and envelope have minimal impact on the image resolution achieved. The passive cavitation image amplitude scales linearly with the cavitation emission energy. Cavitation images for both stable and inertial cavitation can be obtained from the same received data set.


Are MSM willing to SMS for HIV prevention?
Text messaging is a potential HIV-prevention tool for men who have sex with men (MSM), specifically young MSM and MSM of color. To determine the willingness of MSM to receive text messages as part of an HIV-prevention intervention, we administered an online survey to MSM recruited from MySpace.com, which included questions about mobile phone ownership and willingness to participate in a future text message-based HIV research study. Of participants, 85% (n = 5,378) reported owning a mobile phone and 49% (n = 2,483) of mobile phone owners reported being willing to receive text messages in a future HIV research study. Black and Hispanic men were more willing than White non-Hispanic men to receive text messages. Men with a college degree were less willing to receive texts than men with a high school level of education, and men >22 years old were less likely to be willing to receive texts than those younger than 22 years of age. The authors' findings demonstrate that willingness to receive text messages as part of an HIV research study is moderate, and mirrors patterns of text message use in age and race. Variations in willingness should be taken into account when designing and implementing future interventions.


Further data on HBs subtypes: geographical distribution.
1123 HBs antigens from silent carriers of different parts of Europe, Africa and Asia were subtyped and classed in the eight categories previously described: a1y(w1), a2yl(w2), a2(3)y(w3), a3y(w4), ayr, a2ld(w2), a3d(w4) and adr: We have showed that w can be subdivided into the system of a subdeterminants, but for the present time, we do not know if r is a fifth subdeterminant of a. Subtyping was performed by CIEP and by ID using antisera from guinea pigs and goats immunized with selected HBs antigens. With these 8 categories it is possible to greatly increase our knowledge about the geographical distribution of HBs antigen: in Africa six areas can be distinguished: North Africa with a predominance of a2ly(w2) (75%) and with none a3y(w4); areas between North and West Africa where a2ly(w2) and a3y(4) represent respectively 62.8% and 25.7%; West Africa with a great predominance of a3y(w4) (84.5%); Central Africa with less a3y(w4) (53.4%), appearance of a2ld(w2) (8.7%) and presence of a2ly(w2) (37%); East Africa appears to be especially a2ld(w) (only 3 sera from Burundi); South Africa with a great predominance of a2ld(w2) (86%) and with ay subtype represented by a2(3)y(w3), very exceptional in the other parts of Africa. In France, The Netherlands, Hungary, a2ld(w) subtype is predominant, respectively 73.3%, 74% and 63%, a2(3)y(w3) is the main ay subtype in France and the only one in The Netherlands whereas in Hungary the same amount of a2ly(w) and a2(3)(w) is encountered. In Rumania, Italy and Greece, a great predominance of ay subtype is found (80%): a2ly(w2) is predominant in Rumania (66%) and Italy (as in North Africa) whereas a weak predominance of a2(3)y(w3) over a2ly(w2) is found in Greece. In the Antilles, 75% of a2ld(w2) are encountered. In the Far East, a great predominance of adr is found in Laos, Japan and Thailand (100% and 84% respectively) but no adr is encountered in Vietnam where 8 a1y(w1) and 1 ayr are found of of 11 HBs sera. This a1y(w1) subtype has also been found, although infrequently, in some countries of Africa. Among French people who have lived in Africa, many examples are found which show that the HBs subtype is related to the country and does not seen to depend on the host. Among the French who have been contaminated in Indochina all are carriers of adr HBsAg and none exhibits an a1y(w1) subtype.


Beta-adrenergic receptors are expressed across diverse cancers.
Based largely on retrospective analyses and a handful of prospective case reports, pharmacological inhibition of the beta adrenergic receptors using beta blockers has shown clinical anti-cancer efficacy in reproductive cancers, as well as angiosarcoma and multiple myeloma. Because of the potential promise of beta blockers as an adjunct to standard anti-cancer therapy, it is imperative to identify other tumor types expressing beta adrenergic (β-AR) receptors so future preclinical and clinical studies can be directed at the most promising tumor targets. We performed immunohistochemical detection of β1-AR, β2-AR, and β3-AR across 29 of the most common human cancer types (389 tissues total) and 19 matching non-diseased controls (100 tissues total). Our analysis revealed all three β-AR receptors were expressed most strongly in melanoma relative to other cancer types. Other malignancies that revealed relatively higher levels of β-AR receptors were esophagus, pancreas, kidney, and lung cancers. Moreover, particular β-AR receptors exhibited significant overexpression in tumor tissue relative to their matching normal tissue in urogenital/reproductive malignancies including breast, endometrium, ovarian, and urothelial cancer, as well as colon, lung, and thyroid cancer. This study identifies several cancer types expressing the β-AR receptors which should be evaluated in future studies for susceptibility to beta blockade.


Agrobacterium tumefaciens responses to plant-derived signaling molecules.
As a special phytopathogen, Agrobacterium tumefaciens infects a wide range of plant hosts and causes plant tumors also known as crown galls. The complexity of Agrobacterium-plant interaction has been studied for several decades. Agrobacterium pathogenicity is largely attributed to its evolved capabilities of precise recognition and response to plant-derived chemical signals. Agrobacterium perceives plant-derived signals to activate its virulence genes, which are responsible for transferring and integrating its Transferred DNA (T-DNA) from its Tumor-inducing (Ti) plasmid into the plant nucleus. The expression of T-DNA in plant hosts leads to the production of a large amount of indole-3-acetic acid (IAA), cytokinin (CK), and opines. IAA and CK stimulate plant growth, resulting in tumor formation. Agrobacterium utilizes opines as nutrient sources as well as signals in order to activate its quorum sensing (QS) to further promote virulence and opine metabolism. Intriguingly, Agrobacterium also recognizes plant-derived signals including γ-amino butyric acid and salicylic acid (SA) to activate quorum quenching that reduces the level of QS signals, thereby avoiding the elicitation of plant defense and preserving energy. In addition, Agrobacterium hijacks plant-derived signals including SA, IAA, and ethylene to down-regulate its virulence genes located on the Ti plasmid. Moreover, certain metabolites from corn (Zea mays) also inhibit the expression of Agrobacterium virulence genes. Here we outline the responses of Agrobacterium to major plant-derived signals that impact Agrobacterium-plant interactions.


Assessment of p53 protein expression in normal mucosa and benign and malignant lesions of the nasal cavity.
p53 gene mutation is documented in head and neck cancer. No reports exist relating this mutation to normal mucosa or benign and malignant lesions of the nasal cavity. We investigate p53 overexpression using immunohistochemical techniques improved by an antigen retrieval method. p53 protein was analyzed in the following cases: normal, benign [papilloma and inverted papilloma (IP)] and malignant [squamous-cell carcinoma (SCC) arising in IP, SCC alone, adenocarcinoma and small-cell carcinoma]. Both the intensity and rate of positive p53 immunostaining were evaluated using a quantitative Auto-CAD program. Overexpression of p53 protein was not identified in normal mucosa, benign or premalignant lesions; however, approximately 60% is correlated to nasal cancer. p53 overexpression correlates with heavy smoking. Both the IP and SCC portions of SCC synchronous with IP showed similar p53 immunoreactivity. SCC arising in IP shows a lower p53 immunoreactivity than SCC alone. Thus, smoking along with a p53 mutation may be a mutagenic agent in nasal cancers. Alteration of the p53 protein may play an important role in the early stages of the malignant transformation of IP. A low p53 immunoreactivity indicates the presence of wild-type p53 protein. This may show a better response to radiation therapy yielding a better prognosis for SCC arising in IP compared to SCC alone. However, further clinical trials are required to investigate this possibly worthwhile prognostic marker.


[Amplification of genome regions in the somatic cells of mammals resistant to colchicine. III. Localization of the amplified genes in minute chromatin bodies].
Small chromatin bodies (SCB) were revealed in Djungarian hamster cells resistant to colchicine. They looked like single bodies or like clusters of small particles. SCB were localized both in nucleus and cytoplasm. Similar formations were earlier observed in oocytes of insects with amplified extrachromosomal rDNA genes. DNA in the SCB was able to replicate not only during the S phase but also during other phases of the cell cycle. The restriction analysis showed that in cells with SCB DNA amplified sequences were replicated autonomously too. These data indicate that SCB in colchicine-resistant cells contain amplified genes. Besides, SCB double-minute chromosomes (DMs) were observed in some resistant sublines. In one of them, DMs were the only karyotypic alteration. The relationship between SCB, chromosomal homogeneously staining regions (HSRs) and DMs was studied. Single SCB and DMs appeared at the early stage of the development of colchicine-resistance (the level of drug resistance is 16-22). Selection of variants 170-220-fold resistant to colchicine was usually accompanied by the decrease in the cell number with SCB and DMs and by the increase in the amount of cells containing the chromosomes with HSRs. During the further enhancement of drug resistance (700-750), some decrease in the number of cells with HSRs and the appearance of the great number of cells containing large groups of SCB were found. The loss of colchicine-resistance observed during cultivation in colchicine free medium was accompanied by the disappearance of HSRs, emergence of SCB and DMs and further elimination of SCB and DMs from cells. The quantity of autonomously replicating amplified DNA fragments after digestive by HindIII was increased with the enhancement of SCB number in cultures.


[Use of non-linearly transformed speech signals for studying the auditory analyzer].
An opportunity to apply non-linearly transformed speech signals for investigation of auditory analyzer in health and disease is analysed. Possible types of non-linear transformations preserving semantics of initial speech signals are discussed and analytic expressions are derived. Some circuitry problems related to performing these types of transformations are examined. The results of psycho-acoustic experiments on perception of non-linearly transformed speech signals are given.


Effects of 8-chloroadenosine 3',5'-monophosphate and N6-benzyl-cyclic adenosine 5'-monophosphate on cell cycle kinetics of HL-60 leukemia cells.
Site-selective cyclic AMP (cAMP) analogues have been shown to inhibit growth and induce differentiation in several human leukemia cell lines. However, detailed studies of the effects exerted by cAMP analogues on cell cycle kinetics have been lacking. We have examined the effects of 8-Cl-cAMP and N6-benzyl-cAMP on the cell cycle kinetics of the HL-60 human promyelocytic leukemia cell line. A cell cycle study was performed by univariate DNA analysis after 24-72 h of treatment with noncytotoxic concentrations of 8-Cl-cAMP and N6-benzyl-cAMP capable of inducing 50-60% growth inhibition in these cells. HL-60 cells treated with 5 microM 8-Cl-cAMP showed no significant change in the cell distribution in the cycle as compared to the untreated control cells, whereas the treatment with 10 microM N6-benzyl-cAMP transiently increased the percentage of cells in the G0/G1 phase after 48 h, followed by a partial recovery at 72 h. Combined treatment with low doses of 8-Cl-cAMP and N6-benzyl-cAMP, each of which alone produced 20% growth inhibition, exerted a growth inhibitory effect of 65% and delayed increase of the G0/G1 phase by 72 h. To better understand the cell cycle effects induced by 8-Cl-cAMP, flow cytometric analysis of bromodeoxyuridine incorporation was also performed. 8-Cl-cAMP treatment exhibited a slowing down of the cell cycle; thus, the delayed appearance of the G0/G1 cell accumulation after combined treatment could be due to this effect of 8-Cl-cAMP on the HL-60 cell cycle. At a toxic dose, 8-Cl-cAMP brought about a G2M block, whereas N6-benzyl-cAMP brought about an increase of the G0/G1 compartment. G2M block produced by toxic doses of 8-Cl-cAMP was not related to its adenosine metabolite since 8-Cl-adenosine did not produce any specific block in the cell cycle. Our results show, for the first time, that these site-selective cAMP analogues could affect cell cycle kinetics at different points. These data may provide the basis for combination treatments involving cAMP analogues and other agents in the treatment of human leukemia.


[Evaluation of the gas regimen in the damaged tissues].
Dynamics of CO2 and oxygen was studied in the skin of 35 patients with open fractures of the crural bones. The results were compared with homeostasis in the whole blood. It was found that immediately after surgery there is marked acydosis, gas regimen of the skin adjacent to the wound is characterized by hypoxia and hypercapnia. By month 2 after the trauma the excessive amount of organic acids was compensated by falling content of CO2, i.e. development of CO2 alkalosis. A complete compensation was not achieved within the treatment period and normalization of acid-base balance in patients was not observed.


Evaluation of the potential anti-soybean allergic activity of different forms of Lactobacillus delbrueckii subsp. bulgaricus based on cell model in vitro.
Live, inactivated Lactobacillus or their metabolites have various beneficial functions, which may alleviate food allergy. This study aimed to investigate the intervention effects of three forms of Lactobacillus delbrueckii subsp. bulgaricus (Ld) on cell degranulation, intestinal barrier function, and intestinal mucosal immunity against soybean allergy. First, the intervention effect of Ld on cell degranulation was investigated using the KU812 cell degranulation model. Then, the Caco-2 cell inflammation model was used to evaluate their anti-inflammatory capacity, and the cell monolayer model was constructed to test the protective effects of different forms of Ld on the intestinal barrier. Finally, mesenteric lymph node (MLN) cells from mice were used to assess the ability of different forms of Ld to regulate the balance of cytokines associated with food allergy in the immune tissue of the intestinal mucosa. Results showed that live bacteria and heat-inactivated bacteria could inhibit the degranulation of KU812 cells, mainly by significantly inhibiting the release of histamine, IL-6 and TNF-α. Both live bacteria and heat-inactivated bacteria could also suppress the increase of IL-6 and IL-8 in Caco-2 cells induced by lipopolysaccharide (LPS). The culture supernatant of bacteria and live bacteria showed better ability to maintain the integrity and permeability of the intestinal epithelial barrier. In addition, heat-inactivated bacteria could return the values of IFN-γ and IL-10 to normal levels and restore the balance of IFN-γ/IL-4, thereby reversing the immune deviation of MLN cells. Therefore, three forms of Ld have potential for the treatment of soybean allergy.


Barriers to Receiving Follow-up Care Among Childhood Cancer Survivors.
Little is known on why adherence to follow-up care in childhood cancer survivors (CCS) is lacking. This study characterized barriers to adherence to follow-up care among CCS, identified sociodemographic correlates of barriers, and examined whether barriers to follow-up care relate to health-related quality of life. Adult CCS (N=84) were anonymously surveyed via REDCap using the Barriers to Care Questionnaire (BCQ) and the Quality of Life Scale-Cancer Survivor (QOL-CS). Both descriptive and correlation analyses were conducted. The median BCQ total score was 88.5 (interquartile ranges:78.4 to 95.7), with the greatest barriers reported in the Skills (eg, ease of navigating the healthcare system) and Pragmatism subscales (eg, cost). There was a statistically significant correlation between the BCQ total score and the QOL-CS total score (rs=0.47, P <0.0001) and the physical, psychological, and social QOL-CS subscales (all P 's<0.05). The results found that barriers to follow-up care for CCS are mostly related to cost and appointment logistics, and that more barriers to care is associated with lower health-related quality of life among CCS. Identifying barriers to follow-up care is the first step in improving adherence, which would allow for earlier detection of late effects of cancer therapy and thereby result in reductions in morbidity and mortality.


Risk of aspiration in care home residents and associated factors.
Pneumonia is a prevalent cause of death in care home residents. Dysphagia is a significant risk factor of aspiration pneumonia. The purpose of the current study was to screen for risk of aspiration in care home residents in the Netherlands and assess potential risk factors of aspiration. Five experienced speech-language therapists assessed 203 care home residents (115 primarily physically disabled, 88 primarily cognitively impaired) 60 and older in the first week after admission to a care home. In 43 (21.2%) residents, speech-language therapists assessed risk of aspiration and found no significant difference between physically disabled (26.1%) and cognitively impaired (14.8%) residents. After multivariate logistic regression analysis, the final prediction model for risk of aspiration showed Parkinson's disease as a significant factor (odds ratio = 5.11; 95% confidence interval [1.49, 17.52]) . The authors therefore conclude that risk of aspiration is a relevant care problem among Dutch care home residents and requires further assessment.


Brevetoxin in blood, biological fluids, and tissues of sea turtles naturally exposed to Karenia brevis blooms in central west Florida.
In 2005 and 2006, the central west Florida coast experienced two intense Karenia brevis red tide events lasting from February 2005 through December 2005 and August 2006 through December 2006. Strandings of sea turtles were increased in the study area with 318 turtles (n = 174, 2005; n = 144, 2006) stranding between 1 January 2005 and 31 December 2006 compared to the 12-yr average of 43 +/- 23 turtles. Live turtles (n = 61) admitted for rehabilitation showed clinical signs including unresponsiveness, paresis, and circling. Testing of biological fluids and tissues for the presence of brevetoxin activity by enzyme-linked immunosorbent assay found toxin present in 93% (52 of 56) of live stranded sea turtles, and 98% (42 of 43) of dead stranded sea turtles tested. Serial plasma samples were taken from several live sea turtles during rehabilitation and toxin was cleared from the blood within 5-80 days postadmit depending upon the species tested. Among dead animals the highest brevetoxin levels were found in feces, stomach contents, and liver. The lack of significant pathological findings in the majority of animals necropsied supports toxin-related mortality.


Mediation of donor-acceptor distance in an enzymatic methyl transfer reaction.
Enzymatic methyl transfer, catalyzed by catechol-O-methyltransferase (COMT), is investigated using binding isotope effects (BIEs), time-resolved fluorescence lifetimes, Stokes shifts, and extended graphics processing unit (GPU)-based quantum mechanics/molecular mechanics (QM/MM) approaches. The WT enzyme is compared with mutants at Tyr68, a conserved residue that is located behind the reactive sulfur of cofactor. Small (>1) BIEs are observed for an S-adenosylmethionine (AdoMet)-binary and abortive ternary complex containing 8-hydroxyquinoline, and contrast with previously reported inverse (<1) kinetic isotope effects (KIEs). Extended GPU-based computational studies of a ternary complex containing catecholate show a clear trend in ground state structures, from noncanonical bond lengths for WT toward solution values with mutants. Structural and dynamical differences that are sensitive to Tyr68 have also been detected using time-resolved Stokes shift measurements and molecular dynamics. These experimental and computational results are discussed in the context of active site compaction that requires an ionization of substrate within the enzyme ternary complex.


CKD of Uncertain Etiology: A Systematic Review.
Epidemics of CKD of uncertain etiology (CKDu) are emerging around the world. Highlighting common risk factors for CKD of uncertain etiology across various regions and populations may be important for health policy and public health responses. We searched PubMed, Embase, Scopus and Web of Science databases to identify published studies on CKDu. The search was generated in January of 2015; no language or date limits were used. We used a vote-counting method to evaluate exposures across all studies. We identified 1607 articles, of which 26 met inclusion criteria. Eighteen (69%) were conducted in known CKDu-endemic countries: Sri Lanka (38%), Nicaragua (19%), and El Salvador (12%). The other studies were from India, Japan, Australia, Mexico, Sweden, Tunisia, Tanzania, and the United States. Heavy metals, heat stress, and dietary exposures were reported across all geographic regions. In south Asia, family history, agrochemical use, and heavy metal exposures were reported most frequently, whereas altitude and temperature were reported only in studies from Central America. Across all regions, CKDu was most frequently associated with a family history of CKDu, agricultural occupation, men, middle age, snake bite, and heavy metal exposure. Studies examining etiologies of CKDu have reported many exposures that are heterogeneous and vary by region. To identify etiologies of CKDu, designing consistent and comparative multisite studies across high-risk populations may help elucidate the importance of region-specific versus global risk factors.


[Use of the hematological system Technicon H-1 for analysis of the effect of laser irradiation].
The effects of low-energy He-Ne laser (lightguide emission dose power 1.2-1.5 nw) on the morphologic and functional parameters of formed elements of the blood were experimentally studied with the use of the Technicon H-1 hematologic system. 1-300 sec He-Ne laser exposure had no noticeable effect on the traditional hemogram parameters, this fact evidencing that such an exposure is sparing. Changes in the number of nontraditional parameters of the erythro-, leuko-, and thrombocytograms, recorded by the Technicon H-1 system, were detected, such as the degree of leukocytic nuclei segmentation, the mean volume of blood cells, myeloperoxidase activity, etc., these changes indicating functional activation of formed elements of the blood under the effect of laser. These results demonstrate high resolving power of the Technicon H-1 system and recommend this system for estimations of the optimal duration of sessions of intravascular laser irradiation of the blood in the body.


Thallium-199 myocardial perfusion scintigraphy in the diagnosis of restenoses after balloon dilatation and stenting of the coronary arteries.
To evaluate the diagnostic importance of thallium-199 myocardial perfusion single-photon emission computed tomography (SPECT) in the recognition of coronary restenoses and stenoses de novo of varying sites after endovascular treatment of coronary artery disease (CAD). Myocardial perfusion scintigraphy was used to examine forty-six patients presenting with CAD before, 2-3 weeks, 3-6 months and 1-2 years after balloon dilatation and/or stenting of the coronary arteries (CA). The presence, character and magnitude of perfusion defects were estimated. The coronary angioplasty resulted in a 76% decrease of the mean size of transient ischemic zones. The reversible defects of thallium accumulation coexisted after operation with incomplete myocardial revasculization in patients with hemodynamically significant multivessel lesions. In the long-term follow up (3-6 months and 1-2 years after endovascular treatment), aggravation of coronary insufficiency in patients with incomplete revascularization proceeded mainly due to an increase in the size of the areas marked by persistent disturbance of coronary microcirculation determined not only by acute necrotic myocardial infarction but also by transformation of transient ischemic zones to the new stable perfusion defects. As compared to the early times, the patients with verified restenoses and stenoses de novo showed in the later period (3-6 months after coronary angioplasty) a significant increase in the mean size of the transient ischemic zones, exceeding the preoperative level. In six of the eleven patients, the appearance of the new stable defects was marked after 1-2 years in the area of blood supply to the recanalized CA. Meanwhile the condition of myocardial perfusion in the group of patients without restenoses did not undergo any noticeable changes. Myocardial perfusion scintigraphy using thallium-199 chloride allows to objectively evaluate over time the results of endovascular treatment of CAD. Also, there is every probability of success of predicting restenoses and stenoses de novo.


Benchmarking the Performance of Electropolymerized Poly(3,4-ethylenedioxythiophene) Electrodes for Neural Interfacing.
The development of electronics adept at interfacing with the nervous system is an ever-growing effort, leading to discoveries in fundamental neuroscience applied in clinical setting. Highly capacitive and electrochemically stable electronic materials are paramount for these advances. A systematic study is presented where copolymers based on 3,4-ethylenedioxythiophene (EDOT) and its hydroxyl-terminated counterpart (EDOTOH) are electropolymerized in an aqueous solution in the presence of various counter anions and additives. Amongst the conducting materials developed, the copolymer p(EDOT-ran-EDOTOH) doped with perchlorate in the presence of ethylene glycol shows high specific capacitance (105 F g-1 ), and capacitance retention (85%) over 1000 galvanostatic charge-discharge cycles. A microelectrode array-based on this material is fabricated and primary cortical neurons are cultured therein for several days. The microelectrodes electrically stimulate targeted neuronal networks and record their activity with high signal-to-noise ratio. The stability of charge injection capacity of the material is validated via long-term pulsing experiments. While providing insights on the effect of additives and dopants on the electrochemical performance and operational stability of electropolymerized conducting polymers, this study highlights the importance of high capacitance accompanied with stability to achieve high performance electrodes for biological interfacing.


Comparative analysis of isolated cellular organelles by means of soft X-ray contact microscopy with laser-plasma source and transmission electron microscopy.
Soft X-ray contact microscopy (SXCM) is, at present, a useful tool for the examination at submicrometre resolution of biological systems maintained in their natural hydrated conditions. Among current X-ray-generating devices, laser-plasma sources are now easily available and, owing to their pulse nature, offer the opportunity to observe living biological samples before radiation damage occurs, even if the resolution achievable is not as high as with synchrotron-produced X-rays. To assess the potential of laser-plasma source SXCM in the study of cellular organelles, we applied it for the analysis of chloroplasts extracted from spinach leaves and mitochondria isolated from bovine heart and liver. X-ray radiation was generated by a nanosecond laser-plasma source, produced by a single shot excimer XeCl laser focused onto an yttrium target. The images obtained with SXCM were then compared with those produced by transmission electron microscopy observation of the same samples prepared with negative staining, a technique requiring no chemical fixation, in order to facilitate their interpretation and test the applicability of SXCM imaging.


The G243D mutation (afsB mutation) in the principal sigma factor sigmaHrdB alters intracellular ppGpp level and antibiotic production in Streptomyces coelicolor A3(2).
Deficient antibiotic production in an afsB mutant, BH5, of Streptomyces coelicolor A3(2) was recently shown to be due to a mutation (G243D) in region 1.2 of the primary sigma factor sigma(HrdB). Here we show that intracellular ppGpp levels during growth, as well as after amino acid depletion, in the mutant BH5 are lower than those of the afsB(+) parent strain. The introduction of certain rifampicin resistance (rif) mutations, which bypassed the requirement of ppGpp for transcription of pathway-specific regulatory genes, actII-ORF4 and redD, for actinorhodin and undecylprodigiosin, respectively, completely restored antibiotic production by BH5. Antibiotic production was restored also by introduction of a new class of thiostrepton-resistance (tsp) mutations, which provoked aberrant accumulation of intracellular ppGpp. Abolition of ppGpp synthesis in the afsB tsp mutant Tsp33 again abolished antibiotic production. These results indicate that intracellular ppGpp level is finely tuned for successful triggering of antibiotic production in the wild-type strain, and that this fine tuning was absent from the afsB mutant BH5, resulting in a failure to initiate antibiotic production in this strain.


Epoxidation of alpha,beta-unsaturated ketones using hydrogen peroxide in the presence of basic hydrotalcite catalysts
The basic layered hydrotalcites have been used as catalysts for the epoxidation of alpha,beta-unsaturated ketones in heterogeneous reaction media using hydrogen peroxide as an oxidant. A wide variety of alpha,beta-unsaturated ketones were oxidized to the corresponding epoxyketones in excellent yields under mild reaction conditions. For example, 2-cyclohexen-1-one gave 2,3-epoxycyclohexanone in 91% yield at 40 degrees C for 5 h with high efficiency in hydrogen peroxide. The catalytic activity of the hydrotalcites increased as the basicity of their surfaces increased. In the case of the epoxidation of less reactive substrates, adding a cationic surfactant such as n-dodecyltrimethylammonium bromide (DTMAB) to the above oxidation system accelerated the epoxidation reaction. These hydrotalcite catalysts were easily separated from the reaction mixture and were reusable.


COMPLEXES OF F-PILI AND RNA BACTERIOPHAGE.
Cell-free filtrates of F(+) strains of Escherichia coli "inactivate" RNA phages. The active agents have been identified in the electron microscope as thin appendages called F-pili. Complexes of F-pili and phage may be easily assayed because of their retention by membrane filter pads. Calcium ion is required for formation of the complex.


[The treatment of thyroid gland cyst using ND-YAG laser].
The results of treatment of 23 patients with the thyroid gland cyst was summarized. Laser photocoagulation was performed under ultrasonographic control. Peculiarities of the treatment performance using laser for the thyroid gland cyst with more than 10 ml volume were established. Twenty two (95.7%) patients had recovered and in one (4.3%)--the state improvement was noted. In laser photocoagulation for the cystically-transformed nodes the reduction or disappearance of residual nodal tissue was noted, there were no postoperative complications.


Distribution of Elastic Fibers in the Lacrimal Sac and Nasolacrimal Duct of Japanese Cadavers.
To investigate the distribution of elastic fibers in lacrimal sac and nasolacrimal duct of Japanese cadavers. We examined 8 lacrimal sacs and nasolacrimal ducts of 7 Japanese cadavers (4 right sides, 4 left sides; 3 males, 4 females; average age of 89 years at death) that were preserved with 10% buffered formalin. The harvested specimens were transversely sectioned. All specimens were stained with Elastica van Gieson. Micrographs were taken, and then converted to white and black images, and the elastic fiber density of 4 locations (middle and upper levels of lacrimal sac, and middle and lower levels of nasolacrimal duct) was compared. Elastic fibers showed greater distribution in the lamina propria, compared with the submucosal tissue, at all locations (p < 0.001). Elastic fiber density within the lamina propria at the middle lacrimal sac level (13.5% ± 4.3%) was similar to the density observed at the upper lacrimal sac level (13.2% ± 2.3%, p = 0.87) and the lower nasolacrimal duct level (17.8% ± 6.0%, p = 0.088), but was significantly greater than the density observed at the middle nasolacrimal duct level (9.5% ± 3.8%, p = 0.0001). Elastic fibers in the lacrimal sac and nasolacrimal duct are primarily distributed in the lamina propria, with a greater density at the upper and middle lacrimal sac levels, and at the lower nasolacrimal duct level, compared with the middle nasolacrimal duct level. This distribution of elastic fibers likely reflects the magnitude of mechanical stress within the lacrimal drainage system.


Astrocyte activation and reactive gliosis.
Astrocytes become activated (reactive) in response to many CNS pathologies, such as stroke, trauma, growth of a tumor, or neurodegenerative disease. The process of astrocyte activation remains rather enigmatic and results in so-called "reactive gliosis," a reaction with specific structural and functional characteristics. In stroke or in CNS trauma, the lesion itself, the ischemic environment, disrupted blood-brain barrier, the inflammatory response, as well as in metabolic, excitotoxic, and in some cases oxidative crises--all affect the extent and quality of reactive gliosis. The fact that astrocytes function as a syncytium of interconnected cells both in health and in disease, rather than as individual cells, adds yet another dimension to this picture. This review focuses on several aspects of astrocyte activation and reactive gliosis and discusses its possible roles in the CNS trauma and ischemia. Particular emphasis is placed on the lessons learnt from mouse genetic models in which the absence of intermediate filament proteins in astrocytes leads to attenuation of reactive gliosis with distinct pathophysiological and clinical consequences.


Nicotine elevated intracellular Ca²⁺ in rat airway smooth muscle cells via activating and up-regulating α7-nicotinic acetylcholine receptor.
Chronic obstructive pulmonary disease (COPD) is characterized by airway remodeling with airway smooth muscle (ASM) hypertrophy and hyperplasia. Since tobacco use is the key risk factor for the development of COPD and intracellular Ca(2+) concentration ([Ca(2+)]i) plays a major role in both cell proliferation and differentiation, we hypothesized that nicotinic acetylcholine receptor (nAChR) activation plays a role in the elevation of [Ca(2+)]i in airway smooth muscle cells (ASMCs). We examined the expression of nAChR and characterized the functions of α7-nAChR in ASMCs. RT-PCR analysis showed that α2-7, β2, and β3-nAChR subunits are expressed in rat ASMCs, with α7 being one of the most abundantly expressed subtypes. Chronic nicotine exposure increased α7-nAChR mRNA and protein expression, and elevated resting [Ca(2+)]i in cultured rat ASMCs. Acute application of nicotine evoked a rapid increase in [Ca(2+)]i in a concentration-dependent manner, and the response was significantly enhanced in ASMCs cultured with 1 µM nicotine for 48 hours. Nicotine-induced Ca(2+) response was reversibly blocked by the α7-nAChR nicotinic antagonists, methyllycaconitine and α-bungarotoxin. Small interfering RNA suppression of α7-nAChR also substantially blunted the Ca(2+) responses induced by nicotine. These observations suggest that nicotine elevates [Ca(2+)]i in ASMCs through α7-nAChR-mediated signals pathways, and highlight the possibility that α7-nAChR can be considered as a potential target for the treatment of airway remodeling.that nicotine elevates [Ca(2+)]i in ASMCs through α7-nAChR-mediated signals pathways, and highlight the possibility that α7-nAChR can be considered as a potential target for the treatment of airway remodeling.


Cholesterol crystal induced arterial inflammation and destabilization of atherosclerotic plaque.
Evolution of plaque that is prone to rupture is characterized by inflammation and physical changes. Accumulation of low-density lipoprotein in the sub-intima provides esterified cholesterol (ESC) to macrophages and smooth muscle cells that convert it into free cholesterol (FRC) by cholesteryl ester hydrolases (CEHs). Membrane-bound cholesterol carriers transport FRC to high-density lipoprotein (HDL). Impaired HDL transport function and altered composition can lead to extracellular accumulation of FRC, whereas impaired membrane carrier activity can lead to intracellular FRC accumulation. Saturation of FRC can result in cholesterol crystallization with cell death and intimal injury. Disequilibrium between ESC and FRC can impact foam cell and cholesterol crystal (CC) formation. Cholesterol crystals initiate inflammation via NLRP3 inflammasome leading to interleukin-1β (IL-1β) production inducing C-reactive protein. Eventually, crystals growing from within the plaque and associated inflammation destabilize the plaque. Thus, inhibition of inflammation by antagonists to IL-1β or agents that dissolve or prevent CC formation may stabilize vulnerable plaques.


Bone augmentation using rhGDF-5-collagen composite.
The aim of this study was to evaluate the effectiveness of local application of growth differentiation factor-5 (GDF-5)-collagen composite on bone augmentation on the rat calvaria. GDF-5-collagen composite is made from recombinant human GDF-5 (rhGDF-5) and purified bovine type I atelocollagen. The GDF-5 solution was mixed with 0.3% atelocollagen acid solution, and the mixture was lyophilized. The spongy lyophilized material was pressed into the shape of a minidisk to make the GDF-5-collagen composite. The GDF-5-collagen composite contained 1, 10, or 100-microg rhGDF-5. The control collagen composite contained 0-microg rhGDF-5. The GDF-5-collagen composite or control collagen composite was inserted beneath the calvarial periosteum of 4-week-old rats. At 3 weeks after implantation, the implants containing 1-microg rhGDF-5 had mostly induced new bone formation on the cranial side. In the implants containing 10- microg rhGDF-5, bone formation had proceeded to the center of the GDF-5-collagen composite from the periosteal and the cranial sides, and bone marrow was seen focally. The augmented bone showed a connected trabecular structure with abundant vascularization. The implants containing 100-microg rhGDF-5 were nearly entirely replaced by new bone with bone marrow, and the augmented bone was firmly connected with the original bone. Neither cartilage nor bone formation was found in the control collagen composite. Thus, we conclude that the GDF-5-collagen composite may be a superior biomaterial for bone augmentation and this composite could be useful as a local osteoinductive device.


The MODY1 gene for hepatocyte nuclear factor 4alpha and a feedback loop control COUP-TFII expression in pancreatic beta cells.
Pancreatic islet beta cell differentiation and function are dependent upon a group of transcription factors that maintain the expression of key genes and suppress others. Knockout mice with the heterozygous deletion of the gene for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) or the complete disruption of the gene for hepatocyte nuclear factor 4alpha (HNF4alpha) in pancreatic beta cells have similar insulin secretion defects, leading us to hypothesize that there is transcriptional cross talk between these two nuclear receptors. Here, we demonstrate specific HNF4alpha activation of a reporter plasmid containing the COUP-TFII gene promoter region in transfected pancreatic beta cells. The stable association of the endogenous HNF4alpha with a region of the COUP-TFII gene promoter that contains a direct repeat 1 (DR-1) binding site was revealed by chromatin immunoprecipitation. Mutation experiments showed that this DR-1 site is essential for HNF4alpha transactivation of COUP-TFII. The dominant negative suppression of HNF4alpha function decreased endogenous COUP-TFII expression, and the specific inactivation of COUP-TFII by small interfering RNA caused HNF4alpha mRNA levels in 832/13 INS-1 cells to decrease. This positive regulation of HNF4alpha by COUP-TFII was confirmed by the adenovirus-mediated overexpression of human COUP-TFII (hCOUP-TFII), which increased HNF4alpha mRNA levels in 832/13 INS-1 cells and in mouse pancreatic islets. Finally, hCOUP-TFII overexpression showed that there is direct COUP-TFII autorepression, as COUP-TFII occupies the proximal DR-1 binding site of its own gene in vivo. Therefore, COUP-TFII may contribute to the control of insulin secretion through the complex HNF4alpha/maturity-onset diabetes of the young 1 (MODY1) transcription factor network operating in beta cells.


A Randomized-Controlled Trial of Computer-based Prevention Counseling for HIV-Positive Persons (HPTN 065).
Decreasing the risk of HIV transmission from HIV-positive individuals is an important public health priority. We evaluated the effectiveness of a computer-based sexual risk reduction counseling intervention (CARE+) among HIV-positive persons enrolled in care. HIV-positive eligible participants (N=1075) were enrolled from 11 care sites in the Bronx, NY and Washington, DC and randomized 1:1 to either a tablet-based self-administered CARE+ intervention or standard of care (SOC). The primary outcome was the proportion of participants reporting any unprotected vaginal/anal sex at last sex, among all partners, HIV-negative or HIV-unknown-status partners and for primary and non-primary partners. At baseline, 7% of participants in both arms reported unprotected sex with an HIV-negative or HIV-unknown-status partner, while 13% in the CARE+ arm and 17% in the SOC arm reported unprotected sex with any partner. Most participants (88%) were on antiretroviral therapy (ART) at baseline. There was no significant difference in changes over time in unprotected vaginal/anal sex between the CARE+ and SOC arms for any partners (p=0.67) or either HIV-negative or HIV-unknown-status partners (p=0.40). At the Month 12 visit, most participants (85%) either strongly agreed or agreed that computer counseling would be a good addition to in-person counseling by a provider. The CARE+ intervention was not effective at reducing sexual risk behaviors among HIV-positive patients in care, most of whom were on ART. Further research may be warranted around the utility of computer-based counseling for HIV prevention.


Conservative face lift surgery.
Face lift surgery almost always is elective; and, because its purpose is to diminish aging problems, it most often is done in those who are aged. Local and general risks, therefore, should be minimized. Wide undermining dictates flaps dissected more deeply and wounds closed well short of the limits of stretch of skin. Less radical undermining described here produces much smaller total wounds, lessens hazards of hematoma, considerably shortens operative and anesthetic times, reduces risks to nerves and ducts, and allows snugger closures. Details of operative technique, including platysma plication, are demonstrated. Short- and long-term results are shown. They indicate improvement sufficient to justify expanded use of the suggested techniques, particularly in view of diminished morbidity and risks to the general condition of those in the older age group.


Ultrasound imaging of the anorectal malformation during the neonatal period: a comprehensive review.
Anorectal malformation (ARM) is classified as low, intermediate, or high; accurate diagnosis of the type during the early neonatal period is important to determine the appropriate initial surgical approach. This review assesses the role of ultrasound examination in the classification of ARM during the neonatal period, with a focus on landmarks on the sonogram, the approach used for sonography, and the optimal examination timing. The following three factors on the sonogram are used for the classification: location of the fistula, the distance between the distal rectal pouch and the anal dimple (perineum) (P-P distance), and the relationship between the puborectalis muscle and the distal rectal pouch. Three approaches can be used to evaluate ARM by ultrasonography, namely, suprapubic, perineal, and infracoccygeal approaches. Each approach has its own advantages and disadvantages. Optimal timing of the ultrasound examination is also important with respect to each factor to classify ARM. We have described the pitfalls of ultrasound in diagnosis of cases, namely ARM with Down syndrome (which tends to be without fistula), ARM with low birth weight, ARM with unusual location of fistula, ARM with opened fistula (where the P-P distance is unreliable), and cloacal malformation (variation of the high-type ARM).


NSAID and gastropathy: a rheumatologist's review.
Nonsteroidal antiinflammatory drug (NSAID) use, salicylate and nonsalicylate, is all too commonly associated with gastropathy. The problem is reviewed as significantly impacting upon the success of the most common treatment of most forms of arthritis. Blockade of prostaglandin products by NSAID is recently recognized as a basis for the ultimate failure of adaptive cytoprotection to respond to putative threat and restore the gastric mucosa. A cohort of such patients, based upon risk factors especially noted in elderly women taking longterm high sustained doses of NSAID is identified for purposes of closer clinical monitoring. Issues of prophylaxis, adjustment of arthritis regimens to NSAID gastropathy, and gastroprotective measures are reviewed as strategic responses to this recently recognized and described iatrogenic problem of arthritis management.


Circulating MYCN DNA as a tumor-specific marker in neuroblastoma patients.
MYCN oncogene amplification is an established indicator of the aggressiveness of neuroblastomas; it is used internationally for stratifying patients for therapy. The present study shows that high levels of MYCN DNA sequences are present in the peripheral blood of patients with MYCN-amplified neuroblastomas. Circulating MYCN DNA may be a powerful and noninvasive prognostic marker at the time of diagnosis. Furthermore, preliminary data strongly suggest that the release of MYCN sequences in the peripheral blood is an early process in disease progression, permitting us to propose this novel marker for the follow-up of patients after chemotherapy.


Mechanical properties of a bio-inspired robotic knifefish with an undulatory propulsor.
South American electric knifefish are a leading model system within neurobiology. Recent efforts have focused on understanding their biomechanics and relating this to their neural processing strategies. Knifefish swim by means of an undulatory fin that runs most of the length of their body, affixed to the belly. Propelling themselves with this fin enables them to keep their body relatively straight while swimming, enabling straightforward robotic implementation with a rigid hull. In this study, we examined the basic properties of undulatory swimming through use of a robot that was similar in some key respects to the knifefish. As we varied critical fin kinematic variables such as frequency, amplitude, and wavelength of sinusoidal traveling waves, we measured the force generated by the robot when it swam against a stationary sensor, and its velocity while swimming freely within a flow tunnel system. Our results show that there is an optimal operational region in the fin's kinematic parameter space. The optimal actuation parameters found for the robotic knifefish are similar to previously observed parameters for the black ghost knifefish, Apteronotus albifrons. Finally, we used our experimental results to show how the force generated by the robotic fin can be decomposed into thrust and drag terms. Our findings are useful for future bio-inspired underwater vehicles as well as for understanding the mechanics of knifefish swimming.


[Selenium content in human in Sakha Republic].
Sakha Republic is considered to be endemic selenium deficient and poorly investigated region. Analysis of selenium in human sera, hair and nails revealed strongly decreased values. Low selenium concentrations were registered also in meat of domestic animals, fresh-water fish, mushrooms weight, agaricus campester. The possibility of the human selenium content improvement is discussed via import of grain with high selenium concentration.


Can extracellular vesicles be considered as a potential frontier in the treatment of intervertebral disc disease?
As a global public health problem, low back pain (LBP) caused by intervertebral disc degeneration (IDD) seriously affects patients' quality of life. In addition, the prevalence of IDD tends to be younger, which brings a huge burden to individuals and society economically. Current treatments do not delay or reverse the progression of IDD. The emergence of biologic therapies has brought new hope for the treatment of IDD. Among them, extracellular vesicles (EVs), as nanoscale bioactive substances that mediate cellular communication, have now produced many surprising results in the research of the treatment of IDD. This article reviews the mechanisms and roles of EVs in delaying IDD and describes the prospects and challenges of EVs.


A D, D-carboxypeptidase is required for Vibrio cholerae halotolerance.
The biological roles of low molecular weight penicillin-binding proteins (LMW PBP) have been difficult to discern in Gram-negative organisms. In Escherichia coli, mutants lacking these proteins often have no phenotype, and cells lacking all seven LMW PBPs remain viable. In contrast, we report here that Vibrio cholerae lacking DacA-1, a PBP5 homologue, displays slow growth, aberrant morphology and altered peptidoglycan (PG) homeostasis in Luria-Bertani (LB) medium, as well as a profound plating defect. DacA-1 alone among V. cholerae's LMW PBPs is critical for bacterial growth; mutants lacking the related protein DacA-2 and/or homologues of PBP4 or PBP7 displayed normal growth and morphology. Remarkably, the growth and morphology of the dacA-1 mutant were unimpaired in LB media containing reduced concentrations of NaCl (100 mM or less), and also within suckling mice, a model host for the study of cholera pathogenesis. Peptidoglycan from the dacA-1 mutant contained elevated pentapeptide levels in standard and low salt media, and comparative analyses suggest that DacA-1 is V. cholerae's principal DD-carboxypeptidase. The basis for the dacA-1 mutant's halosensitivity is unknown; nonetheless, the mutant's survival in biochemically uncharacterized environments (such as the suckling mouse intestine) can be used as a reporter of low Na(+) content.


[Effect of contrical on proteolytic enzymes of blood serum in acute emotional-pain stress].
General proteolytic and antitryptic blood serum activity in acute emotionally-painful stress was investigated as well as that on the background of the before injected contrical. It was determined that in case of a stress there increases the general proteolytic activity of blood serum and at the same time antiproteolytic activity decreases. The coefficient of the relation of antiproteolytic activity to proteolytic activity of blood serum in case of a stress may become of 50% of the control. The introduction of inhibitor of proteinase contrical before the beginning of stressor influence promotes the decrease of general proteolytic activity to the level of the control indexes.


Sodium channels in presynaptic nerve terminals. Regulation by neurotoxins.
Regulation of Na+ channels by neurotoxins has been studied in pinched-off nerve endings (synaptosomes) from rat brain. Activation of Na+ channels by the steroid batrachotoxin and by the alkaloid veratridine resulted in an increase in the rate of influx of 22Na into the synaptosomes. In the presence of 145 mM Na+, these agents also depolarized the synaptosomes, as indicated by increased fluorescence in the presence of a voltage-sensitive oxacarbocyanine dye [diO-C5(3)]. Polypeptide neurotoxins from the scorpion Leiurus quinquestriatus and from the sea anemone Anthopleura xanthogrammica potentiated the stimulatory effects of batrachotoxin and veratridine on the influx of 22Na into synaptosomes. Saxitoxin and tetrodotoxin blocked the stimulatory effects of batrachotoxin and veratridine, both in the presence and absence of the polypeptide toxins, but did not affect control 22Na influx or resting membrane potential. A three-state model for Na+ channel operation can account for the effects of these neurotoxins on Na+ channels as determined both by Na+ flux measurements in vitro and by electrophysiological experiments in intact nerve and muscle.