Nonparallel Progression of Left Ventricular Structure and Function in Long-Term Peritoneal Dialysis Patients.
Left ventricular hypertrophy and dysfunction are key cardiovascular risk factors of patients on peritoneal dialysis (PD). The purpose of this study was to investigate the dynamic changes of left ventricular (LV) structure and function in patients on long-term PD. Patients who underwent PD catheter insertions from January 2010 to December 2012 in our PD center were enrolled into this study. Cardiac structure and function of those patients were determined by echocardiography (4 times) at 12-month intervals. Patients' biochemical parameters, body mass index, blood pressure, urine output, ultrafiltration, and total fluid removal volume were collected. The use of antihypertensive drugs and active vitamin D3 was also recorded. A total of 40 patients were included. After 3 years of follow-up, patients' PD duration time, LV mass/height2.7 (p = 0.580), interventricular septal thickness (p = 0.216), left ventricular posterior wall thickness (p = 0.216), and LV ejection fraction (p = 0.270) did not show significant changes during the follow-up. In contrast, the E/A ratio (p = 0.004) and e' (p < 0.001) were statistically decreased, and the E/e' ratio (p = 0.006) was increased. Left atrial diameter was increased (p = 0.008), but the changes in left atrial diameter index did not reach statistical significance (p = 0.090). Long-term PD patients maintain stable LV structure and cardiac systolic function, but cardiac diastolic function declines over time.


Full-mouth Rehabilitation of a Ventriculoperitoneal Shunt-treated Hydrocephalic Pediatric Patient: A Case Report.
Hydrocephalus is characterized by accumulation of cerebrospinal fluid in the lateral ventricles of the brain, which results in progressive ventricular dilatation and an increased intracranial pressure. A ventriculoperitoneal shunt (VPS) is the most common treatment for hydrocephalus. Delayed development, behavioral disturbance, chronological changes in the eruption of their teeth, changes in the occlusion, greater accumulation of plaque, and increased caries prevalence are some of the clinical manifestations in these patients, which are encountered by a pediatric dentist. Behavioral disturbance in these patients makes sedation or general anesthesia the most feasible behavior management technique. During dental treatment of shunt-treated patients, care should be taken to avoid applying excessive force on the catheter. A referral to a neurosurgeon is recommended for patients with shunts undergoing invasive dental procedures for assessment of the need for prophylactic antibiotics. The present case report discusses full-mouth rehabilitation of a pediatric patient under general anesthesia who presented with severe early childhood caries and a medical history of ventriculoperitoneal shunt-treated hydrocephalus. How to cite this article: Poonia A, Chengappa MMD, Mitra R, et al. Full-mouth Rehabilitation of a Ventriculoperitoneal Shunt-treated Hydrocephalic Pediatric Patient: A Case Report. Int J Clin Pediatr Dent 2020;13(1):103-106.


[A catalog of mosquito species (Culicidae family) from the Asian region of Russia].
A new checklist of mosquitoes (Culicidae) recorded in the Asian part of Russia includes 79 species. The checklist is provided with taxonomic comments and compared with ones compiled by previous authors. In a comparison to the checklist of Kukharchuk (1980) including 73 species, 10 species are added into the present checklist and 6 species mentioned by this author are excluded, as far they were not actually found in Asian part of Russia. The names of 9 species are chanced according to the International Code of Zoological Nomenclature (1966). In the checklist of Stojanovich and Scott (1995) including 64 species, 5 species were included erraneously and 21 species were missed. The classification and valid species names are listed according to the Catalog of the Mosquitoes of the World (Knight, Stone, 1977) and its supplements (Knight, 1978; Ward, 1984, 1992; Gaffigan, Ward, 1985), except 5 species. These species (Aedes implicatus, Ae. esoensis, Ae. rossicus, Ae. albescens, Ae. subdiversus) are considered in the comments to the checklist.


Adolescent Predictors of Incidence and Persistence of Suicide-Related Outcomes in Young Adulthood: A Longitudinal Study of Mexican Youth.
In recent years, Mexico has seen one of the largest increases in suicide rates worldwide, especially among adolescents and young adults. This study uses data from the 1,071 respondents who participated in a two-wave longitudinal study when they were between 12 and 17 years of age, and again when they were between 19 and 26 years of age. The World Mental Health Composite International Diagnostic Interview assessed suicidal behavior and DSM-IV mental disorders. We used Cox regressions to evaluate which sociodemographic and psychiatric factors and life events predicted the incidence and remission of suicide ideation, plan, and attempt throughout the 8-year span. The 8-year incidence of suicide ideation, plan, and attempt was 13.3%, 4.8%, and 5.9%, respectively. We found that the number of traumatic life events during childhood, no longer being in school, and tobacco use predicted which adolescents developed suicide behaviors as they transitioned into young adulthood. Psychiatric disorders, particularly anxiety disorders, played a larger role in the persistence of those who already had suicidal behaviors, while behavioral disorders played a role in the transition from ideation to attempt. This distinction may be useful for clinicians to assess the risk of suicide.


Identification of p53 Activators in a Human Microarray Compendium.
Biomarkers predictive of molecular and toxicological effects are needed to interpret emerging high-throughput transcriptomic data streams. The previously characterized 63 gene TGx-DDI biomarker that includes 20 genes known to be regulated by p53 was previously shown to accurately predict DNA damage in chemically treated cells. We comprehensively evaluated whether the molecular basis of the DDI predictions was based on a p53-dependent response. The biomarker was compared to microarray data in a compendium derived from human cells using the Running Fisher test, a nonparametric correlation test. Using the biomarker, we identified conditions that led to p53 activation, including exposure to the chemical nutlin-3 which disrupts interactions between p53 and the negative regulator MDM2 or by knockdown of MDM2. The expression of most of the genes in the biomarker (75%) were found to depend on p53 activation status based on gene behavior after TP53 overexpression or knockdown. The biomarker identified DDI chemicals that were strong inducers of p53 in wild-type cells; these p53 responses were decreased or abolished in cells after p53 knockdown by siRNAs. Using the biomarker, we screened ∼1950 chemicals in ∼9800 human cell line chemical vs control comparisons and identified ∼100 chemicals that caused p53 activation. Among the positive chemicals were many that are known to activate p53 through direct and indirect DNA damaging mechanisms. These results contribute to the evidence that the TGx-DDI biomarker is useful for identifying chemicals that cause DDI and activate p53.


Automatic Extraction of Reaction Templates for Synthesis Prediction.
Several tools for the computational planning of synthetic routes have been developed over the last 60 years. Traditionally these have been built on manually or automatically extracted reaction rules or templates obtained from a deep knowledge of organic chemistry in the case of the former, and reaction databases for the latter. Herein we give an introductory overview to the process of automatically extracting reaction templates, starting from methods for reaction centre identification, through to their use in computer aided synthesis planning and the de novo design of compounds.


Molecular basis of cytokine receptor activation.
Cytokines are secreted soluble peptides that precisely regulate multiple cellular functions. Amongst these the GM-CSF/IL-3/IL-5 family of cytokines controls whether hematopoietic cells will survive or apoptose, proliferate, differentiate, migrate, or perform effector functions such as phagocytosis or reactive oxygen species release. Their potent and pleiotropic activities are mediated through binding to high affinity membrane receptors at surprisingly low numbers per cell. Receptor binding triggers a cascade of intracellular signaling events, including reversible phosphorylation of receptor subunits and associated signaling molecules, leading to multiple biological responses, with the prevention of apoptosis or "cell survival" being a key cellular function that underpins all others. Many chronic inflammatory diseases and a number of haematological malignancies are driven by deregulated GM-CSF, IL-3, or IL-5 cytokine receptor signaling, highlighting their importance in disease. A major step in understanding how these cytokine receptors function is to elucidate their three dimensional structure and to relate this to the many signaling pathways emanating from their receptors. We have recently solved the structure of the human GM-CSF receptor complexed to GM-CSF which revealed distinct forms of receptor assembly: a hexamer that comprises two molecules each of GM-CSF, GM-CSF receptor alpha chain and GM-CSF receptor beta chain; and an unexpected dodecamer in which two hexameric complexes associate through a novel site 4. This latter form is necessary to bring JAK2 molecules sufficiently close together to enable full receptor activation. In this review we focus on the most recent insights in cytokine receptor signaling, and in receptor assembly. The stage is now set to link distinct forms of cytokine receptor assembled structures to specific forms of cytokine receptor signaling and function. Armed with this knowledge it may be possible to map distinct cytokine receptor signaling pathways from the cell surface to the cell nucleus which may themselves become new therapeutic targets.


Atypical radiographic appearance and clinical presentation of pulmonary tuberculosis.
Fourteen patients with unusual presentation of pulmonary tuberculosis are described. Often, exposure to the tubercle bacillus was not apparent. In other cases, there was tuberculous infection or reactivation of a previous focus in individuals with altered immunity. The radiographic presentation often differed from the classic cavitating upper lobe disease. Persistent pneumonia, cavities, and nodules were seen in other areas of the lung including the anterior segments and the lung bases. Isolated effusion and solitary nodules were also evident. Increased suspicion of tuberculosis should be maintained when evaluating persistent parenchymal consolidation, effusion, and cavitating pulmonary disease.


The seroprevalence of Lawsonia intracellularis in horses in The Netherlands.
Equine proliferative enteropathy caused by Lawsonia intracellularis is an emerging disease of weanling foals and affects their growth and development. The prevalence of Lawsonia intracellularis in The Netherlands is not known. The aim of the study was to investigate the seroprevalence of Lawsonia intracellularis in horses in The Netherlands. Blood samples were taken from healthy foals before and after weaning and from healthy yearlings and mature horses on farms throughout The Netherlands. These samples were analysed for the presence of Lawsonia intracellularis-specific antibodies with a blocking ELISA. White blood cell count, packed cell volume, and total protein concentration were also measured in all foals. Information regarding housing, pasture access, and contact with pig manure on the premises was obtained for all animals. The prevalence of Lawsonia intracellularis antibodies in foals increased significantly from 15% before weaning to 23% after weaning (p = 0.019); it was 89% in yearlings and 99% in horses older than 2 years. There was no significant difference in seroprevalence between the pasture-kept and stable-confined adult horses (97% and 100%, respectively), and there was no significant influence of contact with pig manure. None of the sampled animals showed clinical disease. In conclusion, the results suggest that Lawsonia intracellularis is widespread in The Netherlands and that seropositivity is not necessarily associated with clinical problems. The high seroprevalence in adult horses suggests long-term persistence of antibodies against Lawsonia intracellularis or constant exposure to the bacterium.


Mechanical device-based methods of managing and treating heart failure.
Despite advances in pharmacological treatments aimed at neurohormonal blockade for heart failure in the setting of left ventricular pump dysfunction, there is still a growing number of patients with advanced symptoms who suffer significant morbidity and mortality. Mechanical stresses and chronic neurohormonal activation conspire to propagate maladaptive ventricular remodeling responsible for the insidious nature of this disease. Recent studies suggest that further pharmacological neurohormonal blockade may not be safe or effective, which has driven development of devices for this patient population. Furthermore, such devices may target fundamental pathophysiological abnormalities that are largely hemodynamic and mechanical in nature that are not addressed by available pharmacological agents. The profound reverse remodeling routinely associated with left ventricular assist device use, reviewed in detail, further validates device-based approaches and should inspire research to find ways to make this recovery more complete and permanent. Accordingly, this review focuses on the multitude of mechanical device-based approaches currently being investigated to manage and treat this population. From devices for monitoring patient status to anticipate congestive heart failure exacerbations and preemptively adjust therapy to devices to support preterminal patients with end-stage disease, it is recognized that these device-based approaches will assume an increasingly important role in treating the growing number of patients with advanced heart failure.


The Use of Wearable Devices to Measure Sedentary Behavior during COVID-19: Systematic Review and Future Recommendations.
The SARS-CoV-2 pandemic resulted in approximately 7 million deaths and impacted 767 million individuals globally, primarily through infections. Acknowledging the impactful influence of sedentary behaviors, particularly exacerbated by COVID-19 restrictions, a substantial body of research has emerged, utilizing wearable sensor technologies to assess these behaviors. This comprehensive review aims to establish a framework encompassing recent studies concerning wearable sensor applications to measure sedentary behavior parameters during the COVID-19 pandemic, spanning December 2019 to December 2022. After examining 582 articles, 7 were selected for inclusion. While most studies displayed effective reporting standards and adept use of wearable device data for their specific research aims, our inquiry revealed deficiencies in apparatus accuracy documentation and study methodology harmonization. Despite methodological variations, diverse metrics, and the absence of thorough device accuracy assessments, integrating wearables within the pandemic context offers a promising avenue for objective measurements and strategies against sedentary behaviors.


The overlooked importance of vagrancy in ecology and evolution.
Vagrancy is the occurrence of individuals outside the normal geographic range of their species. These rare and unpredictable events have long been neglected by the scientific community, belying a growing body of evidence that vagrancy can have an important role in eco-evolutionary processes at both population and community scales.


Lived experiences of caregivers of children with autism spectrum disorder in Kenya.
Autism spectrum disorder (ASD) is a global public health concern. In African countries such as Kenya, there is a greater need for establishing support services for developmental disorders such as ASD. The emotional, social and economic burden of ASD on caregivers is unknown because of a number of challenges. Citizens of Kenya have a unique view of disability and inclusion. To explore the perspectives of caregivers who are responsible for caring for both family and children living with ASD and to highlight the needs of children with ASD as well as the needs of their caregivers. A qualitative, descriptive phenomenological study utilising focus group discussions (FGDs) was conducted. Verbatim transcription was used. QSR N 'Vivo 10 was used to organise and analyse the data. Content analysis was used to identify important ideas and concepts. One theme, namely 'the burden of caring for children with ASD', was identified. Children with ASD and their caregivers experience isolation and stigmatisation. Occupational therapists in Kenya should collaborate with the relevant national and global stakeholders for the promotion of the inclusion of children with ASD and their families. Responsive and context-appropriate occupational therapy interventions may begin to address service barriers. autism spectrum disorder; children; needs of caregivers; context-appropriate services.


Prediction of live birth in frozen-thawed single blastocyst transfer cycles by pre-freeze and post-thaw morphology.
What pre-freeze and post-thaw morphological parameters can be used to predict live birth outcomes after frozen-thawed blastocyst transfer cycles? Pre-freeze blastocoele expansion and trophectoderm (TE) grade and post-thaw degree of re-expansion are the most significant predictors of live birth in frozen-thawed blastocyst transfer cycles. Currently, blastocoele re-expansion after thawing is used to indicate blastocyst cryosurvival and reproductive potential. The predictive roles of other pre-freeze and post-thaw morphological parameters are neglected. This was a retrospective study of all the patients who received a frozen-thawed single blastocyst transfer (n = 1089) at our clinic between March 2008 and October 2011. Pre-freeze morphological parameters analyzed for all blastocysts included grade of blastocoele expansion, inner cell mass and TE. A group of blastocysts (n = 243) were also graded for post-thaw parameters: degree of blastocoele re-expansion, viability and cell contour. Univariate and multivariate generalized estimating equations (GEEs) models were used to identify the confounders that statistically significantly affected live birth outcomes and to investigate the independent effect of significant pre-freeze and post-thaw morphological parameters. Stepwise logistic regression analysis was used to select the best independent morphological predictors of live birth. Pearson correlations and linear regression analyses were performed to determine the relationship between morphological parameters and possible covariates. Multivariate GEE models estimated that the odds of live birth increased by ∼36% for each grade of expansion (P = 0.0061) and decreased by 29% for blastocysts with grade B TE compared with grade A TE (P = 0.0099). Furthermore, the odds of live birth increased by ∼39% (P = 0.0042) for each 10% increase in degree of re-expansion. Blastocoele expansion and TE grade were selected as the most significant pre-freeze morphological predictors of live birth and degree of re-expansion was selected as the best post-thaw parameter for prediction of live birth. Blastocysts with poorer grades of morphology were not cryopreserved or transferred, limiting the ability to generalize our findings for grades of morphology not included in this study. Blastocysts with higher pre-freeze grades of expansion and TE, irrespective of day of cryopreservation, should be given priority when thawing. Subsequently, re-expanding blastocysts, assessed within 2-4 h, with >60% viability should be transferred. No external funding was obtained for this study. There was no competing interest. not applicable.


Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer.
PURPOSE We review the evidence on magnetic resonance imaging (MRI) in staging the affected breast to determine its accuracy and impact on treatment. METHODS Systematic review and meta-analysis of the accuracy of MRI in detection of multifocal (MF) and/or multicentric (MC) cancer not identified on conventional imaging. We estimated summary receiver operating characteristic curves, positive predictive value (PPV), true-positive (TP) to false positive (FP) ratio, and examined their variability according to quality criteria. Pooled estimates of the proportion of women whose surgery was altered were calculated. Results Data from 19 studies showed MRI detects additional disease in 16% of women with breast cancer (N = 2,610). MRI incremental accuracy differed according to the reference standard (RS; P = .016) decreasing from 99% to 86% as the quality of the RS increased. Summary PPV was 66% (95% CI, 52% to 77%) and TP:FP ratio was 1.91 (95% CI, 1.09 to 3.34). Conversion from wide local excision (WLE) to mastectomy was 8.1% (95% CI, 5.9 to 11.3), from WLE to more extensive surgery was 11.3% in MF/MC disease (95% CI, 6.8 to 18.3). Due to MRI-detected lesions (in women who did not have additional malignancy on histology) conversion from WLE to mastectomy was 1.1% (95% CI, 0.3 to 3.6) and from WLE to more extensive surgery was 5.5% (95% CI, 3.1 to 9.5). CONCLUSION MRI staging causes more extensive breast surgery in an important proportion of women by identifying additional cancer, however there is a need to reduce FP MRI detection. Randomized trials are needed to determine the clinical value of detecting additional disease which changes surgical treatment in women with apparently localized breast cancer.


LKB1-AMPK modulates nutrient-induced changes in the mode of division of intestinal epithelial crypt cells in mice.
Nutrient availability influences intestinal epithelial stem cell proliferation and tissue growth. Increases in food result in a greater number of epithelial cells, villi height and crypt depth. We investigated whether this nutrient-driven expansion of the tissue is the result of a change in the mode of intestinal epithelial stem cell division and if LKB1-AMPK signaling plays a role. We utilized in vivo and in vitro experiments to test this hypothesis. C57BL/6J mice were separated into four groups and fed varying amounts of chow for 18 h: (1) ad libitum, (2) 50% of their average daily intake (3) fasted or (4) fasted for 12 h and refed. Mice were sacrificed, intestinal sections excised and immunohistochemically processed to determine the mitotic spindle orientation. Epithelial organoids in vitro were treated with no (0 mM), low (5 mM) or high (20 mM) amounts of glucose with or without an activator (Metformin) or inhibitor (Compound C) of LKB1-AMPK signaling. Cells were then processed to determine the mode of stem cell division. Fasted mice show a greater % of asymmetrically dividing cells compared with the other feeding groups. Organoids incubated with 0 mM glucose resulted in a greater % of asymmetrically dividing cells compared with the low or high-glucose conditions. In addition, LKB1-AMPK activation attenuated the % of symmetric division normally seen in high-glucose conditions. In contrast, LKB1-AMPK inhibition attenuated the % of asymmetric division normally seen in no glucose conditions. These data suggest that nutrient availability dictates the mode of division and that LKB1-AMPK mediates this nutrient-driven effect on intestinal epithelial stem cell proliferation. Impact statement The underlying cell biology of changes in the polarity of mitotic spindles and its relevance to tissue growth is a new concept and, thus, these data provide novel findings to begin to explain how this process contributes to the regeneration and growth of tissues. We find that short-term changes in food intake in vivo or glucose availability in vitro dictate the mode of division of crypt cells. In addition, we find that LKB1-AMPK signaling modulates the glucose-induced changes in the mode of division in vitro. Identifying mechanisms involved in the mode of division may provide new targets to control tissue growth.


Histochemical, immunohistological and scanning electron microscope analysis of tissue retained on spontaneously extruded ventilation tubes.
The aim of this study was to analyse the tissue surrounding prematurely extruded ventilation tubes (grommets). Thirty-one ventilation tubes, including 21 Shah and six Shepherd tubes, that had been extruded naturally into the ear canal were examined. After formalin fixation, material adhering to the tubes was retrieved and processed to paraffin wax. Five tubes were processed for scanning electron microscope (SEM) analysis. Sections were stained using histochemical methods for collagen, keratin and keratohyaline. In addition, the presence of collagen (type I and III), keratin, vimentin, fibronectin, tenascin, factor VIII-related antigen, CD31 and CD45 was tested for by immunohistochemistry. Results showed that all specimens consisted of an acellular fibrous material, oriented in concentric rings parallel to the tube surface that was often associated with small collections of CD45+ inflammatory cells. Two specimens contained collagen that was detectable by histochemical and immunohistological methods. Twelve specimens contained identifiable desquamated epithelial cells containing keratin and keratohyaline. Only one specimen stained positively for connective tissue markers (vimentin, fibrous fibronectin, tenascin) or showed the presence of vascular epithelium. SEM revealed adherent clusters or sheets of plate-like structures, consistent with the presence of epithelial squames, on three of the five ventilation tubes examined. It is concluded that tissue retained on extruded grommets consists of orthokeratinitizing epithelium infiltrated by inflammatory cells, a finding that is consistent with the theory that tube extrusion occurs as a result of squamous epithelial proliferation, medial migration, differentiation and desquamation.


Different anti-oxidant effects of thioredoxin 1 and thioredoxin 2 in retinal epithelial cells.
Age-related macular degeneration (AMD) affects the retina and is the most common cause of blindness in elderly persons in developed countries. The retina is constantly subjected to oxidative stress; to avoid the effects of oxidative stress, retinal pigment epithelial (RPE) cells possess potent anti-oxidant systems. Disruption of these systems leads to dysfunction of RPE cells, which then accelerates the development of AMD. Here, we investigated the role of thioredoxins (TRXs), scavengers of intracellular reactive oxygen species, by assessing the effect of TRX overexpression on cell viability, morphology, NF-κB expression, and mitochondrial membrane potential, in RPE cells. TRX-overexpressing cell lines were generated by infection of an established human RPE cell line (ARPE) with adeno-associated virus vectors encoding either TRX1 or TRX2. We showed that overexpression of TRXs reduced cell death caused by 4-hydroxynonenal (4-HNE)-induced oxidative stress; TRX2 was more effective than TRX1 in promoting cell survival. 4-HNE caused perinuclear NF-κB accumulation, which was absent in TRX-overexpressing cells. Moreover, overexpression of TRXs prevented depolarization of mitochondrial membranes; again, TRX2 was more effective than TRX1 in maintaining the membrane potential. The difference in the protective effects of these TRXs against oxidative stress may be due to their expression profile. TRX2 was expressed in the mitochondria, while TRX1 was expressed in the cytoplasm. Thus, TRX2 may directly protect mitochondria by preventing depolarization. These results demonstrate that TRXs are potent antioxidant proteins in RPE cells and their direct effect on mitochondria may be a key to prevent oxidative stress.


Directional dual-tree complex wavelet packet transform.
Doppler ultrasound systems, which are widely used in cardiovascular disorders detection, have quadrature format outputs. Various types of algorithms were described in literature to process quadrature Doppler signals (QDS), such as phasing filter technique (PFT), fast Fourier transform method, frequency domain Hilbert transform method and complex continuous wavelet transform. However for the discrete wavelet transform (DWT) case, which becomes a common method for processing QDSs, there was not a direct method to recover flow direction from quadrature signals. Traditionally, to process QDSs with DWT, firstly directional signals have to be extracted and later two DWTs must be applied. Although there exists a complex DWT algorithm called dual tree complex discrete wavelet transform (DTCWT), it does not provide directional signal decoding during analysis because of the unwanted energy leaks into its negative frequency bands. Modified DTCWT, which is a combination of PFT and DTCWT, has the capability of extracting directional information while decomposing QDSs into different frequency bands, but it uses an additional Hilbert transform filter and it increases the computational complexity of whole transform. Discrete wavelet packet transform (DWPT), which is a generalization of the ordinary DWT allowing subband analysis without the constraint of dyadic decomposition, can perform an adaptive decomposition of the frequency axis. In this study, a novel complex DWPT, which maps directional information while processing QDSs, is proposed. The success of proposed method will be measured by using simulated quadrature signals.


Computational and experimental studies on the catalytic mechanism of biliverdin-IXbeta reductase.
BVR-B (biliverdin-IXbeta reductase) also known as FR (flavin reductase) is a promiscuous enzyme catalysing the pyridine-nucleotide-dependent reduction of a variety of flavins, biliverdins, PQQ (pyrroloquinoline quinone) and ferric ion. Mechanistically it is a good model for BVR-A (biliverdin-IXalpha reductase), a potential pharmacological target for neonatal jaundice and also a potential target for adjunct therapy to maintain protective levels of biliverdin-IXalpha during organ transplantation. In a commentary on the structure of BVR-B it was noted that one outstanding issue remained: whether the mechanism was a concerted hydride transfer followed by protonation of a pyrrolic anion or protonation of the pyrrole followed by hydride transfer. In the present study we have attempted to address this question using QM/MM (quantum mechanics/molecular mechanics) calculations. QM/MM potential energy surfaces show that the lowest energy pathway proceeds with a positively charged pyrrole intermediate via two transition states. These initial calculations were performed with His(153) as the source of the proton. However site-directed mutagenesis studies with both the H153A and the H153N mutant reveal that His(153) is not required for catalytic activity. We have repeated the calculation with a solvent hydroxonium donor and obtain a similar energy landscape indicating that protonation of the pyrrole is the most likely first step followed by hydride transfer and that the required proton may come from bulk solvent. The implications of the present study for the design of inhibitors of BVR-A are discussed.


A community outbreak of Vero cytotoxin producing Escherichia coli O157 infection linked to a small farm dairy.
A community outbreak of infection with Vero cytotoxin producing Escherichia coli O157 (VTEC 0157) occurred in a small area of north west England in 1996. An outbreak control team was established to investigate the outbreak and implement control measures. Nine people developed symptomatic infections with VTEC O157, and a further three were found to be excreting the bacteria. All were infected with the same genotype of VTEC O157. Three children under 5 years of age and one adult were admitted to hospital. One child developed haemolytic uraemic syndrome. All cases recovered. All primary cases had consumed milk from a particular farm dairy. No other common foods were identified. The farm dairy had a faulty pasteuriser and the potential for post pasteurisation contamination existed. VTEC O157 was isolated from a milk sock specimen and from two cows, but these strains differed from that infecting the cases. All local doctors and the public were alerted and advised about preventative measures. Distribution of unpasteurised milk from the farm was discontinued as was the sale of pasteurised milk when the faulty pasteuriser was discovered. A replacement pasteuriser was installed and checked before milk was released for human consumption. No conclusive evidence of the origin of this outbreak was found, but the farm was the most probable source. The investigations raised concerns about the distribution of VTEC O157 colonised dairy cattle, the natural history of such colonisation, the effectiveness of pasteurisation with respect to the elimination of VTEC O157, and the effectiveness of current legislation for the prevention and control of milkborne infection.


N-terminal fatty acylated His-dPhe-Arg-Trp-NH(2) tetrapeptides: influence of fatty acid chain length on potency and selectivity at the mouse melanocortin receptors and human melanocytes.
The melanocortin system is involved in the regulation of a diverse number of physiologically important pathways including pigmentation, feeding behavior, weight and energy homeostasis, inflammation, and sexual function. All the endogenous melanocortin agonist ligands possess the conserved His-Phe-Arg-Trp tetrapeptide sequence that is postulated to be important for melanocortin receptor molecular recognition and stimulation. Previous studies by our laboratory resulted in the discovery that increasing alkyl chain length at the N-terminal "capping" region of the His-dPhe-Arg-Trp-NH(2) tetrapeptide resulted in a 100-fold increased melanocortin receptor agonist potency. This study was undertaken to systematically evaluate the pharmacological effects of increasing N-capping alkyl chain length of the CH(3)(CH(2))(n)CO-His-dPhe-Arg-Trp-NH(2) (n = 6-16) tetrapeptide template. Twelve analogues were synthesized and pharmacologically characterized at the mouse melanocortin receptors MC1R and MC3R-MC5R and human melanocytes known to express the MC1R. These peptides demonstrated melanocortin receptor selectivity profiles different from those of previously published tetrapeptides. The most notable results of enhanced ligand potency (20- to 200-fold) and receptor selectivity were observed at the MC1R. Tetrapeptides that possessed greater than nine alkyl groups were superior to alpha-MSH in terms of the stimulation of human melanocyte tyrosinase activity. Additionally, the n-pentadecanoyl derivative had a residual effect on tyrosinase activity that existed for at least 4 days after the peptide was removed from the human melanocyte culture medium. These data demonstrate the utility, potency, and residual effect of melanocortin tetrapeptides by adding N-terminal fatty acid moieties.


Surface molecularly imprinted polymers-based electrochemical sensor for bovine hemoglobin recognition.
A novel electrochemical sensor for bovine hemoglobin (BHb) recognition and detection was prepared by a surface molecularly imprinted technique. Aldehyde group-functionalized silica microspheres were modified on an Au electrode surface, and these were subsequently covalently bound with the template molecule, BHb, through imine bonds. Electropolymerization was performed to deposit polypyrrole onto the above modified electrode surface. A three-dimensional macroporous structural sensor was obtained after etching of silica and the extraction of BHb. Differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) were employed to characterize the fabrication process of the sensor using [Fe(CN)6](3-)/[Fe(CN)6](4-) as an electroactive probe. Since all imprinted cavities were situated at the surface of the polymers, the prepared sensor exhibited considerably fast binding kinetics. Compared to other non-template proteins, the sensor showed an excellent recognition capacity for BHb. Moreover, the prepared sensor also exhibited a dependent relationship between the concentration of BHb and the peak current of [Fe(CN)6](3-)/[Fe(CN)6](4-).


Telomere length analysis in goat clones and their offspring.
Incomplete epigenetic reprogramming of the donor genome is believed to be the cause behind the high rate of developmental mortality and post-natal anomalies observed in animal clones. It appears that overt phenotypic abnormalities are not transmitted to their progeny suggesting that epigenetic errors are corrected in the germline of clones. Here, we show variation in telomere lengths among Nigerian dwarf goat clones derived from different somatic cell types and that the offspring of two male clones have significantly shorter telomere lengths than age-matched noncloned animals. Telomere lengths were significantly shorter in skin biopsies of goat clones derived from adult granulosa cells compared to those measured for controls. Telomere lengths were highly variable in male goat clones reconstructed from fetal fibroblasts but their mean terminal repeat fragment (TRF) length was within normal range of normal goats. However, in the progeny of two male clones, mean TRF lengths were considerably shorter than age-matched controls for both skin and leukocyte samples. Evidence for possible inheritance of shortened telomeres was obtained by measuring telomere lengths in testicular biopsies obtained from the clones, which when compared with those from noncloned animals of a similar age were significantly shorter. The offspring exhibited telomere lengths intermediate to the TRF values obtained for their cloned fathers' and age-matched control testes. These results demonstrate that telomere length reprogramming in clones is dependent on the type of donor cell used and that the progeny of clones may inherit telomere length alterations acquired through the cloning procedure.


Regulation of gasdermin D by miR-379-5p is involved in arsenite-induced activation of hepatic stellate cells and in fibrosis via secretion of IL-1β from human hepatic cells.
Arsenic is an environmental toxicant and human carcinogen. The liver is the main site of arsenic storage and metabolism. Exposure to excessive arsenic causes liver damage and release of pro-inflammatory factors, which in turn lead to liver fibrosis. Gasdermin D (GSDMD), a mediator of pyroptosis, has low expression in hepatic tumor cells. In L-02 cells, arsenite caused increases of GSDMD and cleaved caspase-1 levels and decreases of caspase-1 and miR-379-5p levels. It also promoted the release of IL-1β in a concentration- and time-dependent manner. Luciferase reporter assays showed that GSDMD was a direct target of miR-379-5p. In L-02 cells, the over-expression of miR-379-5p blocked the arsenite-induced increases of GSDMD levels and the release of IL-1β, effects that were reversed by up-regulation of GSDMD. LX-2 cells, cultured in the media from arsenite-treated L-02 cells, showed elevated levels of proliferating cell nuclear antigen (PCNA), collagen I, vimentin, and α-smooth muscle actin (α-SMA), which indicated activation of these cells. Activation of LX-2 cells by media from arsenite-treated L-02 cells was inhibited by IL-1β neutralizing antibody. The media from arsenite-treated L-02 cells transfected with an miR-379-5p mimic inhibited the activation of LX-2 cells, a process that was reversed by up-regulation of GSDMD and by co-treatment with human recombinant IL-1β. Chronic exposure to arsenite induced, in liver tissue of mice, morphological damage, collagen deposition, and activation of hepatic stellate cells (HSCs). In liver tissue of arsenite-exposed mice, the levels of miR-379-5p were lower, but the levels of GSDMD and cleaved caspase-1 were elevated, and in sera from arsenite-exposed mice, the IL-1β levels were elevated. These results indicate that, by elevating the secretion of IL-1β, miR-379-5p regulation of GSDMD is involved in arsenite-induced activation of HSCs and in hepatic fibrosis. This establishes a previously unknown molecular mechanism for arsenite-induced liver damage, inflammation, and fibrosis.


A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and degradation.
The circadian clock regulates biological processes from gene expression to organism behavior in a precise, sustained rhythm that is generated at the unicellular level by coordinated function of interlocked transcriptional feedback loops and post-translational modifications of core clock proteins. CLOCK phosphorylation regulates transcriptional activity, cellular localization and stability; however little is known about the specific residues and enzymes involved. We have identified a conserved cluster of serines that include, Ser431, which is a prerequisite phosphorylation site for the generation of BMAL dependent phospho-primed CLOCK and for the potential GSK-3 phosphorylation at Ser427. Mutational analysis and protein stability assays indicate that this serine cluster functions as a phospho-degron. Through the use of GSK-3 activators/inhibitors and kinase assays, we demonstrate that GSK-3beta regulates the degron site by increasing CLOCK phosphorylation/degradation, which correlates with an increase in the expression of CLOCK responsive promoters. Stabilization of phospho-deficient CLOCK delays the phase of oscillation in synchronized fibroblasts. This investigation begins the characterization of a complex phospho-regulatory site that controls the activity and degradation of CLOCK, a core transcription factor that is essential for circadian behavior.


Disruption of ETV6 in intron 2 results in upregulatory and insertional events in childhood acute lymphoblastic leukaemia.
We describe four cases of childhood B-cell progenitor acute lymphoblastic leukaemia (BCP-ALL) and one of T-cell (T-ALL) with unexpected numbers of interphase signals for ETV6 with an ETV6-RUNX1 fusion probe. Three fusion negative cases each had a telomeric part of 12p terminating within intron 2 of ETV6, attached to sequences from 5q, 7p and 7q, respectively. Two fusion positive cases, with partial insertions of ETV6 into chromosome 21, also had a breakpoint in intron 2. Fluorescence in situ hybridisation (FISH), array comparative genomic hybridization (aCGH) and Molecular Copy-Number Counting (MCC) results were concordant for the T-cell case. Sequences downstream of TLX3 on chromosome 5 were deleted, leaving the intact gene closely apposed to the first two exons of ETV6 and its upstream promoter. qRT-PCR showed a significant upregulation of TLX3. In this study we provide the first incontrovertible evidence that the upstream promoter of ETV6 attached to the first two exons of the gene was responsible for the ectopic expression of a proto-oncogene that became abnormally close as the result of deletion and translocation. We have also shown breakpoints in intron 2 of ETV6 in two cases of insertion with ETV6-RUNX1 fusion.


Toward Spatiotemporally Controlled Synthesis of Photoresponsive Polymers: Computational Design of Azobenzene-Containing Monomers for Light-Mediated ROMP.
Density functional theory calculations have been used to identify the optimum design for a novel, light-responsive ring monomer expected to allow spatial and temporal control of ring-opening metathesis polymerization (ROMP) via light-mediated changes in ring strain energy. The monomer design leverages ring-shaped molecules composed of 4,4'-diaminoazobenzene (ABn) closed by alkene-α,ω-dioic acid linkers. The atomic geometries, formation enthalpies and ring strain energies of azobenzene (AB)-containing rings with various length linkers have been calculated. The AB(2,2) monomer is identified as having optimal properties for light-mediated ROMP, including high thermodynamic stability, low ring strain energy (RSE) with cis-AB, and high RSE with trans-AB. Time-dependent DFT calculations have been used to explore the photoisomerization mechanism of isolated AB and AB-containing rings, and calculations show that trans-to-cis and cis-to-trans photoisomerization of the optimal AB(2,2) ring molecule can be achieved with monochromatic green and blue light, respectively. The AB(2,2) monomer identified here is expected to allow precise, reversible, spatial and temporal light-mediated control of ROMP through AB photoisomerization, and to have promising potential applications in the fabrication of patterned and/or responsive AB-containing polymer materials.


A robust classic.
In the present research, we argue for the robustness of illusory correlations (ICs, Hamilton & Gifford, 1976) regarding two boundary conditions suggested in previous research. First, we argue that ICs are maintained under extended experience. Using simulations, we derive conflicting predictions. Whereas noise-based accounts predict ICs to be maintained (Fielder, 2000; Smith, 1991), a prominent account based on discrepancy-reducing feedback learning predicts ICs to disappear (Van Rooy et al., 2003). An experiment involving 320 observations with majority and minority members supports the claim that ICs are maintained. Second, we show that actively using the stereotype to make predictions that are met with reward and punishment does not eliminate the bias. In addition, participants' operant reactions afford a novel online measure of ICs. In sum, our findings highlight the robustness of ICs that can be explained as a result of unbiased but noisy learning.


Nature of the stimulating cell in the syngeneic and the allogeneic mixed lymphocyte reaction in mice.
Thymus cells from CBA and BALB/c mice are stimulated by syngeneic peripheral lymphoid cells in a "one-way" mixed lymphocyte reaction. The stimulating cell appears to be a mature B cell. Spleen cells from neonatal mice and thymus cells or bone marrow cells from adult mice are not able to induce DNA synthesis in syngeneic thymus cells, although they stimulate significantly allogeneic thymocytes. The ability of peripheral B cells to serve as stimulating cell in a syngeneic reaction develops with the age of the animal. The marginal stimulation of syngeneic thymus cells when 90% pure peripheral T cells were used as stimulating cells indicated that T cells alone were ineffective in stimulating in syngeneic mixed lymphocyte reaction. However they stimulated effective allogeneic thymocytes. On a cell-to-cell basis, light density splenic lymphocytes stimulated both syngeneic and allogeneic thymocytes better than did more dense lymphocytes. The data obtained suggest that stimuli other than those responsible for allogeneic stimulation induce proliferation of syngeneic thymus cells under identical culture conditions.


Unusual computed tomographic presentation of cerebral toxoplasmosis.
The computed tomographic appearance of three cases of cerebral toxoplasmosis is described. Two of the patients were children with Hodgkin disease and the third was an adult with systemic lupus erythematosus. All patients were severely immunosuppressed. Computed tomography showed single or multiple hypodense rounded areas with peripheral annular contrast enhancement, suggesting pyogenic cerebral abscesses. Pathologic correlation is presented. The importance of diagnosis and early treatment is emphasized.


A study of diffusion in poly(ethyleneglycol)-gelatin based semi-interpenetrating networks for use in wound healing.
Semi-interpenetrating networks (sIPNs) designed to mimic extracellular matrix via covalent crosslinking of poly(ethylene glycol) diacrylate in the presence of gelatin have been shown to aid in wound healing, particularly when loaded with soluble factors. Ideal systems for tissue repair permit an effective release of therapeutic agents and flow of nutrients to proliferating cells. Appropriate network characterization can, consequently, be used to convey an understanding of the mass transfer kinetics necessary for materials to aid in the wound healing process. Solute transport from and through sIPNs has not yet been thoroughly evaluated. In the current study, the diffusivity of growth factors and nutrients through the polymeric system was determined. Transport of keratinocyte growth factor was modeled by treating the sIPN as a plane sheet into which the protein was loaded. The diffusion coefficient was determined to be 4.86 × 10-9 ± 1.86 × 10-12 cm2/s. Glucose transport was modeled as flow through a semi-permeable membrane. Using lag-time analysis, the diffusion coefficient was calculated to be 2.25 × 10-6 ± 1.98 × 10-7 cm2/s. The results were evaluated in conjunction with previous studies on controlled drug release from sIPNs. As expected from Einstein-Stokes equation, diffusivity decreased as molecular size increased. The results offer insight into the structure-function design paradigm and show that release from the polymeric system is diffusion controlled, rather than dissolution controlled.


[Health challenges as the second millenium is ending. Conceptual epidemiology, social pathology, medicine and professional ethics].
In this article it is outlined the work of doctor Bustamante in fighting against diseases such as yellow fever, typhus, malaria, and smallpox; and the development and impel that this professional gave to preventive and social medicine is pointed out. It is established that health care professionals currently must not only highly studied and prepared, as they should manage all features related with public health, but also change-men-and-women who are capable to influence future generations, which will be the responsible in relocating men at the equilibrium point concerned to their health. Said equilibrium point is not only modified in its biopsychosocial aspect, but also its essence is deeply affected. This paper is a warning to physicians to fight together in response to humanity, that has set their confidence in them, as the current problem of drugs and dependence to drugs unhinges everything wholeness. To doctor Suarez is intolerable that, in spite of technological advances in the world, yet exist deaths caused by pneumonia or diarrhea. The hazards of the century are frightened: nuclear war and AIDS; but the characteristics that have distinguished human species and allowed its survival and superation are trusted: mental activity, ability of judgement, and consciousness; which are valuable for a deep philosophic discussion that allows us to continue our advance. An enumeration of the medicine achievements in this century is made.


Implications of health reform for retiree health benefits.
This Issue Brief examines how current health reform legislation being debated in Congress will impact the future of retiree health benefits. In general, the proposals' provisions will have a mixed impact on retiree health benefits: In the short term, the reinsurance provisions would help shore up early retiree coverage and Medicare Part D coverage would become more valuable to retirees. In the longer term, insurance reform combined with new subsidies for individuals enrolling for coverage through insurance exchanges, the maintenance-of-effort provision affecting early retiree benefits, increases to the cost of providing drug benefits to retirees, and enhanced Medicare Part D coverage, would all create significant incentives for employers to drop coverage for early retirees and drug coverage for Medicare-eligible retirees. REINSURANCE PROGRAM FOR EARLY RETIREES: Proposed legislation includes a provision to create a temporary reinsurance program for employers providing health benefits to retirees over age 55 and not yet eligible for Medicare. Given the temporary nature of the program, it is intended to provide employers an incentive to maintain benefits until the health insurance exchange is fully operational. At that point, employers will have less incentive to provide health benefits to early retirees, and retirees will have less need for former employers to maintain a program. MEDICARE DRUG BENEFITS: The House-passed bill would initially reduce the coverage gap (the so-called "doughnut hole") for individuals in the Medicare Part D program by $500 and eliminate it altogether by 2019. The bill currently before the Senate would also reduce the coverage gap by $500, but does not call for eliminating it. Both would also provide a 50 percent discount to brand-name drug coverage in the coverage gap. These provisions increase the value of the Medicare Part D drug program to Medicare-eligible beneficiaries relative to drug benefits provided by employers. TAX TREATMENT OF EMPLOYER SUBSIDIES UNDER MMA: The Medicare Modernization Act provides subsidies to employers that continue to offer prescription drug coverage through a retiree health benefits program. This subsidy is currently not counted as taxable income to the employer receiving it. Both the House and Senate bills would effectively repeal this tax exclusion. This would have two effects: The real cost of providing retiree health benefits to Medicare-eligible retirees would increase, and an employer's FAS 106 liability would increase immediately. The increase in the cost of retiree drug benefits will cause employers to re-evaluate the subsidy, compared with other available options. Moving retirees to Medicare Part D may become even more attractive to employers if the coverage gap is reduced and/or eliminated. POSTRETIREMENT BENEFIT CHANGES: With some exceptions, the House-passed legislation would prohibit employers from changing the benefits offered to retirees and their beneficiaries once a person has retired. This provision could have a number of different effects: More employers may move toward capping their contributions; employers that want to maintain retiree health benefits may react by cutting the health benefits of active workers; employers may eliminate retiree health benefits altogether to avoid being locked into providing a permanent benefit; or they may drop benefits if they think there is no need to provide them.


Sodium currents in segments of human heart cells.
Isolated human heart cells were partially drawn into the lumen of a plastic tube and cleaved at the partitioning tube wall by intraluminal suction pulses. The extraluminal segment (10 to 20 percent of the cell length) was suitable for intracellular perfusion and voltage clamp. The time and voltage dependence of the sodium current, and the responses to changes in driving force and channel blockers, illustrate the potential of these preparations as models for the study of membrane channels.


Changes in the corpus callosum in women with late-stage bipolar disorder.
This study investigated the differences in corpus callosum (CC) volumes between women with early-stage and late-stage bipolar I (BP I) disorder using the criteria previously described in the literature. We compared women with early- and late-stage BP I using criteria described in the Staging Systems Task Force Report of the International Society for Bipolar Disorders. We included 20 patients with early stage and 21 patients with late-stage BP I and a group of 25 healthy controls. Patients and controls underwent structural magnetic resonance imaging. Information on the clinical features of bipolar disorder was collected using a standardized questionnaire. Anatomical volumes of five regions of CC were compared between the three groups. Women with late-stage BP I disorder had reduced posterior CC volumes compared with early-stage bipolar I patients and controls (F = 6.05; P = 0.004). The difference was significant after controlling for age, comorbidity with post-traumatic stress disorder, psychotic symptoms during mood episodes, and current use of medication. The posterior CC was significantly decreased in volume in women with late-stage bipolar disorder. These findings suggest that CC may be an anatomical target of neuroprogression in the course of bipolar disorder in women.


Genotype and phenotype in Parkinson's disease: lessons in heterogeneity from deep brain stimulation.
Variation in the genetic risk(s) of developing Parkinson's disease (PD) undoubtedly contributes to the subsequent phenotypic heterogeneity. Although patients with PD who undergo deep brain stimulation (DBS) are a skewed population, they represent a valuable resource for exploring the relationships between heterogeneous phenotypes and PD genetics. In this series, 94 patients who underwent DBS were screened for mutations in the most common genes associated with PD. The consequent genetic subgroups of patients were compared with respect to phenotype, levodopa (l-dopa), and DBS responsiveness. An unprecedented number (29%) of patients tested positive for at least 1 of the currently known PD genes. Patients with Parkin mutations presented at the youngest age but had many years of disease before needing DBS, whereas glucocerebrosidase (GBA) mutation carriers reached the threshold of needing DBS earlier, and developed earlier cognitive impairment after DBS. DBS cohorts include large numbers of gene positive PD patients and can be clinically instructive in the exploration of genotype-phenotype relationships.


Adverse effects of saline neurolysis on a chronically compressed rat sciatic nerve.
We have evaluated the effect of saline neurolysis compared with a simple decompression procedure on chronically compressed sciatic nerves in rats. Eight months after the initiation of nerve compression within a silicone tube, rats were divided into three groups of 35. In group I, saline was injected subepineurially at the compressed segment of the nerve after removal of the tube (decompression plus saline neurolysis). The nerves in group II were treated by removal of the tube only (simple decompression). In group III the tubes were left in place. Adding saline neurolysis to decompression provided no histological, morphometric, electrophysiological, or vascular advantages up to four months, and even gave worse results than simple decompression. We conclude that saline neurolysis has no beneficial effect on a chronically compressed nerve and it is not recommended for clinical use.


[Coronary vessel intimal sequence extraction based on prior boundary constraints in optical coherence tomography image].
Optical coherence tomography (OCT) is a new technique applied in cardiovascular system. It can detect vessel intimal, small structure of plaque surface and discover small lesions with its high axial resolution and quantification character. Especially with the application of OCT in characterization of coronary atherosclerotic plaque, diagnosis and treatment strategy making, optimizing percutaneous coronary intervention therapy and assessment after stent planting make the OCT become an efficient tool for cardiovascular disease diagnosis and treatment. This paper presents a novel coronary vessel intimal sequence extraction method based on prior boundary constraints in OCT image. On the basis of conventional Chan-Vese model, we modified the evolutionary weight function to control the evolutionary rate of boundary by adding local information of boundary curve. At the same time, we added the gradient energy term and intimal boundary constraint term based on priori boundary condition to further control the evolutionary of boundary curve. At last, coronary vessel intimal is extracted in a sequence way. The comparison with vessel intimal, manual segmented by clinical scientists (golden standard), indicates that our coronary vessel intimal extraction method is robust to intimal boundary blur, distortion, guide wire shadow and plaque disturbs. The results of this study can be applied to clinical aid diagnosis and precise diagnosis and treatment.


Polyamine oxidase is one of the key elements for oxidative burst to induce programmed cell death in tobacco cultured cells.
Programmed cell death plays a critical role during the hypersensitive response in the plant defense system. One of components that triggers it is hydrogen peroxide, which is generated through multiple pathways. One example is proposed to be polyamine oxidation, but direct evidence for this has been limited. In this article, we investigated relationships among polyamine oxidase, hydrogen peroxide, and programmed cell death using a model system constituted of tobacco (Nicotiana tabacum) cultured cell and its elicitor, cryptogein. When cultured cells were treated with cryptogein, programmed cell death occurred with a distinct pattern of DNA degradation. The level of hydrogen peroxide was simultaneously increased, along with polyamine oxidase activity in apoplast. With the same treatment in the presence of alpha-difluoromethyl-Orn, an inhibitor of polyamine biosynthesis, production of hydrogen peroxide was suppressed and programmed cell death did not occur. A gene encoding a tobacco polyamine oxidase that resides in the apoplast was isolated and used to construct RNAi transgenic cell lines. When these lines were treated with cryptogein, polyamines were not degraded but secreted into culture medium and hydrogen peroxide was scarcely produced, with a concomitant suppression of cell death. Activities of mitogen-activated protein kinases (wound- and salicylic acid-induced protein kinases) were also suppressed, indicating that phosphorylation cascade is involved in polyamine oxidation-derived cell death. These results suggest that polyamine oxidase is a key element for the oxidative burst, which is essential for induction of programmed cell death, and that mitogen-activated protein kinase is one of the factors that mediate this pathway.


Comparison of five D-dimer reagents and application of an age-adjusted cut-off for the diagnosis of venous thromboembolism in emergency department.
There is still a considerable uncertainty concerning D-dimer cut-off values used in exclusion of venous thromboembolic (venous thromboembolism, VTE) disease, especially among the elderly patients. The objectives were to compare five different D-dimer reagents in the daily practice of an emergency department and to test retrospectively the performances of an age-adjusted cut-off. A total of 473 consecutive ambulatory outpatients suspected of VTE (confirmed VTE = 21) were included in this study. Five commercially available tests were assessed: STA-Liatest D-Di (LI), AxSYMD-Dimer (AX), VIDAS D-Dimer (VI), INNOVANCE D-Dimer (IN), and HemosIL D-Dimer HS (HS). When using a cut-off value of 500 ng/ml fibrinogen equivalent units (FEUs), D-dimer reagents differ in their abilities to avoid further testing. Indeed, LI allowed exclusion of VTE diagnosis in statistically more patients than VI, AX, and IN but not HS. The use of an age-adjusted cut-off is cost-effective without increasing significantly the number of false negative results. The interest of such strategy is more or less pronounced, depending on the type of D-dimer reagent. The application of an age-adjusted cut-off may be useful to reduce differences among D-dimer reagents to lower costly imaging studies. Prospective validation studies on large cohorts of patients are required to determine the safety of such strategy.


Risk of neoplastic change in large gastric hyperplastic polyps and recurrence after endoscopic resection.
Gastric hyperplastic polyps (GHPs) have a risk of neoplastic transformation reaching 5 %. Current endoscopic resection techniques appear suboptimal with a high risk of local recurrence. This study assessed the outcomes of endoscopic resection for GHPs and identified risk factors for recurrence and neoplastic transformation. This retrospective, multicenter, European study included adult patients with at least one GHP ≥ 10 mm who underwent endoscopic resection and at least one follow-up endoscopy. Patients with recurrent GHPs or hereditary gastric polyposis were excluded. All data were retrieved from the endoscopy, pathology, and hospitalization reports. From June 2007 to August 2018, 145 GHPs in 108 patients were included. Recurrence after endoscopic resection was 51.0 % (74 /145) in 55 patients. R0 resection or en bloc resection did not impact the risk of polyp recurrence. In multivariate analysis, cirrhosis was the only risk factor for recurrence (odds ratio [OR] 4.82, 95 % confidence interval [CI] 1.33 - 17.46; P = 0.02). Overall, 15 GHPs (10.4 %) showed neoplastic transformation, with size > 25 mm (OR 10.24, 95 %CI 2.71 - 38.69; P < 0.001) and presence of intestinal metaplasia (OR 5.93, 95 %CI 1.56 - 22.47; P = 0.01) being associated with an increased risk of neoplastic transformation in multivariate analysis. Results confirmed the risk of recurrence and neoplastic transformation of large GHPs. The risk of neoplastic change was significantly increased for lesions > 25 mm, with a risk of high grade dysplasia appearing in polyps ≥ 50 mm. The risk of recurrence was high, particularly in cirrhosis patients, and long-term follow-up is recommended in such patients.


Civic engagement as a retirement role for aging Americans.
Public attention directed toward the civic engagement of retired Americans has increased considerably. The purpose of this research was to define civic engagement as a retirement role and differentiate individuals who met this role definition from other retirees. Retirees who met our definition of civic engagement were identified from a sample of 683 retired older adults living in a rural Midwestern state. Using a multinomial logistic regression analysis, we contrasted this group of engaged retirees to three other groups of retirees: (a) those who were neither working nor volunteering, (b) those who had returned to work in part-time or seasonal occupations, and (c) those who volunteered for fewer than 5 hours each week. The analyses indicated that individuals assigned to the group of engaged retirees were similar across 24 variables. This group of engaged retirees differed from the other groups by gender, education level, and health status; retirement motives and planning efforts; primary retirement activities; and attitudes about volunteering and returning to work. This research supported the contention that civic engagement could be defined as a formal retirement role, as engaged retirees differ significantly from those who volunteer less, work in noncivic roles, or do neither. Further, we resolved that associating the act of volunteering, in itself, with civic engagement may no longer be appropriate for retired older adults. The definition of civic engagement as a retirement role should also include those individuals who return to work in organizations that pursue specific civic activities.


Psoriasis in general practice.
This report, based on a resource pack for primary care nurses, describes the features of psoriasis and reviews current prevention and treatments. The pack emphasises the important role of nurses in helping people to maintain their confidence and independence in the face of this chronic disease.


Updated long-term outcomes of salvage surgery after stereotactic body radiotherapy for early-stage non-small-cell lung cancer.
There is dearth of data regarding the long-term survival outcomes of salvage surgery after stereotactic body radiotherapy for early-stage non-small-cell lung cancer, as previous studies have included a short follow-up period. There is also scarce information on the management of re-relapse in previous studies. This study examined the long-term survival outcomes of patients who underwent salvage surgery for isolated local relapse (LR). We reviewed consecutive patients who underwent salvage surgery for isolated LR after stereotactic body radiotherapy for early-stage non-small-cell lung cancer between 1999 and 2015. All patients were followed up until death or at least 5 years from salvage surgery. Twelve patients were included for analysis. The median follow-up from isolated LR was 62.4 (range: 14.3-152.1) months. The 5-year overall survival rate was 58.3%, updated from 79.5% in our previous report. During the interim, new re-relapses did not occur, whereas there were 5 additional deaths. The median survival after re-relapse was 32.6 months. Our follow-up report confirmed that our patient selection for salvage surgery appeared to be appropriate and that long-term follow-up is required to assess the outcomes of patients undergoing salvage surgery. Long-term follow-up would provide detailed information on late re-relapses, treatment and outcomes of re-relapses and mortality from any causes.


Increased left ventricular extracellular volume and enhanced twist function in type 1 diabetic individuals.
Individuals with type 1 diabetes (T1D) characteristically have high glycemic levels that over time can result in reactive fibrosis and abnormalities in myocardial function. T1 mapping with magnetic resonance imaging (MRI) can estimate the extent of reactive fibrosis by measurement of the extracellular volume fraction (ECV). The extent of alterations in the ECV and associated changes in left ventricular (LV) function and morphology in individuals with T1D is unknown. Fourteen individuals with long-term T1D and 14 sex-, age-, and body mass index-matched controls without diabetes underwent MRI measurement of myocardial T1 and ECV values as well as LV function and morphology. Ventricular mass, volumes, and global function (LVEF and circumferential/longitudinal/radial strain) were similar in those with T1D and controls. However, those with T1D had larger myocardial ECV (22.1 ± 1.8 vs. 20.1 ± 2.1, P = 0.008) and increased native (noncontrast) myocardial T1 values (1,211 ± 44 vs. 1,172 ± 43 ms, P < 0.001) as compared with controls. Both the ECV and native T1 values significantly correlated with several components of torsion and circumferential-longitudinal shear strain (Ecl, the shear strain component associated with twist). Individuals with T1D had increased systolic torsion (P = 0.035), systolic torsion rate (P = 0.032), peak Ecl (P = 0.001), and rates of change of systolic (P = 0.007) and diastolic (P = 0.007) Ecl Individuals with T1D, with normal structure, LVEF, and strain, have increased extracellular volume and increased native T1 values with associated augmented torsion and Ecl These measures may be useful in detecting the early stages of diabetic cardiomyopathy and warrant larger prospective studies.NEW & NOTEWORTHY Individuals with type 1 diabetes, with normal left ventricular structure and function (ejection fraction and strain), have signs of interstitial fibrosis, measured with MRI as increased extracellular volume fraction and increased native myocardial T1, which significantly correlated with a number of measures of augmented left ventricular twist function. These measures may be useful in detecting the early stages of diabetic cardiomyopathy.


Open access endoscopy for hospitalized patients.
Most requests for gastroenterology consultations for hospitalized patients are for endoscopic procedures. Open access endoscopy has been evaluated in several institutions for outpatients. Our aim was to evaluate an open access policy for hospitalized patients. Since April of 1996, patients hospitalized in the Soroka Medical Center have been referred directly for upper endoscopy (esophagogastroduodenoscopy, EGD) and flexible sigmoidoscopy (FS). The numbers of procedures and consultation requests between July 1, 1996, and September 30, 1996, were compared with the corresponding months of 1995. A survey of physician satisfaction with the new open access system was conducted. The mean number of monthly consultations during the study period was 30.7 +/- 2.4, compared with 119.3 +/- 5.4 during the same months in 1995 (p = 0.006). Open access endoscopy was performed on 114 patients during the study period. Upper GI bleeding (n = 41) and abdominal pain (n = 33) were the most common indications for EGD. There were nine duodenal ulcers, five gastric ulcers, and eight gastric carcinomas. Sixteen patients (21%) had normal EGDs. The most common indications for FS were rectal bleeding (n = 24) and diarrhea (n = 13). Seven patients had colorectal cancer; 12 FSs were normal. In all, 286 EGDs and FSs were conducted in the study period compared with 253 in 1995 (not significant). All physicians expressed satisfaction with the new system and favored its continuation. The open access policy for hospitalized patients led to a considerable reduction in requests for consultations, with no significant increase in the number of endoscopies. The majority of patients referred directly for endoscopy had appropriate indications.


Improved method for detection of anti-tissue antibody by indirect immunofluorescence using fixed tissue.
Techniques have been developed which allow paraffin embedded, fixed tissue to be used for indirect immunofluorescence. Antibody to parietal cells, mitochondria, actin, adrenal gland, parathyroid tissue, thyroglobulin, thyroid microsomes, and pancreas islet cells cen be detected. The procedure offers improved histology and decreased technical time for the indirect immunofluorescence technique.


Conservation and development projects in the Brazilian Amazon: lessons from the Community Initiative Program in Rondônia.
Community-based conservation and development has become the prevailing programmatic paradigm of conservation organizations and development donors over the last 20 years, spawning a myriad of integrated conservation and development projects (ICDP) around the world. Appealing for its ambitious aspiration to harmonize sustainable economic development at the local level with the conservation of legally established protected areas (e.g., parks and reserves), the ICDP approach recently has drawn criticism from conservation biologists for failing to ensure adequate protection of biodiversity. Development planners and economists have also raised questions about the financial sustainability of ICDPs in practice and the replicability of the model from highly local contexts to larger regional scales. This paper briefly reviews the central elements of the concept of integrated conservation and development and the emerging debate over its effectiveness. A description of the Community Initiative Program (CIP), a pilot program of the Rondônia Natural Resources Management project (PLANAFLORO) in the western Brazilian Amazon state of Rondônia, follows. The CIP is a significant experiment because it boldly attempted to apply the principles of ICDP to the regional scale involving numerous different communities in one program simultaneously. Based on the author's mid-term review of the CIP in 1999, the development and conservation impacts of the program are considered. While the CIP has not significantly curbed the degradation of protected areas in Rondônia as intended, the evidence suggests lower rates of deforestation in municipios (i.e. counties) with the highest concentrations of CIP projects. Although the economic development impacts are mixed, approximately 50% of the projects delivered tangible benefits to local communities. Lessons learned from the CIP are presented in the final section. Among the lessons learned from the CIP, detailed in the final section, are several that will be familiar to other ICDP evaluators: the importance of thematic coherence in initial project design, the need for explicit attention on environmental conservation objectives, deficient institutional capacity of implementing organizations, inadequate attention to women's concerns and roles in community projects, and lack of technical criteria for measuring project sustainability.


Addressing the smoking-hypertension paradox in pregnancy: insight from a multiethnic US birth cohort.
Smoking during pregnancy has been associated with reduced risk of a spectrum of hypertensive (HTN) disorders, known as the "smoking-hypertension paradox." We sought to test potential epidemiologic explanations for the smoking-hypertension paradox. We analyzed 8510 pregnant people in the Boston Birth Cohort, including 4027 non-Hispanic Black and 2428 Hispanic pregnancies. Study participants self-reported tobacco, alcohol, cannabis, opioids, or cocaine use during pregnancy. We used logistic regression to assess effect modification by race/ethnicity, and confounding of concurrent substances on hypertensive disorders or prior pregnancy. We also investigated early gestational age as a collider or competing risk for pre-eclampsia, using cause-specific Cox models and Fine-Gray models, respectively. We replicated the paradox showing smoking to be protective against hypertensive disorders among Black participants who used other substances as well (aOR: 0.61, 95% CI: 0.41, 0.93), but observed null effects for Hispanic participants (aOR: 1.14, 95% CI: 0.55, 2.36). In our cause-specific Cox regression, the effects of tobacco use were reduced to null effects with pre-eclampsia (aOR: 0.81, 95% CI: 0.63, 1.04) after stratifying for preterm birth. For the Fine-Gray competing risk analysis, the paradoxical associations remained. The smoking paradox was either not observed or reversed after accounting for race/ethnicity, other substance use, and collider-stratification due to preterm birth. These findings offer new insights into this paradox and underscore the importance of considering multiple sources of bias in assessing the smoking-hypertension association in pregnancy.


Chemical Therapies for Congenital Disorders of Glycosylation.
Congenital disorders of glycosylation (CDG) are ultrarare, genetically and clinically heterogeneous metabolic disorders. Although the number of identified CDG is growing rapidly, there are few therapeutic options. Most treatments involve dietary supplementation with monosaccharides or other precursors. These approaches are relatively safe, but in many cases, the molecular and biochemical underpinnings are incomplete. Recent studies demonstrate that yeast, worm, fly, and zebrafish models of CDG are powerful tools in screening repurposed drugs, ushering a new avenue to search for novel therapeutic options. Here we present a perspective on compounds that are currently in use for CDG treatment or have a potential to be applied as therapeutics in the near future.


From validity to clinical utility: the influence of circulating tumor DNA on melanoma patient management in a real-world setting.
Melanoma currently lacks a reliable blood-based biomarker of disease activity, although circulating tumor DNA (ctDNA) may fill this role. We investigated the clinical utility (i.e., impact on clinical outcomes and interpretation of radiographic data) of measuring ctDNA in patients with metastatic or high-risk resected melanoma. Patients were prospectively accrued into ≥ 1 of three cohorts, as follows. Cohort A: patients with radiographically measurable metastatic melanoma who underwent comparison of ctDNA measured by a BEAMing digital PCR assay to tissue mutational status and total tumor burden; when appropriate, determinations about initiation of targeted therapy were based on ctDNA data. Cohorts B and C: patients with BRAF- or NRAS-mutant melanoma who had either undergone surgical resection of high-risk disease (cohort B) or were receiving or had received medical therapy for advanced disease (cohort C). Patients were followed longitudinally with serial ctDNA measurements with contemporaneous radiographic imaging to ascertain times to detection of disease activity and progressive disease, respectively. The sensitivity and specificity of the ctDNA assay were 86.8% and 100%, respectively. Higher tumor burden and visceral metastases were found to be associated with detectable ctDNA. In two patients in cohort A, ctDNA test results revealed a targetable mutation where tumor testing had not; both patients experienced a partial response to targeted therapy. In four of 30 patients with advanced melanoma, ctDNA assessments indicated evidence of melanoma activity that predicted radiographic evidence of disease progression by 8, 14, 25, and 38 weeks, respectively. CtDNA was detectable in three of these four patients coincident with radiographic evaluations that alone were interpreted as showing no evidence of neoplastic disease. Our findings provide evidence for the clinical utility of integrating ctDNA data in managing patients with melanoma in a real-world setting.


Limited form of Wegener's granulomatosis in a patient with Crohn's disease. A case report.
Wegener's granulomatosis (WG) is a multisystemic disease of unknown etiology characterized by necrotizing vasculitis and granulomatous inflammation. Although, the gastrointestinal tract can be involved in this vasculitis, the association between WG and Crohn's disease (CD) exists and was previously described. We report the case of a 29 year-old Tunisian white patient previously diagnosed with CD, presenting 3 years later with a perforated nasal septum, mucosal ulcers and sinusitis. He had also a skin ulcerative eruption of the trunk. There was no evidence of a flare of his CD. A computed tomography scan of the head showed nasal septal perforation, and maxillary pansinusitis. A biopsy from the nasal septum demonstrated nasal mucosa with extensive necrotizing granulomatous reaction associated with vasculitis. The patient was diagnosed as having limited form of Wegener's granulomatosis. He was treated with prednisone 60 mg/day and methotrexate 15 mg weekly. After Two months of treatment, he had no complaints, skin eruption and orofacial lesions were improved. Although, the gastrointestinal tract can be involved in patients with WG, the association with a CD exists and was previously described. The distinction between the two conditions and their possible coexistence is very important and requires histological examination of involved tissue.


[Advances in nicotine pretreatment and determination method].
Nicotine is an important indicator in the quality evaluation of tobacco and its related products. Moreover, it is essential to monitor nicotine presence in the environment, food, and human organs. Therefore, the development of a suitable and efficient determination method is crucial to precisely detect nicotine in various samples and complicated matrices. This article reviews the methods of sample preparation (molecular imprinting technology and solid phase/liquid phase microextraction) and methods for nicotine analysis, such as spectrophotometry, liquid chromatography, gas chromatography, capillary electrophoresis, and electrochemical methods, reported in recent years. The advancement in the applications and scopes of these methods are discussed. Furthermore, the sensitivity, accuracy, and detection efficiency of these methods are elaborated on the basis of the reported nicotine determination methods.


Low-density lipoprotein postsecretory modification, monocyte function, and circulating adhesion molecules in type 2 diabetic patients with and without macrovascular complications: the effect of alpha-tocopherol supplementation.
Although diabetes confers an increased propensity toward accelerated atherogenesis, data are lacking on monocyte activity in type 2 diabetic patients with (DM2-MV) and without (DM2) macrovascular disease compared with control subjects. Thus, we tested whether (1) postsecretory modifications of LDL (glycation and oxidation), monocyte proatherogenic activity, and circulating levels of soluble cell adhesion molecules (sCAMs) are more pronounced in DM2-MV than in DM2 and control subjects and (2) RRR-alpha-tocopherol (AT) therapy, 1200 IU/d for 3 months, has a similar effect in the 3 groups (n=25 per group). Although LDL glycation was increased in both diabetic groups compared with control subjects, AT therapy had no significant effect on glycation. AT therapy significantly decreased LDL oxidizability in all 3 groups. Diabetic monocytes released significantly more superoxide anion (O(2)(-)) and interleukin-1beta (IL-1beta) and exhibited greater adhesion to endothelium than control subjects. AT therapy significantly decreased the release of O(2)(-), IL-1beta, tumor necrosis factor-alpha, and monocyte-endothelium adhesion in all 3 groups. There was no significant difference between the 2 diabetic groups for any of the above parameters. sICAM levels were significantly elevated in both diabetic groups compared with controls. AT therapy resulted in a significant decrease in sCAMs. This is the first demonstration of increased IL-1beta secretion and increased adhesion of monocytes to endothelium from normotriglyceridemic diabetic subjects and of decreased monocyte activity and sCAMs with AT therapy in diabetic subjects with and without macrovasculopathy.


Early recognition of patients with axial spondyloarthritis-evaluation of referral strategies in primary care.
Chronic inflammatory back pain (IBP) is frequently reported in axial SpA (axSpA) but also in the general population. We evaluated a recently proposed two-step referral system for early recognition of axSpA in primary care and compare it with other combinations of symptoms and SpA-related items. Consecutive chronic back pain patients ≤45 years of age answered a questionnaire and were seen by a primary care physician who decided whether HLA-B27 needed to be determined. They were then referred to a rheumatologist who made the diagnosis. Generally sticking to the two-step system with HLA-B27 as an additional option, combinations with a sensitivity ≥90% and a likelihood ratio >4 were compared. A total of 326 patients were included, 46 of whom were diagnosed with axSpA (14.1%). The sensitivity of the strategy was 87%, the specificity was 56.8% and the positive and negative predictive values were 24.8% and 96.4%, respectively. A 'good response to NSAIDs', 'morning stiffness >30 min' and 'elevated C-reactive protein' performed best, with a sensitivity of 91%, specificity of 67%, positive predictive value of 31% and negative predictive value of 98%. On that basis, only three patients had to be seen by a rheumatologist to diagnose one. The earlier proposed referral system worked well but was outperformed by other combinations with high sensitivity and better specificity, which deserve to be prospectively studied.


Animal models of major depression: drawbacks and challenges.
Major depression is a leading contributor to the global burden of disease. This situation is mainly related to the chronicity and/or recurrence of the disorder, and to poor response to antidepressant therapy. Progress in this area requires valid animal models. Current models are based either on manipulating the environment to which rodents are exposed (during the developmental period or adulthood) or biological underpinnings (i.e. gene deletion or overexpression of candidate genes, targeted lesions of brain areas, optogenetic control of specific neuronal populations, etc.). These manipulations can alter specific behavioural and biological outcomes that can be related to different symptomatic and pathophysiological dimensions of major depression. However, animal models of major depression display substantial shortcomings that contribute to the lack of innovative pharmacological approaches in recent decades and which hamper our capabilities to investigate treatment-resistant depression. Here, we discuss the validity of these models, review putative models of treatment-resistant depression, major depression subtypes and recurrent depression. Furthermore, we identify future challenges regarding new paradigms such as those proposing dimensional rather than categorical approaches to depression.


Characteristics of community dwelling elderly not vaccinated for pneumococcus in 1998 and 2001.
We estimate proportions and numbers of elderly (>65 years old) not vaccinated for pneumococcus in 1998 and 2001 by ethnic group, socioeconomic status, health history, and access and use of health care. Self-reported lifetime pneumococcal vaccination and participant characteristics were obtained from 10,624 community dwelling elderly in the 1998 and 2001 National Health Interview Surveys (NHIS). Robust descriptive and inferential statistical analyses were fit. Outcome. Non-receipt of pneumococcal vaccination. In 2001, about 13 million (or 45% of all) community dwelling elderly were unvaccinated against pneumococcus, including 11.5 million who saw a doctor at least once, 4 million who received an influenza vaccination and 2.3 million who were hospitalized, during the previous year. In 1998 and 2001 non-US born, Hispanic, African-American, and Medicaid recipient elderly were disproportionately un-vaccinated, with about 65% of each group not vaccinated in 2001. In 2001, lifetime pneumonia vaccination of community dwelling elderly (55%) was below the goal (60%) for Healthy People 2000. While there has been important progress in improving overall vaccination rates, much more needs to be done to attain national goals and reduce large, persistent racial/ethnic and socioeconomic disparities. Lack of a usual source of healthcare and lower frequency of physician visits were among the factors associated with non-vaccination. However, most unvaccinated individuals had seen a physician in the last year, and many had received influenza vaccination or been hospitalized, suggesting the need for more consistent implementation and monitoring of guidelines for routine pneumococcal vaccination in healthcare settings.


Incidence of respiratory viruses in Peruvian children with acute respiratory infections.
Acute respiratory infections are responsible for high morbi-mortality in Peruvian children. However, the etiological agents are poorly identified. This study, conducted during the pandemic outbreak of H1N1 influenza in 2009, aims to determine the main etiological agents responsible for acute respiratory infections in children from Lima, Peru. Nasopharyngeal swabs collected from 717 children with acute respiratory infections between January 2009 and December 2010 were analyzed by multiplex RT-PCR for 13 respiratory viruses: influenza A, B, and C virus; parainfluenza virus (PIV) 1, 2, 3, and 4; and human respiratory syncytial virus (RSV) A and B, among others. Samples were also tested with direct fluorescent-antibodies (DFA) for six respiratory viruses. RT-PCR and DFA detected respiratory viruses in 240 (33.5%) and 85 (11.9%) cases, respectively. The most common etiological agents were RSV-A (15.3%), followed by influenza A (4.6%), PIV-1 (3.6%), and PIV-2 (1.8%). The viruses identified by DFA corresponded to RSV (5.9%) and influenza A (1.8%). Therefore, respiratory syncytial viruses (RSV) were found to be the most common etiology of acute respiratory infections. The authors suggest that active surveillance be conducted to identify the causative agents and improve clinical management, especially in the context of possible circulation of pandemic viruses.


A current overview of the Papaya meleira virus, an unusual plant virus.
Papaya meleira virus (PMeV) is the causal agent of papaya sticky disease, which is characterized by a spontaneous exudation of fluid and aqueous latex from the papaya fruit and leaves. The latex oxidizes after atmospheric exposure, resulting in a sticky feature on the fruit from which the name of the disease originates. PMeV is an isometric virus particle with a double-stranded RNA (dsRNA) genome of approximately 12 Kb. Unusual for a plant virus, PMeV particles are localized on and linked to the polymers present in the latex. The ability of the PMeV to inhabit such a hostile environment demonstrates an intriguing interaction of the virus with the papaya. A hypersensitivity response is triggered against PMeV infection, and there is a reduction in the proteolytic activity of papaya latex during sticky disease. In papaya leaf tissues, stress responsive proteins, mostly calreticulin and proteasome-related proteins, are up regulated and proteins related to metabolism are down-regulated. Additionally, PMeV modifies the transcription of several miRNAs involved in the modulation of genes related to the ubiquitin-proteasome system. Until now, no PMeV resistant papaya genotype has been identified and roguing is the only viral control strategy available. However, a single inoculation of papaya plants with PMeV dsRNA delayed the progress of viral infection.


The disruption of the epithelial mesenchymal trophic unit in COPD.
Progression of COPD is associated with a measurable increase in small airway wall thickness resulting from a repair and remodeling process that involves fibroblasts of the epithelial mesenchymal trophic unit (EMTU). The present study was designed to examine the organization of fibroblasts within the lamina propria of small airways with respect to their contacts with the epithelium and with each other in persons with COPD. Transmission electron microcopy (TEM) and three-dimensional (3D) reconstructions of serial TEM sections were used to estimate the frequency and determine the nature of the contacts between the epithelium and fibroblasts within the EMTU in small airways from 5 controls (smokers with normal lung function), from 6 persons with mild (GOLD-1) and 5 with moderate (GOLD-2) COPD. In airways from control lungs fibroblasts make frequent contact with cytoplasmic extensions of epithelial cells through apertures in the epithelial basal lamina, but the frequency of these fibroblast-epithelial contacts is reduced in both mild and moderate COPD compared to controls (p < 0.01). The 3D reconstructions showed that the cytoplasmic extensions of lamina propria fibroblasts form a reticulum with fibroblast-fibroblast contacts in an airway from a control subject but this reticulum may be reorganized in airways of COPD patients. Development of COPD is associated with significant disruption of the EMTU due to a reduction of contacts between fibroblasts and the epithelium.


[The negative and positive phases of the reaction of the hypothalamo-hypophyseal-gonadal system in female rats to the administration of sex hormones].
I.m. administration of estradiol benzoat in physiological doses decreased 3-fold the lutropin secretion and follitropin secretion by one third, in ovariectomised rats. The same dose in intact rats decreases the lutropin level in the blood and gonadoliberin contents in the medial eminence by the negative feedback mechanism. In 4-6 hrs after injection the positive effect of estradiol is at its highest level, the lutropin level in the blood increases by 80-100 times, the follitropin--by 2-3 times. Therefore, estradiol plays a decisive role in positive as well as negative effects on the lutropin secretion, whereas its effect upon follitropin secretion is less obvious. The gonadoliberin transport in negative phase of estradiol effect is mainly performed through the medial eminence whereas the positive effect of estradiol needs a participation of organum vasculosum of the lamina terminalis too.


Integrated poly(dimethysiloxane) with an intrinsic nonfouling property approaching "absolute" zero background in immunoassays.
The key to achieve a highly sensitive and specific protein microarray assay is to prevent nonspecific protein adsorption to an "absolute" zero level because any signal amplification method will simultaneously amplify signal and noise. Here, we develop a novel solid supporting material, namely, polymer coated initiator integrated poly(dimethysiloxane) (iPDMS), which was able to achieve such "absolute" zero (i.e., below the detection limit of instrument). The implementation of this iPDMS enables practical and high-quality multiplexed enzyme-linked immunosorbent assay (ELISA) of 11 tumor markers. This iPDMS does not need any blocking steps and only require mild washing conditions. It also uses on an average 8-fold less capture antibodies compared with the mainstream nitrocellulose (NC) film. Besides saving time and materials, iPDMS achieved a limit-of-detection (LOD) as low as 19 pg mL(-1), which is sufficiently low for most current clinical diagnostic applications. We expect to see an immediate impact of this iPDMS on the realization of the great potential of protein microarray in research and practical uses such as large scale and high-throughput screening, clinical diagnosis, inspection, and quarantine.


Smoking and obesity are associated factors in acne inversa: results of a retrospective investigation in 100 patients.
Acne inversa is a chronic, recurring acneiform skin disease with inflammation of the follicular epithelium of the sebaceous glands and the terminal hair follicle. It primarily manifests in the intertriginous areas. So far, the aetiology of acne inversa is unknown. Smoking, amongst others, is being discussed and should be evaluated as a possible aetiological factor. In this study a retrospective investigation was carried out in 100 patients with acne inversa. The parameters; age, BMI, sex, weight, height, location of acne inversa, quantity of smoking, smoking behaviour and the date of initial diagnosis of acne inversa were considered. In most cases, the acne inversa is located in the axillary and inguinal areas. Overall, 96% of the 100 patients had a positive, long standing, on average almost 20-year, smoking history. On average, over 20 cigarettes are smoked daily. Over 50% of the patients are overweight. Merely 26.1% fall into the normal weight category. Our results suggest that especially smoking, but also obesity, may present an aetiologically relevant factor in the origin of acne inversa.


[Ion channels, induced by amphotericin B introduced unilaterally into lipid bilayers].
Single ionic channels of approximately 10 pS in magnitude and approximately 100 ms duration (in 2 M KCl solution) were recorded when amphotericin B (AB) was added to one side of a lipid bilayer. Using blocking ions it has been shown that these channels are asymmetrical half-pores (similar to those postulated by Marty and Finkelstein) which are capable of forming long-living symmetrical pores if AB is added to both sides of the membrane.