The Diagnostic Accuracy of the Pitch Glide to Identify Aspiration in Patients with Respiratory Diseases: A Pilot Study.
Initial research has been conducted to determine the diagnostic accuracy of the pitch glide during the clinical swallow evaluation to identify aspiration in adults after stroke. Findings suggest that reduced pitch glide can predict aspiration in patients with dysphagia after stroke. This study aimed to identify the diagnostic accuracy of the pitch glide in detecting aspiration, pharyngeal residue and hyo-laryngeal excursion during swallowing in adults with respiratory diseases. 17 adults (9 males and 8 females) with dysphagia who had a background of respiratory diseases (chronic obstructive pulmonary disease = 11; lower respiratory tract infection = 6) were consecutively recruited in an acute hospital setting. Participants completed two pitch glide tasks (/a/ and /i/) immediately before a videofluoroscopic swallowing study (VFSS). Pitch glide recordings were analysed by blinded researchers both acoustically (Praat software) to obtain maximum F0, pitch range and auditory-perceptually using a binary scale ("normal" or "abnormal"). Clinicians blinded to pitch glide ratings rated 5 mL, 10 mL and a sip of liquid swallows during VFSS using the Penetration-Aspiration Scale, Bolus Residue Scale and hyolaryngeal component of the MBS Measurement Tool for Swallow Impairment. Receiver operating characteristic curve, Pearson correlations and independent sample t tests were used to address the research questions. Maximum F0 of sound /a/ had high sensitivity and specificity in identifying aspiration on 10 mL of liquids during VFSS. Both pitch glides (/a/ and /i/) had moderate sensitivity and specificity in predicting aspiration on a sip of liquids. However, auditory-perceptual measures of pitch glide had weak accuracy in identifying people who were aspirating during VFSS. Finally, all pitch glide measures (acoustic and auditory-perceptual) had low accuracy in predicting pharyngeal residue and hyolaryngeal excursion. Based on this initial pilot study, acoustic pitch glide of sound /a/ is an accurate way to predict aspiration on 10 mL of liquids in patients with respiratory diseases. Based on findings from this study, both auditory-perceptual and acoustic analyses of pitch glide could not identify residue and hyolaryngeal excursion.


The Effect of Reflexology on the Pain-Insomnia-Fatigue Disturbance Cluster of Breast Cancer Patients During Adjuvant Radiation Therapy.
To evaluate the effects of reflexology treatment on quality of life, sleep disturbances, and fatigue in breast cancer patients during radiation therapy. A total of 72 women with breast cancer (stages 1-3) scheduled for radiation therapy were recruited. Women were allocated upon their preference either to the group receiving reflexology treatments once a week concurrently with radiotherapy and continued for 10 weeks or to the control group (usual care). The Lee Fatigue Scale, General Sleep Disturbance Scale, and Multidimensional Quality of Life Scale Cancer were completed by each patient in both arms at the beginning of the radiation treatment, after 5 weeks, and after 10 weeks of reflexology treatment. The final analysis included 58 women. The reflexology treated group demonstrated statistically significant lower levels of fatigue after 5 weeks of radiation therapy (p < 0.001), compared to the control group. It was also detected that although the quality of life in the control group deteriorated after 5 and 10 weeks of radiation therapy (p < 0.01 and p < 0.05, respectively), it was preserved in the reflexology group, which also demonstrated a significant improvement in the quality of sleep after 10 weeks of radiation treatment (p < 0.05). Similar patterns were obtained in the assessment of the pain levels experienced by the patients. The results of the present study indicate that reflexology may have a positive effect on fatigue, quality of sleep, pain, and quality of life in breast cancer patients during radiation therapy. Reflexology prevented the decline in quality of life and significantly ameliorated the fatigue and quality of sleep of these patients. An encouraging trend was also noted in amelioration of pain levels.


American Clinical Neurophysiology Society Guideline 2: Guidelines for Standard Electrode Position Nomenclature.
This revision to the EEG Guidelines is an update incorporating current electroencephalography technology and practice and was previously published as Guideline 5. While the 10-10 system of electrode position nomenclature has been accepted internationally for almost two decades, it has not been used universally. The reasons for this and clinical scenarios when the 10-10 system provides additional localizing information are discussed in this revision. In addition, situations in which AF1/2, AF5/6, PO1/2 and PO5/6 electrode positions may be utilized for EEG recording are discussed.


Multiple drivers of the COVID-19 spread: The roles of climate, international mobility, and region-specific conditions.
Following its initial appearance in December 2019, coronavirus disease 2019 (COVID-19) quickly spread around the globe. Here, we evaluated the role of climate (temperature and precipitation), region-specific COVID-19 susceptibility (BCG vaccination factors, malaria incidence, and percentage of the population aged over 65 years), and human mobility (relative amounts of international visitors) in shaping the geographical patterns of COVID-19 case numbers across 1,020 countries/regions, and examined the sequential shift that occurred from December 2019 to June 30, 2020 in multiple drivers of the cumulative number of COVID-19 cases. Our regression model adequately explains the cumulative COVID-19 case numbers (per 1 million population). As the COVID-19 spread progressed, the explanatory power (R2) of the model increased, reaching > 70% in April 2020. Climate, host mobility, and host susceptibility to COVID-19 largely explained the variance among COVID-19 case numbers across locations; the relative importance of host mobility and that of host susceptibility to COVID-19 were both greater than that of climate. Notably, the relative importance of these factors changed over time; the number of days from outbreak onset drove COVID-19 spread in the early stage, then human mobility accelerated the pandemic, and lastly climate (temperature) propelled the phase following disease expansion. Our findings demonstrate that the COVID-19 pandemic is deterministically driven by climate suitability, cross-border human mobility, and region-specific COVID-19 susceptibility. The identification of these multiple drivers of the COVID-19 outbreak trajectory, based on mapping the spread of COVID-19, will contribute to a better understanding of the COVID-19 disease transmission risk and inform long-term preventative measures against this disease.


A single common electrophoretic abnormality of glucocorticoid receptors in human leukemia cells.
We determined the mol wt of glucocorticoid receptors in human leukemia cells in order to detect glucocorticoid receptor defects that might cause glucocorticoid resistance. Glucocorticoid receptors in intact cells were affinity labeled with [3H]dexamethasone-21-mesylate and were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Receptors in normal human peripheral blood mononuclear cells and six human leukemia cell lines had mol wt of 97,000. Malignant cells from ten of 25 patients with leukemia contained electrophoretically abnormal glucocorticoid receptors having mol wt of 55,000 in addition to normal size receptors (Mr = 97,000). The receptor abnormality was not restricted to a particular type of leukemia and was seen in cells from both newly diagnosed patients and patients who had received prior chemotherapy, including prednisone. The abnormal receptor was not generated when cells having only normal size receptors were assayed under conditions that favor proteolysis or when cytosol from cells containing the abnormal receptor form was mixed with cytosol from cells containing only normal size receptors. The mol wt of the abnormal receptors in human leukemia cells was the same as the mol wt of receptors in mutant mouse lymphoma cell lines, S49 143R and S49 55R, which have the nuclear transfer-increased phenotype of glucocorticoid resistance. This work describes for the first time a single common electrophoretic abnormality of glucocorticoid receptors in human leukemia cells. Further investigation of glucocorticoid receptor defects in human leukemia cells could lead to an improved understanding of the mechanisms of glucocorticoid resistance in leukemia as well as a method of predicting which patients are likely to be resistant to glucocorticoid therapy.


[Nurses' social representations of work-related stress in an emergency room].
The aim of this study was to understand the social representations of nurses in the emergency room and their relationship to stress. This descriptive, exploratory study was performed using a qualitative approach, with Social Representations Theory being the prime focus. Research was conducted at a benchmark public hospital for emergency services in the municipality of Natal/RN. The sample consisted of 10 nurses. A content analysis approach was used for data analysis. The results indicate that the relationship between nurses' social representations of work and stress is a complex and multi-faceted phenomenon that contributes to the development of physical, emotional and mental illnesses, and exhaustion.


An Evaluation of the Performance of the IMMY Aspergillus Galactomannan Enzyme-Linked Immunosorbent Assay When Testing Serum To Aid in the Diagnosis of Invasive Aspergillosis.
The objectives of this study were to evaluate the performance of the recently released IMMY Aspergillus galactomannan enzyme immunoassay (IMMY GM-EIA) when testing serum samples and to identify the optimal galactomannan index (GMI) positivity threshold for the diagnosis of invasive aspergillosis (IA). This was a retrospective case/control study, comprising 175 serum samples obtained from 131 patients, 35 of whom had probable or possible invasive fungal disease (IFD) as categorized using recently revised, internationally accepted definitions. The IMMY GM-EIA was performed following the manufacturer's instructions. Performance parameters were determined and receiver operator characteristic analysis was used to identify an optimal GMI threshold. Concordance with the Bio-Rad Aspergillus Ag assay (Bio Rad GM-EIA) and IMMY sona Aspergillus lateral flow assay was assessed. The median GMIs generated by the IMMY GM-EIA for samples originating from probable IA/IFD cases (n = 31), possible IFD (n = 4), and control patients (n = 100) were 0.61, 0.11, and 0.14, respectively, and were comparable to those of the Bio-Rad GM-EIA (0.70, 0.04, and 0.04, respectively). Overall qualitative observed sample agreement between the IMMY GM-EIA and Bio-Rad GM-EIA was 94.7%, generating a kappa statistic of 0.820. At a GMI positivity threshold of ≥0.5, the IMMY GM-EIA had a sensitivity and specificity of 71% and 98%, respectively. Reducing the threshold to ≥0.27 generated sensitivity and specificity of 90% and 92%, respectively. The IMMY GM-EIA provides a comparable alternative to the Bio-Rad GM-EIA when testing serum samples. Further prospective, multicenter evaluations are required to confirm the optimal threshold and associated clinical performance.


Effects of the Vertical Malocclusion Types on the Dimension of the Mandibular Condyle.
This study aimed to find the relationship between mandibular condyle morphology and dental malocclusion in patients with anterior open bite, deep bite, and normal overbite. Eighty patients were included in this retrospective study. All patients had skeletal Class II pattern. The initial panoramic radiographs of patients were digitized using a software program, and groups were compared in terms of condylar height, width, area, and perimeter. In addition, changes in the condyle surface shape were detected using the same panoramic radiographs. The mean width was 1.55±0.06 cm in the open bite group, 1.48±0.06 cm in the deep bite group, and 1.38±0.07 cm in the normal bite group. The mean height was 2.17±0.08 cm in the open bite group, 1.95±0.06 cm in the deep bite group, and 1.97±0.08 cm in the normal bite group. The mean area was 2.33±0.13 cm2 in the open bite group, 2.09±0.11 cm2 in the deep bite group, and 2.04±0.14 cm2 in the normal bite group. There was no statistical significant difference between groups in terms of condyle measurements and condyle surface shapes. The results suggest that the vertical malocclusion type does not have a considerable effect on the mandibular condyle measurements and surface shapes.


Agrobacterium-Mediated Immature Embryo Transformation of Recalcitrant Maize Inbred Lines Using Morphogenic Genes.
Demonstrated here is a detailed protocol for Agrobacterium-mediated genetic transformation of maize inbred lines using morphogenic genes Baby boom (Bbm) and Wuschel2 (Wus2). Bbm is regulated by the maize phospholipid transferase gene (Pltp) promoter, and Wus2 is under the control of a maize auxin-inducible (Axig1) promoter. An Agrobacterium strain carrying these morphogenic genes on transfer DNA (T-DNA) and extra copies of Agrobacterium virulence (vir) genes are used to infect maize immature embryo explants. Somatic embryos form on the scutella of infected embryos and can be selected by herbicide resistance and germinated into plants. A heat-activated cre/loxP recombination system built into the DNA construct allows for removal of morphogenic genes from the maize genome during an early stage of the transformation process. Transformation frequencies of approximately 14%, 4%, and 4% (numbers of independent transgenic events per 100 infected embryos) can be achieved for W22, B73, and Mo17, respectively, using this protocol.


Transcranial Doppler and systemic hemodynamic studies in septic shock.
The present study outlines the relationship between cerebral and systemic hemodynamics in patients with septic shock. Sepsis is an immune mediated systemic disease in which the systemic vascular resistance (SVR) often decreases as a result of a Gram negative sepsis. The result is a hyperdynamic systemic circulation with redistribution phenomena in different organ systems. In order to study the effect of sepsis on cerebral vessels 20 patients with septic shock (12 men, 8 women, mean age 57.9 years) were subjected to both pulmonary artery catheter and transcranial Doppler (TCD) monitoring. The data were correlated to the APACHE II score and outcome. The study showed that cerebral mean and end-diastolic blood flow velocities (BFV) in the middle cerebral arteries significantly enhanced if the SVR-index decreases. In some patients a severely reduced SVRI (below 500 dynes.s/cm5.m2) was observed in combination with a downstroke latent steal phenomenon. TCD abnormalities were strongly related to disease severity and outcome. The increased BFV are explained by a mild vasospasm of the basal cerebral arteries. TCD appears to be a valuable tool to monitor the cerebral hemodynamics in these patients. They are particularly at risk for ischemic brain damage if they are subjected to therapeutic or spontaneous hyperventilation, which can potentially be detected by TCD.


Nonatopic asthma is associated with helminth infections and bronchiolitis in poor children.
Asthma is common in urban centres in Latin America, but atopic asthma may not be the main phenotype among children. Helminth infections are highly prevalent in poor populations, and it was hypothesised that they attenuate allergic asthma, whereas other factors are related to the expression of a nonatopic wheeze/asthma phenotype. A total of 1,982 children from Southern Brazil with a mean+/-sd age of 10.1+/-0.76 yrs completed asthma questionnaires, and 1,011 were evaluated for intestinal parasites and atopy using skin-prick tests (SPTs). Wheeze in the previous 12 months was reported by 25.6%, and 9.3% showed current asthma; 13% were SPT-positive and 19.1% were positive for any helminths. Most children with either wheeze or asthma were SPT-negative; however, severe wheeze was more prevalent among the atopic minority. Helminth infections were inversely associated with positive SPT results. Bronchiolitis before the age of 2 yrs was the major independent risk factor for asthma at age 10 yrs; high-load Ascaris infection, a family history of asthma and positive SPT results were also asthma risk factors. Most asthma and wheeze are of the nonatopic phenotype, suggesting that some helminths may exert an attenuating effect on the expression of the atopic portion of the disease, whereas viral bronchiolitis predisposes more specifically to recurrent airway symptoms.


A cell-molecular approach predicts vertebrate evolution.
In contrast to the conventional use of genes to determine the evolution of phenotypes, we have functionally integrated epithelial-mesenchymal interactions that have facilitated lung phylogeny and ontogeny in response to major geologic epochs. As such, this model reveals the underlying principles of lung physiology based on the evolutionary interactions between internal and external selection pressures, providing a novel understanding of lung biology. As a result, it predicts how cell-molecular changes in this process can cause disease and offers counterintuitive insights to diagnosis and treatment based on evolutionary principles.


Characterization of chromosomal aberrations in human gastric carcinoma cell lines using chromosome painting.
Using chromosome painting, a study of chromosomal abnormalities was performed in six gastric carcinoma cell lines (SNU-484, 601, 620, 638, 668, 719) from Korean patients. Each carcinoma cell line had unique modal karyotypic characteristics and showed a variable number of numerical and structural clonal cytogenetic aberrations. SNU-484, SNU-620, and SNU-668 had near-triploidy; SNU-601, SNU-638, and SNU-719 had near-diploidy. The origins of the marker chromosomes of these cell lines were identified by fluorescence in situ hybridization with constructed painting probes. In all of six cell lines, rearrangement of chromosome 17 resulting in partial deletion of 17p (and/or partial duplication of 17q) was found. The most frequent marker was a partial gain of chromosome 7 with the breakpoints on 7q22 and 7q31. The nonrandom rearrangements of chromosomes were also determined on 1q32, 5q11-q22, 8q, 14q22, 14q34, and 15q15; suggesting that they may be the candidate regions for the isolation of the genes related to gastric cancer.


Characterization of Solubilizing Nanoaggregates Present in Different Versions of Simulated Intestinal Fluid.
The absorption of hydrophobic drugs and nutrients from the intestine is principally determined by the amount that can be dissolved by the endogenous fluids present in the gut. Human intestinal fluids (HIFs) comprise a complex mixture of bile salts, phospholipids, steroids and glycerides that vary in composition in the fed and fasted state and between subjects. A number of simulated intestinal fluid (SIF) compositions have been developed to mimic fasted and fed state intestinal conditions and allow the in vitro determination of drug solubility as a proxy for the maximum dissolved concentration it is possible to reach. In particular these solvents are used during the development of lipophilic and poorly water-soluble drugs but questions remain around the differences that may arise from the source and methods of preparation of these fluids. In this work, a range of SIFs were studied using small-angle X-ray scattering (SAXS), cryogenic-transmission electron microscopy (cryo-TEM) and molecular dynamics (MD) simulations in order to analyze their structures. In-house prepared SIFs based on sodium taurodeoxycholate (NaTDC) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) formed oblate ellipsoidal micelles irrespective of lipid concentration and preparation conditions. In contrast, commercially available SIFs based on sodium taurocholate and lecithin formed prolate ellipsoidal micelles in the fed state and vesicles in the fasted state. These structural variations are the likely reason for the dramatic differences sometimes observed in the solubility enhancements for hydrophobic drugs, nutrients and digestion products when using different SIFs. However, the structural homogeneity of the NaTDC/DOPC micelles makes them ideal candidates for standardizing SIF formulations as the structures of the solubilizing nanoaggregates therein are not sensitive to the preparation method.


Presence of a transcriptionally active glucocorticoid receptor alpha in lens epithelial cells.
The purpose of this study was to determine whether lens epithelial cells (LECs) contain a glucocorticoid receptor (GR) that is transcriptionally active and that is able to induce production of known glucocorticoid-inducible proteins. Protein and mRNA were obtained from human, rabbit, and bovine lens epithelia and from cultured human lens epithelial cells (B3, hLECs) and rabbit lens epithelial cells (N/N1003A, rLECs). Paraffin-embedded sections were prepared from human lenses for immunohistochemical localization of GR. RT-PCR was performed to amplify portions of GR, and the products were sequenced. Protein samples were analyzed by Western blot. hLECs and rLECs were transfected with pTAT3-luc and assayed for luciferase activity after treatment with dexamethasone (Dex) and/or RU486. Dex-treated LECs were also analyzed by quantitative real-time PCR and by Western blot for expression of specific mRNA and proteins. By PCR and sequencing, products consistent with GR sequences were obtained from human, rabbit, and bovine lenses and from hLECs and rLECs. The complete GRalpha sequence was obtained from rLECs and was found to be 89% identical with human GR. A 1757-bp 3' fragment of bovine GRalpha cDNA was also amplified from bovine lens. By Western blot, bands of approximately 94 kDa, the expected size of GR, were identified from human, rabbit, and bovine lens samples and from hLECs and rLECs, using anti-GR antibodies. Anti-GR antisera localized GR to both the cytosol of anterior and bow region LECs and to the nuclei of epithelial and early-differentiating lens fiber cells. Luciferase expression was induced in pTAT3-luc-transfected rLECs and hLECs by Dex treatment and this expression was partially (rLECs) or completely (hLECs) blocked by pretreatment with RU486. mRNA levels for type-1 glucocorticoid-induced target genes and also mRNA and protein levels for type-2 genes were upregulated after Dex exposure. The data confirm the existence of GR in hLECs, indicate that GR is present in rLECs, and resolve the controversy over the presence of GR in bovine lens. The GRalpha in hLECs and rLECs was shown to be transcriptionally active and the expression levels in hLECs of mRNAs and proteins known to be regulated by glucocorticoids were modified in these cells by glucocorticoid treatment.


Direct binding to Rsp5p regulates ubiquitination-independent vacuolar transport of Sna3p.
The sorting of integral membrane proteins such as carboxypeptidase S (Cps1p) into the luminal vesicles of multivesicular bodies (MVBs) in Saccharomyces cerevisiae requires ubiquitination of their cytosolic domains by the ubiquitin ligases Rsp5p and/or Tul1p. An exception is Sna3p, which does not require ubiquitination for entry into MVBs. The mechanism underlying this ubiquitination-independent MVB sorting pathway has not yet been characterized. Here, we show that Sna3p sorting into the MVB pathway depends on a direct interaction between a PPAY motif within its C-terminal cytosolic tail and the WW domains of Rsp5p. Disruption of this interaction inhibits vacuolar targeting of Sna3p and causes its accumulation in a compartment that overlaps only partially with MVBs. Surprisingly, Sna3p does require a functional ubiquitin-ligase HECT domain within Rsp5p; however, the dependence of Sna3p on HECT domain activity is distinct from that of Cps1p. Last, we show that Sna3p requires neither Tul1p nor the transmembrane adaptor protein Bsd2p for its MVB sorting. Our data demonstrate that Sna3p follows a novel ubiquitination-independent, but Rsp5p-mediated, sorting pathway to the vacuole.


Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas.
Preclinical animal experiments support the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor (IGF-IR/AS ODN) as an effective potential antitumor agent. We performed a human pilot safety and feasibility study using an IGF-IR/AS ODN strategy in patients with malignant astrocytoma. Autologous glioma cells collected at surgery were treated ex vivo with an IGF-IR/AS ODN, encapsulated in diffusion chambers, reimplanted in the rectus sheath within 24 hours of craniotomy, and retrieved after a 24-hour in situ incubation. Serial posttreatment assessments included clinical examination, laboratory studies, and magnetic resonance imaging scans. Other than deep venous thrombosis noted in some patients, no other treatment-related side effects were observed. IGF-IR/AS ODN-treated cells, when retrieved and assessed, were < or = 2% intact by trypan blue exclusion, and none of the intact cells were viable in culture thereafter. Parallel Western blots disclosed IGF-IR downregulation to < or = 10% after ex vivo antisense treatment. At follow-up, clinical and radiographic improvements were observed in eight of 12 patients, including three cases of distal recurrence with unexpected spontaneous or postsurgical regression at either the primary or the distant intracranial site. Ex vivo IGF-IR/AS ODN treatment of autologous glioma cells induces apoptosis and a host response in vivo without unusual side effects. Subsequent transient and sustained radiographic and clinical improvements warrant further clinical investigations.


A platform for combined DNA and protein microarrays based on total internal reflection fluorescence.
We have developed a novel microarray technology based on total internal reflection fluorescence (TIRF) in combination with DNA and protein bioassays immobilized at the TIRF surface. Unlike conventional microarrays that exhibit reduced signal-to-background ratio, require several stages of incubation, rinsing and stringency control, and measure only end-point results, our TIRF microarray technology provides several orders of magnitude better signal-to-background ratio, performs analysis rapidly in one step, and measures the entire course of association and dissociation kinetics between target DNA and protein molecules and the bioassays. In many practical cases detection of only DNA or protein markers alone does not provide the necessary accuracy for diagnosing a disease or detecting a pathogen. Here we describe TIRF microarrays that detect DNA and protein markers simultaneously, which reduces the probabilities of false responses. Supersensitive and multiplexed TIRF DNA and protein microarray technology may provide a platform for accurate diagnosis or enhanced research studies. Our TIRF microarray system can be mounted on upright or inverted microscopes or interfaced directly with CCD cameras equipped with a single objective, facilitating the development of portable devices. As proof-of-concept we applied TIRF microarrays for detecting molecular markers from Bacillus anthracis, the pathogen responsible for anthrax.


D-dimer as a Predictor of Altered Coagulation in HIV Patients in Nigeria.
Recent medical advances have improved the quality of life and correspondingly reduced the morbidity and mortality associated with HIV infection. However increased life expectancy has led to a relative rise in comorbidities and complications such as alterations in coagulation systems. This study is aimed at the evaluation of D-dimer level as a predictor of thromboembolic risk in HIV patients. A total of 152 HIV positive and negative subjects and control respectively attending the PEPFAR clinic UCH in Ibadan were recruited both for a questionnaire-based survey and a coagulation profile screening. Activated Partial Thromboplastin Time (APTT), Prothrombin Time (PT), D-dimer level the viral load indices of the HIV patients and their CD4 counts were also evaluated. In the subjects, the D-dimer level was significantly higher (193.6 ± 177.00ng/ml) than the controls (118.10 ± 140.58ng/ml) while a significantly lower APTT was also reported (36.22 ± 4.05 seconds) compared to the controls (41.14 ± 8.87 seconds). An evaluation of the coagulation profile in the Highly Active Antiretroviral Therapy (HAART) naïve and experienced group revealed only a significant increase (417.4) in the CD4 count whilst no difference was observed in the coagulation profile. In our study, a higher predisposition to a hypercoagulable state presenting as a short APTT was observed. This finding along with the higher D-dimer level underscores the relevance of the evaluation of this biomarker as an important predictor of thromboembolic event risk.


Transcriptional activation of heat shock protein 90 mediated via a proximal promoter region as trigger of caspofungin resistance in Aspergillus fumigatus.
Invasive aspergillosis is a deadly infection for which new antifungal therapies are needed. Heat shock protein 90 (Hsp90) is an essential chaperone in Aspergillus fumigatus representing an attractive antifungal target. Using a thiamine-repressible promoter (pthiA), we showed that genetic repression of Hsp90 significantly reduced virulence in a murine model of invasive aspergillosis. Moreover, substituting the A. fumigatus hsp90 promoter with 2 artificial promoters (potef, pthiA) and the Candida albicans hsp90 promoter resulted in hypersensitivity to caspofungin and abolition of the paradoxical effect (resistance at high caspofungin concentrations). By inducing truncations in the hsp90 promoter, we identified a 100-base pair proximal sequence that triggers a significant increase of hsp90 expression (≥1.5-fold) and is essential for the paradoxical effect. Preventing this increase of hsp90 expression was sufficient to abolish the paradoxical effect and therefore optimize the antifungal activity of caspofungin.


[Microcirculation in white atrophy].
There are two clinical phenomena which, owing to the French School, are still subject to violent criticism: the phenomenon described by M. Raynaud (1862) and the white atrophy termed Milian's (1929). Perhaps badly defined by the authors, the facts have been reviewed, but microcirculation - that of gauges less than 30 to 50 m - does not occupy the whole picture. The proof is that in direct capillaroscopy, functional explorations and biopsy are strikingly monotonous and lacking in exactitude. Capillaroscopy provides the usual aspects of cicatrization, "capillary" neogenesis and their histogenic disorders: central avascular zone, corona limited with loops in "club" formation, or in "clusters" owing to their confluence, "key" loops at the periphery near to the normal loops. These "neocapillaries" pose problems of the immaturity of the neovascular elements and of hydraulics in venous stasis. Of course, there are disorders of capillary permeability, and these are linked especially with vascular neogenesis, but it would not be reasonable to speak of "cutaneous infarctus", or "vascularitis", the necessary criteria being absent. On the contrary, we believe that it all comes down to a "histoangiopathy" by deterioration of the pericapillary sheath of proteoglycanes and of the interstitial conjunctiva. The anomalies are of the type of the deteriorations in plastic polymers and the apparatus of the endarterial bloc, which are included. A "trapping" of the leucocytes in the declivitous areas must also play a part.


Remnant-like particle-cholesterol concentrations in patients with type 2 diabetes mellitus and end-stage renal disease.
Lipid abnormalities contribute significantly to the increased risk of cardiovascular disease in diabetic and end-stage renal disease (ESRD) patients. Accumulating evidence supports a proatherogenic role for remnant lipoproteins. Thus, the aim of the present study was to compare remnant-like particle-cholesterol (RLP-C) in type 2 diabetic and ESRD patients with age- and gender-matched controls. Using an immunoaffinity assay, we measured RLP-C concentrations in 48 type 2 diabetic patients with (n = 24) and without (n = 24) macrovascular complications, and 24 age- and gender-matched controls, as well as in 38 ESRD patients on hemodialysis (n = 19) and peritoneal dialysis (n = 19), and 19 age- and gender-matched controls. RLP-C correlated significantly with plasma triglycerides (TGs; r = 0.8). When compared with controls, RLP-C concentrations were significantly higher in type 2 diabetic patients with and without macrovascular complications (median, 0.22 and 0.17 mmol/L vs 0.14 mmol/L; P <0.0002 and <0.01, respectively); diabetic patients with macrovascular complications also had significantly higher RLP-C than diabetic patients without macrovascular complications (P <0.05). However, when RLP-C/TG ratios were computed, only diabetic patients with macrovascular complications showed significantly higher RLP-C/TG ratios compared with controls (P <0.05). Regarding ESRD, RLP-C concentrations were significantly increased in patients on both hemodialysis and peritoneal dialysis compared with controls (median, 0.23 and 0.21 mmol/L vs 0.13 mmol/L; P <0.0001). Whereas RLP-C was increased in ESRD patients on hemodialysis with TGs <2.26 mmol/L compared with controls, RLP-C/TG ratios were not significantly increased in these patients. Type 2 diabetic patients with macrovascular disease demonstrated increased RLP-C and RLP-C/TG ratios, whereas ESRD patients showed only increased RLP-C concentrations.


Dealing with malaria in the last 60 years. A personal experience.
Dealing with malaria in the last 60 years is seen by the author in the perspective of his own experience. His malaria work, which began in 1941, covered the study of the habits of the mosquitoes dwelling in the savanna country of Eastern Colombia and the effect on malaria transmission of the newly introduced DDT residual spraying. The success of the campaign he later directed in Sarawak and Brunei contributed to the launching by WHO of its global malaria eradication campaign. Further successful work in Uganda showed the possibility of effective control and even eradication in highland country but left unsolved the problem of how to interrupt transmission of holoendemic malaria in Africa. The author's work with WHO in the Middle East showed to what extent social and economic conditions could influence the course of a malaria campaign. This was also the experience in America, both in Colombia in the author's early work and later in Mexico during an evaluation of the national malaria programme. Development of insecticide resistance was also encountered in his career and the refractoriness of the European vectors was also observed in his work as a malariologist.


Hepatitis B virus in the Arab world: where do we stand?
The epidemiology of viral hepatitis is of great importance for planning and managing health provision for all the countries in the Arab world. However, data on viral hepatitis are not readily available in a large percentage of Arab countries. Hepatitis B virus (HBV) is considered to be one of the most important causes of chronic hepatitis, cirrhosis and hepatocellular carcinoma. A systematic electronic search of published literature was conducted to extract data on epidemiology and risk factors for the analysis of HBV infection among the countries in the Arab world. The prevalence of chronic HBV infection was found to be decreasing in some Arab countries although it was still unacceptably high. This was particularly evident in the Arabian Gulf region, in Lebanon, Egypt and Libya. The age-specific prevalence varied from country to country with decline in prevalence being noted among children in the Gulf States and among Libyan women. These declines in prevalence are most likely to be related to the Expanded Immunization Programme. The alarmingly high prevalence of chronically infected patients in some areas and the widespread differences in HBV prevalence between Arab nations may be explained by the variation in risk factors involved. This situation calls for targeted approaches to tackle HBV-related mortality and morbidity. Precise HBV infection prevalence data are needed at the national and the sub-national level to estimate the disease burden, guide health intervention programmes and evaluate vaccine efficiency.


K-Ion Slides in Prussian Blue Analogues.
We study the phenomenology of cooperative off-centering of K+ ions in potassiated Prussian blue analogues (PBAs). The principal distortion mechanism by which this off-centering occurs is termed a "K-ion slide", and its origin is shown to lie in the interaction between local electrostatic dipoles that couple through a combination of electrostatics and elastic strain. Using synchrotron powder X-ray diffraction measurements, we determine the crystal structures of a range of low-vacancy K2M[Fe(CN)6] PBAs (M = Ni, Co, Fe, Mn, Cd) and establish an empirical link between composition, temperature, and slide-distortion magnitude. Our results reflect the common underlying physics responsible for K-ion slides and their evolution with temperature and composition. Monte Carlo simulations driven by a simple model of dipolar interactions and strain coupling reproduce the general features of the experimental phase behavior. We discuss the implications of our study for optimizing the performance of PBA K-ion battery cathode materials and also its relevance to distortions in other, conceptually related, hybrid perovskites.


Hydration motifs of ammonium bisulfate clusters of relevance to atmospheric new particle formation.
Clusters of ammonia or amines and sulfuric acid are predicted to drive the formation of new particles from atmospheric trace gases, but the role of water in this process, or even the extent of hydration of the clusters, is not well known. We present vibrational spectra of exactly mass-selected clusters of ammonia or dimethylamine and sulfuric acid with zero to four water molecules bound. These hydrated clusters are synthesized by storing initially-dry clusters in an ion trap held at 180 K with a small partial pressure of water vapor. Analysis of the spectra shows that hydration occurs first at the ammonium NH groups, rather than the bisulfate OH or between the conjugate acids and bases, and that binding to the bisulfate OH only becomes favorable if an additional hydrogen bond acceptor is in the vicinity. These spectra are compared to quantum chemical predictions to evaluate the specific structural motifs present. Broadly speaking, they reveal classes of isomers with similar overall binding motifs but different specific arrangements of water within these motifs. The structures determined for each ensuing hydrate can be explained by addition of one water to the next lower hydrate, without the need for significant rearrangement of the cluster or hydrate structures. Taken together, these observations suggest that multiple hydration isomers may play a role in atmospheric conditions, but substantial barriers to water rearrangement may direct the mechanism of sequential hydration, and entropic contributions to the heats of formation may play an important role in models of new particle formation.


Complications associated with carotid endarterectomy.
A discussion of some of the complications associated with carotid endarterectomy is presented. Accurate knowledge of anatomy is essential in preventing injury to nerves, blood vessels and other regional anatomical structures. Complications following carotid artery operation may be severe and must be avoided if possible. Indications for carotid endarterectomy are still controversial. The final decision for or against operation rests on the judgment of the vascular surgeon.


An integrative multi-scale analysis of the dynamic DNA methylation landscape in aging.
Recent studies have demonstrated that the DNA methylome changes with age. This epigenetic drift may have deep implications for cellular differentiation and disease development. However, it remains unclear how much of this drift is functional or caused by underlying changes in cell subtype composition. Moreover, no study has yet comprehensively explored epigenetic drift at different genomic length scales and in relation to regulatory elements. Here we conduct an in-depth analysis of epigenetic drift in blood tissue. We demonstrate that most of the age-associated drift is independent of the increase in the granulocyte to lymphocyte ratio that accompanies aging and that enrichment of age-hypermethylated CpG islands increases upon adjustment for cellular composition. We further find that drift has only a minimal impact on in-cis gene expression, acting primarily to stabilize pre-existing baseline expression levels. By studying epigenetic drift at different genomic length scales, we demonstrate the existence of mega-base scale age-associated hypomethylated blocks, covering approximately 14% of the human genome, and which exhibit preferential hypomethylation in age-matched cancer tissue. Importantly, we demonstrate the feasibility of integrating Illumina 450k DNA methylation with ENCODE data to identify transcription factors with key roles in cellular development and aging. Specifically, we identify REST and regulatory factors of the histone methyltransferase MLL complex, whose function may be disrupted in aging. In summary, most of the epigenetic drift seen in blood is independent of changes in blood cell type composition, and exhibits patterns at different genomic length scales reminiscent of those seen in cancer. Integration of Illumina 450k with appropriate ENCODE data may represent a fruitful approach to identify transcription factors with key roles in aging and disease.


A case of diffuse neurofibroma of the scalp.
A neurofibroma is a benign tumor of the peripheral nerve sheath characterized by proliferation of Schwann cells, perineural cells, and endoneurial fibroblasts. Different types of neurofibromas can be identified, including localized, plexiform, and diffuse types. Neurofibromas can involve any site on the body skin. The diffuse variant is rare and occurs primarily in children and young adults. It involves the skin and subcutaneous tissue in a plaque-like fashion on the head and neck regions. We present a case of a 10-year-old boy who had a diffuse neurofibroma on the scalp.


Ghrelin receptor antagonism and satiety attenuate Pavlovian-instrumental transfer.
Animals rely on learned cues to guide their behaviour for rewards such as food. The Pavlovian-instrumental transfer (PIT) task can be used to investigate the influence of Pavlovian stimuli on instrumental responding. Ghrelin, an orexigenic peptide, and its receptor, growth hormone secretagogue receptor 1A (GHS-R1A), has received growing interest for its role in reward-motivated learning and behaviours. A significant population of GHS-R1A have been identified within the ventral tegmental area (VTA), a critical node in the mesolimbic reward circuit that is necessary for the expression of PIT. As ghrelin has been found to increase dopaminergic activity in the VTA, we predicted that GHS-R1A antagonism with JMV-2959 would attenuate PIT. Further, given the relationship between hunger levels and changes in ghrelin signalling, we sought to compare the effects GHS-R1A antagonism with those of satiety, hypothesizing parallel effects, with each attenuating PIT. Rats received daily sessions of Pavlovian and then instrumental training over 3 weeks. Across three experiments, we examined the effects of a shift to satiety, or treatment with the GHS-R1A antagonist JMV-2959, either peripherally or directly into the VTA. We found that presentations of a stimulus paired with food reward enhanced responding for food across all conditions, thus demonstrating the expected PIT effect. Further, GHS-R1A antagonism, both peripherally and within the VTA, as well as satiety significantly reduced the magnitude of the PIT effect compared to control conditions. These results clarify our understanding of ghrelin signalling in PIT and begin to elucidate the role of feeding-related peptides in the modulation of reward-related responding.


Reduced hippocampal volume in adolescents with psychotic experiences: A longitudinal population-based study.
Smaller hippocampal volumes are among the most consistently reported neuroimaging findings in schizophrenia. However, little is known about hippocampal volumes in people who report psychotic experiences. This study investigated differences in hippocampal volume between young people without formal diagnoses who report psychotic experiences (PEs) and those who do not report such experiences. This study also investigated if any differences persisted over two years. A nested case-control study of 25 adolescents (mean age 13.5 years) with reported PEs and 25 matched controls (mean age 13.36 years) without PEs were drawn from a sample of 100 local schoolchildren. High-resolution T1-weighted anatomical imaging and subsequent automated cortical segmentation (Freesurfer 6.0) was undertaken to determine total hippocampal volumes. Comprehensive semi-structured clinical interviews were also performed including information on PEs, mental diagnoses and early life stress (bullying). Participants were invited for a second scan at two years. 19 adolescents with PEs and 19 controls completed both scans. Hippocampal volumes were bilaterally lower in the PE group compared to the controls with moderate effects sizes both at baseline [left hippocampus p = 0.024 d = 0.736, right hippocampus p = 0.018, d = 0.738] and at 2 year follow up [left hippocampus p = 0.027 d = 0.702, right = 0.048 d = 0.659] throughout. These differences survived adjustment for co-morbid mental disorders and early life stress. Psychotic experiences are associated with total hippocampal volume loss in young people and this volume loss appears to be independent of possible confounders such as co-morbid disorders and early life stress.


Developing a model to determine the effects of adverse drug events in hospital inpatients.
A study was conducted to develop a model to identify adverse drug events (ADEs) and quantify their effect on quality and cost in a large tertiary care hospital. The drug-ADE relationship between unfractionated heparin and heparin-induced bleeding was studied for all inpatients receiving heparin infusions at the hospital between January 1 and December 31, 2004. Activated partial thromboplastin time (aPTT) values were used to help determine if the patients received blood products in response to excessive anticoagulation with heparin. The number of aPTT values of > or =150 seconds and the last aPTT value before discharge were evaluated. The key outcome measures were length of stay, cost per admission, and mortality. Of the 1455 admissions to the hospital, 122 patients received blood products before receiving heparin infusion only, 264 received blood products after receiving the drug only, 221 received blood products both before and after, and 848 who received the drug never received blood products. Differences in full cost and length of stay between the group receiving heparin infusion only and the groups receiving both blood products were significant. Differences in mortality between the group only receiving heparin infusion and the groups receiving both heparin infusion and blood products were also significant. Using the model developed to study the effect of heparin-induced bleeding, we found that the cost per patient day was highest for patients receiving blood products after heparin infusion treatment. There was a positive correlation between one or more aPTT values of > or =150 seconds and undesirable patient outcomes.


Asymptomatic isolated human glycerol kinase deficiency associated with splice-site mutations and nonsense-mediated decay of mutant RNA.
Isolated glycerol kinase deficiency (GKD) is an X-linked inborn error of metabolism that is either symptomatic or asymptomatic. GKD is due to deletions of, or mutations within, the GK gene, and there is no genotype-phenotype correlation. We identified three patients with asymptomatic GKD, determined that they had GK splice-site mutations, and studied the stability of their GK mRNA to understand the molecular mechanism of the GKD. All three patient mutations caused a frameshift and introduction of a premature stop codon. A fourth patient had an Alu insertion in intron 4 that led to alternative splicing. To study the effect of splice-site mutations on RNA species, we performed reverse transcriptase PCR and found only normal-sized products for all patients. Incubation with anisomycin to block nonsense-mediated decay (NMD), revealed two RNA species for each individual. Sequence analysis revealed that the larger bands represented the wild-type GK RNA and smaller bands represented mutant misspliced RNA, suggesting that the abnormal RNA species were targeted by NMD. Normal RNA species observed in each patient are likely responsible for their mild phenotypes. We speculate that influences on RNA processing and protein stability represent modifiers of the GKD phenotype.


A feasibility study for NOn-Traditional providers to support the management of Elderly People with Anxiety and Depression: The NOTEPAD study Protocol.
Anxiety and depression are common among older people, with up to 20% reporting such symptoms, and the prevalence increases with co-morbid chronic physical health problems. Access to treatment for anxiety and depression in this population is poor due to a combination of factors at the level of patient, practitioner and healthcare system. There is evidence to suggest that older people with anxiety and/or depression may benefit both from one-to-one interventions and group social or educational activities, which reduce loneliness, are participatory and offer some activity. Non-traditional providers (support workers) working within third-sector (voluntary) organisations are a valuable source of expertise within the community but are under-utilised by primary care practitioners. Such a resource could increase access to care, and be less stigmatising and more acceptable for older people. The study is in three phases and this paper describes the protocol for phase III, which will evaluate the feasibility of recruiting general practices and patients into the study, and determine whether support workers can deliver the intervention to older people with sufficient fidelity and whether this approach is acceptable to patients, general practitioners and the third-sector providers. Phase III of the NOTEPAD study is a randomised controlled trial (RCT) that is individually randomised. It recruited participants from approximately six general practices in the UK. In total, 100 participants aged 65 years and over who score 10 or more on PHQ9 or GAD7 for anxiety or depression will be recruited and randomised to the intervention or usual general practice care. A mixed methods approach will be used and follow-up will be conducted 12 weeks post-randomisation. This study will inform the design and methods of a future full-scale RCT. ISRCTN, ID: ISRCTN16318986 . Registered 10 November 2016. The ISRCTN registration is in line with the World Health Organization Trial Registration Data Set. The present paper represents the original version of the protocol. Any changes to the protocol will be communicated to ISRCTN.


Family structure and the transition to early parenthood.
With the rise in out-of-wedlock childbearing and divorce in the last quarter of the twentieth century, an increasing proportion of children have been exposed to a variety of new family forms. Little research has focused on the consequences of childhood family structure for men's transition to fatherhood or on the family processes that account for the effects of family structure on the likelihood that young women and men become first-time unmarried parents, what we now call "fragile families." The data come from the linked Children and Young Adult samples of the 1979 National Longitudinal Survey of Youth (NLSY79), which provide information on the children of the women of the NLSY79 from birth until they enter young adulthood. Females growing up with a single parent and males experiencing an unstable family transition to parenthood early, particularly to nonresidential fatherhood for males. For males, the effects are strongly mediated by parenting processes and adolescent behaviors and are shaped by economic circumstances. Having experienced multiple transitions as a child is associated with a reduced likelihood that males father their first child within marriage and an increased likelihood that they become fathers within cohabitation, demonstrating how changes in family structure alter family structure patterns over time and generations.


Ventricular arrhythmias in trials of thrombolytic therapy for acute myocardial infarction. A meta-analysis.
Although thrombolytic therapy reduces long-term mortality in acute myocardial infarction, many clinicians remain concerned about an increased risk of ventricular arrhythmias associated with the use of these agents. To determine whether thrombolytic therapy increases the risk of ventricular tachyarrhythmias and whether an increase in arrhythmias could be responsible for the increased mortality seen in the first 24 hours after lytic therapy, we performed a meta-analysis of 15 randomized trials of thrombolysis in acute myocardial infarction in which the odds of developing in-hospital ventricular fibrillation (VF) and ventricular tachycardia (VT) in patients receiving thrombolysis was compared with that of patients receiving placebo. For trials that reported the incidence of VF during the first 6 hours after thrombolysis, the summary odds ratio for developing VF in the thrombolytic group was 0.98 (95% confidence interval [CI], 0.6 to 1.6; P = .94). For trials that reported the incidence of VF during the first hospital day, the summary odds ratio for developing VF was 1.00 (95% CI, 0.85 to 1.2; P = .95). The summary odds ratio for the development of VF at any time during hospitalization in the thrombolytic group was 0.83 (95% CI, 0.76 to 0.90; P < .0001). In trials that reported the incidence of VT any time during hospitalization, the summary odds ratio for the development of VT in the thrombolytic group was 1.34 (95% CI, 1.15 to 1.55; P < .0001). The likelihood of developing VF in the early hours after thrombolysis for acute myocardial infarction is similar in patients receiving thrombolytics or placebo. However, throughout the hospital course, the risk of VF is greater in patients receiving placebo, whereas the risk of VT is higher in patients receiving thrombolysis.


Electrophysiological properties of ventricular muscle obtained from spontaneously diabetic mice.
The electrophysiological properties of cardiac muscle in KK/Ta mouse (hereafter referred to as KK mouse), an animal model of human non-insulin-dependent diabetes mellitus, were investigated, and the findings compared with those obtained from a non-diabetic control mouse (C57BL/6J mouse; referred to as B6 mouse). The ages of the B6 mice were 23.9 +/- 5.4 weeks (n = 24) and those of the KK mice used were 25.7 +/- 10.8 weeks (n = 34). The KK mice had mild obesity, hyperglycemia and hyperinsulinemia. Ventricular muscles from both mice were examined by light microscopy. Partial myocardial fibrosis and filament disorder in the ventricular muscles were found only in the KK mice. The resting membrane potential of the ventricular muscle was less negative in the KK mice than in the control mice. The maximum rate of rise in the upstroke of the action potential was significantly decreased in the KK mice compared with that of the control mice. These suggest a decrease in a time-independent K+ current (IK1) in the KK mice. The duration of the action potential (APD) at all levels of repolarization was significantly longer in the KK mice than in the B6 mice. A blocker of transient outward current (I(to)), 4-aminopyridine, significantly prolonged the APD of the B6 mice, but failed to prolong it in the KK mice, suggesting that Ito in the diabetic mice is very small. A Ca2+ channel blocker, CoCl2, dramatically lengthened all levels of APD in both groups, suggesting that there is no difference between B6 mice and KK mice in L-type Ca2+ current via Ca2+ channels. These suggest the malfunction or deficiency of ionic channels which carry, at least Ito and IK1 in diabetic mice.


Dendritic cell inhibition is connected to exhaustion of CD8+ T cell polyfunctionality during chronic hepatitis C virus infection.
Although chronic viral infections have evolved mechanisms to interfere with aspects of pathogen recognition by dendritic cells (DCs), the role that these APCs play in virus-specific T cell exhaustion is unclear. Herein we report that NS3-dependent suppression of Toll/IL-1 domain-containing adapter-inducing IFN-beta- and IFN-beta promoter stimulator-1- but not MyD88-coupled pathogen-recognition receptor-induced synthesis of proinflammatory cytokines (IL-12 and TNF-alpha) from DCs by hepatitis C virus (HCV) is a distinctive feature of a subgroup of chronically infected patients. The result is decreased CD8(+) T cell polyfunctional capacities (production of IFN-gamma, IL-2, TNF-alpha, and CD107a mobilization) that is confined to HCV specificities and that relates to the extent to which HCV inhibits DC responses in infected subjects, despite comparable plasma viral load, helper T cell environments, and inhibitory programmed death 1 receptor/ligand signals. Thus, subjects in whom pathogen-recognition receptor signaling in DCs was intact exhibited enhanced polyfunctionality (i.e., IL-2-secretion and CD107a). In addition, differences between HCV-infected patients in the ability of CD8(+) T cells to activate multiple functions in response to HCV did not apply to CD8(+) T cells specific for other immune-controlled viruses (CMV, EBV, and influenza). Our findings identify reversible virus evasion of DC-mediated innate immunity as an additional important factor that impacts the severity of polyfunctional CD8(+) T cell exhaustion during a chronic viral infection.


Beta blockers exposure and traumatic brain injury: a literature review.
Traumatic brain injury (TBI) continues to carry a significant public health burden and is anticipated to worsen worldwide over the next century. Recently the authors of several articles have suggested that exposure to beta blockers may improve mortality rates following TBI. The exact mechanism through which beta blockers mediate this effect is unknown. In this paper, the authors review the literature regarding the safety of beta blockers in patients with TBI. The findings of several recent retrospective cohort studies are examined and implications for future investigation are discussed. Future questions to be addressed include: the specific indications for the use of beta blockers in patients with TBI, the optimal type and dose of beta blocker given, the end point of beta blocker therapy, and the safety of beta blockers in cases of severe TBIs.


Quality of life of children living in HIV/AIDS-affected families in rural areas in Yunnan, China.
The aim of this study was to explore the main influencing factors of the health-related quality of life (HRQL) of children living in HIV/AIDS-affected families in rural areas in Yunnan, China. The HRQL of 116 children aged 8-17 from HIV/AIDS-affected families and 109 children from unaffected families was evaluated by the Chinese Version of PedsQL 4.0. Some potential influencing factors were questioned, such as demographic characteristics, the families' social and economic status, foster models, children's self-esteem, etc. The HRQL of children's caregivers may also have been among the influencing factors, as measured by short-form 36 (SF-36). Multiple regression analysis was used to explore the influence of independent variables on children's HRQL. The findings showed that children from HIV/AIDS-affected families reported lower scores of HRQL than those from unaffected families, especially in domains of psychosocial functioning, emotional functioning, and school functioning. Results of multiple regression analysis showed that lower levels of children's self-esteem and caregivers' SF-36 reduced the majority of PedsQL domains. Children living with grandparents reported higher PedsQL scores in psychosocial health, social functioning, and school functioning. Disclosure of parental HIV/AIDS status reduced children's PedsQL scores in emotional functioning and social functioning. Caregivers spending more hours accompanying the children appeared to increase the PedsQL scores in psychosocial health and school functioning. The findings indicate that the child's self-esteem, the caregiver's perceived quality of life, the child's foster pattern, the average hours of company provided by the caregiver, and whether the child was informed of the parent's HIV/AIDS status are important factors influencing HRQL. Interventions aiming at these factors should be developed to improve the HRQL of children affected by HIV/AIDS.


Acute procedural interventions after pediatric blunt abdominal trauma: A prospective multicenter evaluation.
Pediatric intra-abdominal injuries (IAI) from blunt abdominal trauma (BAT) rarely require emergent intervention. For those children undergoing procedural intervention, our aim was to understand the timing and indications for operation and angiographic embolization. We prospectively enrolled children younger than 16 years after BAT at 14 Level I Pediatric Trauma Centers over a 1-year period. Patients with IAI who received an intervention (IAI-I) were compared with those who did not receive an intervention using descriptive statistics and univariate analysis; p less than 0.05 was considered significant. Two hundred sixty-one (11.9%) of 2,188 patients had IAI. Forty-five (17.2%) IAI patients received an acute procedural intervention (38 operations, seven angiographic embolization). The mean age for patients requiring intervention was 7.1 ± 4.1 years and not different from the population. Most patients (88.9%) with IAI-I were normotensive. IAI-I patients were significantly more likely to have a mechanism of motor vehicle collision (66.7% vs. 38.9%), more likely to present as a Level I activation (44.4% vs. 26.9%), more likely to have a Glascow Coma Scale less than 14 (31.1% vs. 15.5%), and more likely to have an abnormal abdominal physical examination (93.3% vs. 65.7%) than patients that did not require acute intervention. All patients underwent computed tomography scan before intervention. Operations consisted of laparotomy (n = 21), laparoscopy converted to open (n = 11), and laparoscopy alone (n = 6). The most common surgical indications were hollow viscus injury (HVI) (11 small bowel, 10 colon, 6 small bowel/colon, 2 duodenum). All interventions for solid organ injury, including seven angioembolic procedures, occurred within 8 hours of arrival; many had hypotension and received a transfusion. Procedural interventions were more common for HVI than for solid organ injury (59.2% vs. 7.6%). Postoperative mortality from IAI was 2.6%. Acute procedural interventions for children with IAI from BAT are rare, predominantly for HVI, are performed early in the hospital course and have excellent clinical outcomes. Prognostic/epidemiologic study, level III; therapeutic study, level IV.


[Characteristics of hematopoiesis regeneration in subcutaneous bone implants in aging mice].
Femurs from both young and old mice were implanted subcutaneously to young syngeneic recipients. 2-2.5 months after surgery femoral marrow grafts were repopulated with nucleated cells and macrophage-granulocyte precursor cells irrespective of the donor's age. Marrow depletion of femurs prior to implantation caused a sharp decrease in hemopoietic repopulation of implants from old, but not young, donors. It is concluded that age-dependent functional peculiarities of stromal microenvironment can be visualized owing to the extraordinary local regenerative demand.


Biliopancreatic diversion in the surgical treatment of morbid obesity.
Biliopancreatic diversion is a malabsorptive technique of bariatric surgery that has gained wide acceptance in the Western world. It is performed in one of two ways: In its classic form it consists of partial gastrectomy with a Roux-en-Y gastroenterostomy; in its duodenal switch form a vertical sleeve gastrectomy is combined with a duodenoenterostomy. Both techniques realize diversion of biliopancreatic juice, thereby creating a mild form of malabsorption. Weight loss has been approximately 70% of initial excess weight, exceeding that obtained with most other bariatric procedures. Iron, calcium, and vitamin deficiencies may occur, especially with classic biliopancreatic diversion, and must be prevented with adequate supplements during vigorous follow-up. Weight loss is followed by a substantial reduction in the co-morbidities that are present in many morbidly obese patients. Biliopancreatic diversion should be included in each obesity clinic program and be proposed for morbidly obese patients who are having difficulty with the prospect of continuous restraint of food intake or problems due to failed gastric restrictive interventions. The postoperative results in such patients have been good and have substantially improved quality of life and self-esteem in this category of morbidly obese patients.


ALK is a therapeutic target for lethal sepsis.
Sepsis, a life-threatening organ dysfunction caused by infection, is a major public health concern with limited therapeutic options. We provide evidence to support a role for anaplastic lymphoma kinase (ALK), a tumor-associated receptor tyrosine kinase, in the regulation of innate immunity during lethal sepsis. The genetic disruption of ALK expression diminishes the stimulator of interferon genes (STING)-mediated host immune response to cyclic dinucleotides in monocytes and macrophages. Mechanistically, ALK directly interacts with epidermal growth factor receptor (EGFR) to trigger serine-threonine protein kinase AKT phosphorylation and activate interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) signaling pathways, enabling STING-dependent rigorous inflammatory responses. Moreover, pharmacological or genetic inhibition of the ALK-STING pathway confers protection against lethal endotoxemia and sepsis in mice. The ALK pathway is up-regulated in patients with sepsis. These findings uncover a key role for ALK in modulating the inflammatory signaling pathway and shed light on the development of ALK-targeting therapeutics for lethal systemic inflammatory disorders.


[Taxonomic significance of the fatty acid composition of bacteria of the genera Bordetella and Haemophilus].
Bacteria of the species B. parapertussis and B. bronchiseptica have proved to be identical in their fatty-acid composition with a high level (35.7-39%) of methylene-hexadecanoic acid, found to be absent in B. pertussis in experimental conditions. At the same time the total content of methylene-hexadecanoic acid and its biosynthetic precursor, hexadecenoic acid, in the first two Bordetella species is similar to the content of hexadecenoic acid in B. pertussis, which, along with the presence of common characteristics in the sign under consideration (the low level of C18:1), indicates the close relationship of these three Bordetella species. Bacteria of the species H. influenzae, H. parainfluenzae, H. aegyptius, H. aphrophilus have similar fatty-acid composition with the prevalence of hexadecanoic and hexadecenoic acids and the low level of fatty acids with 18 carbon atoms. The data on fatty-acid composition may suggest the presence of philogenetic links between the genera Bordetella and Haemophilus.


Immunoblot analysis and comparative IgE responses of atopic patients to extracts of the domestic mite Blomia tropicalis.
The domestic mite Blomia tropicalis is found in subtropical and tropical environments, and its clinical importance as a sensitizing agent in allergic disease is widely accepted. To investigate the IgE reactivity to allergens present in extracts of the domestic mite B. tropicalis, and compare the IgE responses to these allergens by asthmatics, patients with atopic dermatitis and allergic rhinitis, as well as nonatopic controls. Extracts from B. tropicalis were used for skin tests. The B. tropicalis specific IgE in the serum were measured using the FAST Plus Test and immunoblot analysis. A total of 199 volunteers participated in the study. The data show that 18 out of 29 polypeptide bands present in extracts of this mite species were recognized by the allergic and control sera. Of these allergens, four showed a high IgE binding frequency and had relative molecular weights of 104, 80, 68 and 14 kDa. The 14 kDa allergen demonstrated the highest IgE binding frequency. Sera from atopic patients reacted to more allergens than sera from patients controls. Extracts from pure bodies of B. tropicalis contain one immunodominant and three important allergens. A common characteristic between all of the sera tested was the high degree of serum IgE reactivity observed to the 14 kDa allergen.


[Ultrasound-guided fine needle puncture of the abdominal organs: indications, results, risks].
2072 patients underwent ultrasonically guided fine-needle biopsy. 1384 patients could be assessed with regard to the final diagnosis. 854 patients underwent fine-needle biopsy of the liver, 322 of the pancreas and 218 of retroperitoneal lesions. The effective sampling rate was 97% for liver biopsies, 86% for pancreas biopsies and 87% for the biopsy of the retroperitoneum. The sensitivity for the detection of malignancies was 90% in liver biopsies, 69% in pancreatic biopsies and 85% in biopsies of the retroperitoneum. The specificity of cytological findings was 100%. Complications occurred in 13 cases. There were two fatalities due to of bleeding, resulting in a complication rate of 0.6% and a lethality of 0.1% of all biopsied patients. The biopsy of the liver proved most dangerous with a complication rate of 1.4%. The bleeding risk of a haemangioma (2.5%) was nearly the same as the bleeding risk of a malignant liver tumour (1.5%).


A hospital-based prospective study of perinatal infection with human immunodeficiency virus type 1.
Most infants with pediatric acquired immunodeficiency syndrome and infections with human immunodeficiency virus type 1 (HIV-1) are infected perinatally by their mothers. To determine the proportion of exposed infants who are infected, we conducted a hospital-based prospective study in HIV-1-infected women whose infants were delivered at a single metropolitan hospital in Miami, Fla. A population of uninfected women and their infants was also enrolled and followed longitudinally for 2 years to assess laboratory and clinical measurements. The median follow-up is now 18 months for 82 infants born to HIV-1-infected mothers. The proportion of infected infants in this group is 0.30 (25/82). None of the infants born to 110 HIV-1-seronegative mothers were seropositive. Infected infants were easily distinguished from noninfected infants by virus isolation. No single immunologic or hematologic measure was predictive of infection for all infants at risk for HIV-1 infection who were 6 months of age or younger. As a group, however, infected infants could be distinguished from uninfected index infants by a number of immunologic measures by 6 months of age; the absolute number of CD4+ lymphocytes and the CD4+/CD8+ lymphocyte ratio were the variables most predictive of infection. As in retrospective studies, clinical disease developed in 80% of infected infants within the first 24 months of life. This study provides documentation of HIV-1 perinatal transmission risk and early correlates of infection in young infants from a single hospital.


Intratumoral pseudoaneurysms in hepatocellular carcinoma: do they occur de novo without any prior intervention? A tertiary care center experience of 6 years.
Intratumoural pseudoaneurysms (ITPA) within hepatocellular carcinomas (HCC) usually arise as postprocedural complications of endovascular therapies or surgical procedures. Their de novo presence in HCC without any prior interventions has not been adequately described in medical literature. To evaluate and quantify the presence of intratumoural pseudoaneurysms (ITPA) within hepatocellular carcinomas (HCC) prior to any intervention. Retrospective cross-sectional review of 519 patients with HCC at a tertiary care university hospital with the purpose to evaluate and quantify the presence of ITPA present prior to any therapy. Patients' baseline data along with viral marker status, alpha fetoprotein (AFP) levels, imaging findings, and any prior treatment provided were recorded. Multi-detector computed tomography (MDCT) scans of selected patients were reviewed for presence of any ITPA and their incidence was calculated. ITPAs without any prior therapy were found in 5% (25/519) of patients with HCC. Seventeen of 25 (68%) patients had liver cirrhosis while eight of 25 (32%) patients were non-cirrhotic on imaging. Multiple ITPAs were seen in 44% (11/25) of patients. Eight percent (2/25) of patients had pseudoaneurysm-associated hemorrhage, 20% (5/25) had lung metastasis, 12% (3/25) had portal vein thrombosis, 8% (2/25) had hepatic vein thrombosis, and 16% (4/25) had peritumoral hematoma. The incidence of de novo ITPAs occurring in patients with HCC without any prior therapy or intervention was 0.24%. These cases provide a unique insight into an additional feature of HCC and usefulness of recognizing the ITPAs on imaging studies. Although de novo ITPAs in HCC are uncommon, occurring with an incidence rate of 0.24%, their presence in hypervascular hepatic lesion may point towards the diagnosis of HCC. Additionally, they should be accounted for in management planning as they can lead to complications of rupture and hemorrhage.


The human genome contains over a million autonomous exons.
Mammalian mRNA and lncRNA exons are often small compared to introns. The exon definition model predicts that exons splice autonomously, dependent on proximal exon sequence features, explaining their delineation within large introns. This model has not been examined on a genome-wide scale, however, leaving open the question of how often mRNA and lncRNA exons are autonomous. It is also unknown how frequently such exons can arise by chance. Here, we directly assayed large fragments (500-1000 bp) of the human genome by exon trapping, which detects exons spliced into a heterologous transgene, here designed with a large intron context. We define the trapped exons as "autonomous." We obtained ∼1.25 million trapped exons, including most known mRNA and well-annotated lncRNA internal exons, demonstrating that human exons are predominantly autonomous. mRNA exons are trapped with the highest efficiency. Nearly a million of the trapped exons are unannotated, most located in intergenic regions and antisense to mRNA, with depletion from the forward strand of introns. These exons are not conserved, suggesting they are nonfunctional and arose from random mutations. They are nonetheless highly enriched with known splicing promoting sequence features that delineate known exons. Novel autonomous exons are more numerous than annotated lncRNA exons, and computational models also indicate they will occur with similar frequency in any randomly generated sequence. These results show that most human coding exons splice autonomously, and provide an explanation for the existence of many unconserved lncRNAs, as well as a new annotation and inclusion levels of spliceable loci in the human genome.


Trends in diabetes mortality identified from death certificates in Colombia, 1979-2017.
To describe the mortality trends of diabetes mellitus (DM) in Colombia, by sex and age group, from 1979 to 2017. We carried out an ecological study using mortality data from the Colombian National Administrative Department of Statistics. Crude and age-standardized annual mortality rates per 100 000 people were estimated. Trends of standardized rates were described by sex and age groups. Joinpoint regression models were performed to study mortality trends. Throughout the whole period, the total number of DM recorded deaths in Colombia was 200 650, 58% (116 316) in women (p<0.05). The age-standardized mortality rates (ASMR) by sex increased from 13.2 to 26.6 deaths per 100 000 in women and from 10.1 to 22.7 in men from 1979 to 1999. We observed a decrease from 26.6 to 15.4 per 100 000 in women, and from 22.7 to 15.9 in men for the period 1999-2017. The joinpoint regression analysis showed that the average annual percentage change of the period did not vary in both sexes (men: -0.2%, 95% CI -1.0 to 1.4%; women: 0.7%, 95% CI -0.1 to 1.6%). The DM mortality showed a decreasing trend after 2000 in women and 2004 in men. Primary and secondary prevention programs must continue to be strengthened for an earlier diagnosis of diabetes.


Exposure to Community Violence Among Low-Income African American Youth in Chicago: A Latent Class Analysis.
African American youth are exposed to some of the highest rates of exposure to community violence. However, few studies have explored factors related to exposures and various subtypes of exposures to community violence (i.e., no exposure, witnessing only and being a witness/victim). Among a matched sample of 129 African American youth and their caregivers, no exposure to community violence was correlated with being heterosexual versus being a lesbian, gay, bisexual, and transgender (LGBT) person, having parents who owned their homes versus rented, and having higher authoritarian parenting attitudes. In addition, being a witness/victim of community violence was correlated with any youth substance use, lower levels of school bonding, having less future orientation, less parental home ownership, and an adverse family history. Practice and programmatic considerations are discussed based on these findings.


Nephrotic syndrome resulting in thromboembolic disease and disseminated intravascular coagulation in a dog.
Thromboembolic disease and progression to disseminated intravascular coagulation (DIC) are potential life-threatening complications for dogs with nephrotic syndrome. Platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), plasma concentration of fibrinogen degradation products (FDPs), antithrombin III (ATIII), protein C, and plasminogen were used to identify hemostatic abnormalities in a dog with nephrotic syndrome. Pulmonary thromboembolic disease was diagnosed by thoracic radiography, arterial blood gas analysis, and pulmonary scintigraphy. Prompt recognition and treatment of hemostatic complications is necessary in dogs with nephrotic syndrome.


A Medicago truncatula H+-pyrophosphatase gene, MtVP1, improves sucrose accumulation and anthocyanin biosynthesis in potato (Solanum tuberosum L.).
We recently cloned MtVP1, a type I vacuolar-type H(+)-translocating inorganic pyrophosphatase from Medicago truncatula. In the present study, we investigated the cellular location and the function of this H(+)-PPase in Arabidopsis and potato (Solanum tuberosum L.). An MtVP1::enhanced green fluorescent protein fusion was constructed, which localized to the plasma membrane of onion epidermal cells. Transgenic Arabidopsis thaliana overexpressing MtVP1 had more robust root systems and redder shoots than wild-type (WT) plants under conditions of cold stress. Furthermore, overexpression of MtVP1 in potato accelerated the formation and growth of vegetative organs. The tuber buds and stem base of transgenic potatoes became redder than those of WT plants, but flowering was delayed by approximately half a month. Interestingly, anthocyanin biosynthesis was promoted in transgenic Arabidopsis seedlings and potato tuber buds. The sucrose concentration of transgenic potato tubers and tuber buds was enhanced compared with that of WT plants. Furthermore, sucrose concentration in tubers was higher than that in tuber buds. Although there was no direct evidence to support Fuglsang's hypothetical model regarding the effects of H(+)-PPase on sucrose phloem loading, we speculated that sucrose concentration was increased in tuber buds owing to the increased concentration in tubers. Therefore, overexpressed MtVP1 enhanced sucrose accumulation of source organs, which might enhance sucrose transport to sink organs, thus affecting anthocyanin biosynthesis.


Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia.
Schizophrenia is a neurodevelopmental disorder featuring chronic, complex neuropsychiatric features. The etiology and pathogenesis of schizophrenia are not fully understood. Oxidative-antioxidant imbalance is a potential determinant of schizophrenia. Oxidative, nitrosative, or sulfuric damage to enzymes of glycolysis and tricarboxylic acid cycle, as well as calcium transport and ATP biosynthesis might cause impaired bioenergetics function in the brain. This could explain the initial symptoms, such as the first psychotic episode and mild cognitive impairment. Another concept of the etiopathogenesis of schizophrenia is associated with impaired glucose metabolism and insulin resistance with the activation of the mTOR mitochondrial pathway, which may contribute to impaired neuronal development. Consequently, cognitive processes requiring ATP are compromised and dysfunctions in synaptic transmission lead to neuronal death, preceding changes in key brain areas. This review summarizes the role and mutual interactions of oxidative damage and impaired glucose metabolism as key factors affecting metabolic complications in schizophrenia. These observations may be a premise for novel potential therapeutic targets that will delay not only the onset of first symptoms but also the progression of schizophrenia and its complications.


Low-density lipoprotein cholesterol and high-sensitivity C-reactive protein lowering with atorvastatin in patients of South Asian compared with European origin: insights from the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study.
The aim of this study was to determine the effects of atorvastatin in patients of South Asian versus European origin who participated in the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study. ACTFAST was a 12-week prospective, open-label study in patients at high risk for atherosclerosis (European origin, n = 1978; South Asian origin, n = 64). Compared with patients of European origin, patients of South Asian origin were younger, were less likely to smoke, and had lower body mass index, systolic blood pressure, low-density lipoprotein cholesterol (LDL-C) and triglycerides. Because significant differences were observed in baseline characteristics between patient groups, case control propensity scores were used. In the unmatched analysis, South Asians had greater LDL-C response to atorvastatin than patients of European origin. However, after propensity matching, atorvastatin lowered LDL-C and high-sensitivity C-reactive protein (hs-CRP) to a similar degree in both groups, with no differences in safety profile. The authors observed no correlation between change in hs-CRP and LDL-C concentrations in either population. In conclusion, atorvastatin lowered both LDL-C and hs-CRP to a similar degree in patients of South Asian or European origin, suggesting usual starting doses of atorvastatin (with appropriate monitoring), rather than lower starting doses as has been advocated by some, may be used in patients of South Asian origin.


[Operative treatment of secondary hyperparathyroidism in patients with terminal chronic renal insufficiency in programmed hemodialysis].
The phosphorous-calcic metabolism disorders and secondary hyperparathyroidism (HPTH) occurs nearly in all patients, to whom programmed hemodialysis (PHD) is applied. In majority of observations these disorders become compensated while administration of cholecalciferol (vitamin D3), calcitriol and etc. In 23 patients surgical treatment was performed to correct these disorders. Performance of subtotal parathyroidectomy (STPTHE) had promoted biochemical indexes normalization and the secondary HPTH clinical manifestations regression. The medicamental therapy nonefficacy, progressing osteoporosis, cutaneous itch, which is not connected the PHD procedure, raising of content of the ionized calcium and the alkaline phosphatase activity as well in the blood serum constitute indications for the STPTHE conduction.


Multi-informant path models of the influence of psychosocial and treatment-related variables on adherence and metabolic control in adolescents with type 1 diabetes mellitus.
We assessed the associations between metabolic control and adherence and a broad range of adolescent and family characteristics (e.g., gender, family structure), treatment-related variables (e.g., disease duration, treatment modality), and psychosocial factors (e.g., symptoms of depression and anxiety, parental support, self-efficacy) in a nationwide study of Danish adolescents (age 12-17 years) with type 1 diabetes mellitus (T1DM). Sixty-four percent of invited families participated by completing a survey and providing a blood sample. Two path models of associations between generic and diabetes-related family factors, adolescent self-efficacy, emotional difficulties, and metabolic control and adherence were tested, one for adolescents and one for caregivers. Demographic variables were included as covariates. Both path models demonstrated a satisfying model fit. In both models, metabolic control was associated with adherence, age, and T1DM duration. In the adolescent model, metabolic control was also related to treatment modality, single-parent household, caregiver non-support, and anxiety, whereas in the caregiver model metabolic control was associated with family conflict and caregiver support. In both models, adherence was related to age, duration, treatment modality, family conflict, caregiver support, family functioning, and emotional difficulties of the adolescent. In the adolescent model, adherence was also related to adolescent self-efficacy, whereas in the caregiver model adherence was associated with adolescent gender and caregiver non-support and support. Adolescent self-efficacy, emotional well-being, and difficulties related to adolescent/caregiver interaction appeared to be particularly important, as indicated by their stronger association with adherence and/or metabolic control. The results highlight the value of applying a multi-informant approach to address the psychosocial well-being of adolescents with diabetes in a large national sample. Self-efficacy, emotional, and family-related difficulties are important aspects to address in both clinical care and future research regarding adolescents with T1DM.


Repin1 deficiency in adipose tissue improves whole-body insulin sensitivity, and lipid metabolism.
Replication initiator 1 (Repin1) gene encodes for a zinc-finger protein and has been implicated in the regulation of adipocyte cell size and glucose transport in vitro. Here, we investigate the consequences of reduced adipose tissue (AT) Repin1 expression in vivo. We have inactivated the Repin1 gene in adipose tissue (iARep-/-) at an age of 4 weeks using tamoxifen-inducible gene targeting strategies on the background of C57BL/6NTac mice. Furthermore, we differentiated human primary adipocytes derived from subcutaneous AT in vitro and knocked down REPIN1 using siRNA technique to measure glycerol release. Conditional Repin1 inactivation results in decreased AT mass, smaller adipocytes in both, subcutaneous and epigonadal AT compared to controls. Compared to controls, iARep-/- mice were more insulin sensitive, had better glucose tolerance and lower LDL-, HDL- and total cholesterol. Significantly lower AT expression of the Repin1 target genes Cd36 and Lcn2 may contribute to the phenotype of iARep-/- mice. Knockdown of REPIN1 in human in vitro differentiated adipocytes revealed an increased glycerol release. In conclusion, deficiency of Repin1 in AT causes alterations in AT morphology and function, which may underlay lower body weight and improved parameters of insulin sensitivity, glucose and lipid metabolism.


Luteolin potentiates the sensitivity of colorectal cancer cell lines to oxaliplatin through the PPARγ/OCTN2 pathway.
Oxaliplatin is a chemotherapeutic agent used in the treatment of colorectal cancers. However, the mechanism controlling the cellular uptake and efflux of oxaliplatin is not completely understood. Organic cation/carnitine transporter 2 (OCTN2) is a member of the solute carrier superfamily and is a determinant of oxaliplatin uptake. OCTN2 is regulated by peroxisome proliferator-activated receptor γ (PPARγ) binding to the PPAR-response element within the first intron. Luteolin is a naturally occurring flavonoid and an agonist of PPARγ. Thus, we hypothesize that luteolin-mediated OCTN2 expression and activity potentiate the sensitivity of cancer cells to oxaliplatin. In this study, luteolin increased mRNA and protein expression of OCTN2 in a time-dependent and dose-dependent manner in colorectal cancer SW480 cells. This induction was attenuated by PPARγ antagonist GW9662 as well as by PPARγ knockdown, suggesting that the induction by luteolin is dependent on PPARγ. In uptake studies, luteolin increased the binding affinity of OCTN2 toward oxaliplatin and enhanced intracellular concentration of oxaliplatin. This finding is likely because of the increase of PDZ domain containing 1 (PDZK1) and PDZ domain containing 3 (PDZK2), which are known to facilitate the expression of OCTN2 on the cell surface and/or enhance transporter activity. Moreover, cell viability and cell apoptosis assays showed that luteolin increased oxaliplatin uptake and intracellular accumulation through OCTN2. Thus, our study showed that luteolin increased the sensitivity of colorectal cancer SW480 cells to oxaliplatin, likely through the PPARγ/OCTN2 pathway.


Clinical Practice Guideline for Enteroscopy.
Management of small bowel diseases has evolved since the advent of capsule endoscopy (CE) and balloon-assisted enteroscopy (BAE). One of the most common indications for enteroscopy is obscure gastrointestinal bleeding (OGIB), followed by small bowel stenosis, tumors, and inflammatory bowel disease. Although enteroscopes have been regarded as useful tools, correct guidelines are required to ensure that we manipulate these enteroscopes safely and efficiently in clinical practice. Herein, the Japanese Gastroenterological Endoscopy Society has developed 'Clinical Practice Guidelines for Enteroscopy' in collaboration with the Japanese Society of Gastroenterology, the Japanese Gastroenterological Association, and the Japanese Association for Capsule Endoscopy. These guidelines are based on the evidence available until now, but small bowel endoscopy is a relatively new technology, so the guidelines include recommendations based on a consensus reached among experts when the evidence has not been considered sufficient. These guidelines were not designed to be disease-based, but focus on how we should use small bowel CE and BAE in everyday clinical practice.


In vivo analysis of key elements within the renin regulatory region.
Renin is responsible for initiating the enzymatic cascade that results in the production of angiotensin II, the major effector molecule of the renin-angiotensin system (RAS). Extensive information on the regulatory region of the renin gene has been derived by transient transfection studies in vitro, particularly using the As4.1 cell line. To verify key factors within the regulatory region of renin in vivo, homologous recombination was used to introduce a green fluorescent protein (GFP) cassette into exon one of the renin gene contained within a 240 kb bacterial artificial chromosome (BAC) to create a construct that has GFP expression controlled by the renin regulatory region (RenGFP BAC). Within the regulatory region of the RenGFP BAC construct we independently deleted the enhancer, as well as mutated the HOX-PBX site within the proximal promoter element. Transgenic lines were generated for each of these BAC constructs and GFP expression was analyzed throughout a spectrum of tissues positive for renin expression including the kidney, adrenal gland, gonadal artery, and submandibular gland. The results described within this manuscript support the interpretation that the renin enhancer is critical for regulating baseline expression where as the Hox/Pbx site is important for the tissue specificity of renin expression.


Sialyllactose suppresses angiogenesis by inhibiting VEGFR-2 activation, and tumor progression.
The oligosaccharides in human milk have various biological functions. However, the molecular mechanism(s) underlying the anti-angiogenic action of sialylated human milk oligosaccharides (HMOs) are still unclear. Here, we show that siallylactose (SL) found in human milk can inhibit the activation of vascular endothelial growth factor (VEGF)-mediated VEGF receptor-2 (VEGFR-2) by binding to its VEGF binding site (second and third IgG-like domains), thus blocking downstream signal activation. SL also inhibits growth of VEGF-stimulated endothelial cells. In endothelial cells treated with VEGF, SL diminished tube formation, migration, and the arrangement of actin filament. In addition, SL clearly suppressed VEGF-induced neovascularization in an in vivo Matrigel plug assay. Notably, SL prevented the growth of tumor cells, and angiogenesis on tumor tissues in in vivo mice models allotransplanted with Lewis lung carcinoma, melanoma, and colon carcinoma cells. Taken together, we have demonstrated that the sialylated milk oligosaccharide sialyllactose functions as an inhibitor of angiogenesis through suppression of VEGF-mediated VEGFR-2 activation in endothelial cells, Accordingly, it could be a novel candidate for the development of anti-angiogenic drugs without any side effects.


Evolution of passerine incubation behavior: influence of food, temperature, and nest predation.
Incubation behavior is one component of reproductive effort and thus influences the evolution of life-history strategies. We examined the relative importance of body mass, frequency of mate feeding, food, nest predation, and ambient temperature to explain interspecific variation in incubation behavior (nest attentiveness, on- and off-bout durations, and nest trips per hour) using comparative analyses for North American passerines in which only females incubate. Body mass and frequency of mate feeding explained little variation in incubation behavior. We were also unable to detect any influence of foot; diet and foraging strategy explained little interspecific variation in incubation behavior. However, the typical temperature encountered during reproduction explained significant variation in incubation behavior: Species breeding in colder environments take shorter bouts off the nest, which prevents eggs from cooling to temperatures below the physiological zero temperature. These species must compensate for shorter off-bouts by taking more of them (thus shorter on-bouts) to obtain needed energy for incubation. Nest predation also explains significant variation in incubation behavior among passerines: Species that endure high nest predation have evolved an incubation strategy (long on- and off-bouts) that minimizes activity that could attract predators. Nest substrate explained additional variation in incubation behavior (cavity-nesting birds have shorter on-bouts and make more frequent nest trips), presumably because nest predation and/or temperature varies among nest substrates. Thus, nest predation can influence reproductive effort in a way previously not demonstrated--by placing a constraint on parental activity at the nest. Incubating birds face an ecological cost associated with reproductive effort (predation of entire brood) that should be considered in future attempts to explain avian life-history evolution.


Similar non-random processes maintain diversity in two tropical rainforests.
Quadrat-based analysis of two rainforest plots of area 50 ha, one in Panama (Barro Colorado Island, BCI) and the other in Malaysia (Pasoh), shows that in both plots recruitment is in general negatively correlated with both numbers and biomass of adult trees of the same species in the same quadrat. At BCI, this effect is not significantly influenced by treefall gaps. In both plots, recruitment of individual species is negatively correlated with the numbers of trees of all species in the quadrats, but not with overall biomass. These observations suggest, but do not prove, widespread frequency-dependent effects produced by pathogens and seed-predators that act most effectively in quadrats crowded with trees. Within-species correlations of mortality with numbers or biomass are not found in either plot, indicating that most frequency-dependent mortality takes place before the trees reach 1 cm in diameter. Stochastic effects caused by BCI's more rapid tree turnover may contribute to a larger variance in diversity from quadrat to quadrat at BCI, although they are not sufficient to explain why BCI has fewer than half as many tree species as Pasoh. Finally, in both plots quadrats with low diversity show a significant increase in diversity over time, and this increase is stronger at BCI. This process, like the frequency-dependence, will tend to maintain diversity over time. In general, these non-random forces that should lead to the maintenance of diversity are slightly stronger at BCI, even though the BCI plot is less diverse than the Pasoh plot.