Trypanosoma cruzi heat-shock protein-70 kDa,alone or fused to the parasite KMP11 antigen, induces functional maturation of murine dendritic cells.
We analyse the effect of Trypanosoma cruzi heat-shock protein-70 (HSP70) on the maturation of murine dendritic cells (DC)generated from bone marrow precursor cells. The results obtained show that HSP70, both alone and fused to the KMP11 antigen, as well as a HSP70 fragment, is capable of maturing murine DC. Mature DC have enhanced expression of IL12, TNF-alpha cytokines, costimulation molecules and activation markers, showing a clear increase in the allostimulatory capacity. These findings suggest that T. cruzi HSP70 may be a very useful vehicle for developing DC-based immunoprophylaxis and therapy against infections.


More information equates with less anxiety. Reducing anxiety in cervical screening.
1. Anxiety may be a factor influencing attendance for cervical screening. 2. Anxiety may be caused by stress and embarrassment of the test procedure and/or misunderstanding its purpose. 3. Women who were given the routine procedure were compared with a study group who were given an extra 10 minutes discussion by nurses. 4. The study group rated the explanation as being clearer, and after receiving the result they reported significantly less anxiety than those in the routine group.


Podocyte-associated mRNA profiles in kidney tissue and in urine of patients with active lupus nephritis.
Glomerular deposition of immune complexes and inflammation induce podocyte injury in lupus nephritis (LN). This study hypothesized that the severity of the histological lesions of LN affects podocyte-associated mRNAs profiles in kidney tissue and in urine. Thirty-three patients with LN were grouped according to the presence of mild mesangial (classes I and II) or moderate-to-severe immune complex deposition, proliferation and/or inflammation (classes III, IV and V) in kidney biopsy. Tissue and urine mRNA of nephrin, podocin, podocalyxin, α-actinin-4, transient receptor potential cation channel 6, and of growth factors VEGF-A and TGF-β1 and the transcription factor FOXP3 were measured using real time polymerase chain reaction. These mRNAs were correlated with histological severity of LN, extent of glomerular immune deposits, and tissue infiltrating cells. Podocyte-associated mRNAs were inhibited in renal tissue of patients with LN irrespective of histological class when compared to controls. However, significantly higher expression of podocyte mRNAs in urine, including those of growth factors and FOXP3, were found in patients with moderate-to-severe nephritis, mostly in class III and IV proliferative forms. The number of invading CD8+ T cells, B cells and macrophages correlated positively with urine podocyte-associated mRNAs. Urine podocyte mRNAs also correlated with proteinuria. Inhibition of podocyte-associated mRNAs in kidney tissue suggests that podocyte injury occurs regardless of class severity of LN. Increased urinary excretion of podocyte mRNAs, mostly in patients with moderate-to-severe lesions, may reflect a greater burden of glomerular damage with detachment of podocytes into the urine.


Pemphigus vulgaris presented with cheilitis.
Background. Pemphigus vulgaris is an autoimmune blistering disease affecting the mucous membrane and skin. In 50 to 70% of cases, the initial manifestations of pemphigus vulgaris are oral lesions which may be followed by skin lesions. But it is unusual for the disease to present with initial and solitary persistent lower lip lesions without progression to any other location. Main Observations. We report a 41-year-old woman with dry crusted lesions only on the lower lip, clinically resembling actinic cheilitis and erosive lichen planus, but histopathological evaluation showed unexpected results of suprabasal acantholysis and cleft compatible with pemphigus vulgaris. We treated her with intralesional triamcinolone 10 mg/mL for 2 sessions and 2 g cellcept daily. Patient showed excellent response and lesions resolved completely within 2 months. In one-year follow-up, there was no evidence of relapse or any additional lesion on the other sites. Conclusion. Cheilitis may be the initial and sole manifestation of pemphigus vulgaris. Localized and solitary lesions of pemphigus vulgaris can be treated and controlled without systemic corticosteroids.


Transdifferentiation mediated tumor suppression by the endoplasmic reticulum stress sensor IRE-1 in C. elegans.
Deciphering effective ways to suppress tumor progression and to overcome acquired apoptosis resistance of tumor cells are major challenges in the tumor therapy field. We propose a new concept by which tumor progression can be suppressed by manipulating tumor cell identity. In this study, we examined the effect of ER stress on apoptosis resistant tumorous cells in a Caenorhabditis elegans germline tumor model. We discovered that ER stress suppressed the progression of the lethal germline tumor by activating the ER stress sensor IRE-1. This suppression was associated with the induction of germ cell transdifferentiation into ectopic somatic cells. Strikingly, transdifferentiation of the tumorous germ cells restored their ability to execute apoptosis and enabled their subsequent removal from the gonad. Our results indicate that tumor cell transdifferentiation has the potential to combat cancer and overcome the escape of tumor cells from the cell death machinery.


Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity.
Cellular senescence acts as a potent barrier to tumorigenesis and contributes to the anti-tumor activity of certain chemotherapeutic agents. Senescent cells undergo a stable cell cycle arrest controlled by RB and p53 and, in addition, display a senescence-associated secretory phenotype (SASP) involving the production of factors that reinforce the senescence arrest, alter the microenvironment, and trigger immune surveillance of the senescent cells. Through a proteomics analysis of senescent chromatin, we identified the nuclear factor-κB (NF-κB) subunit p65 as a major transcription factor that accumulates on chromatin of senescent cells. We found that NF-κB acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined. In cultured fibroblasts, NF-κB suppression causes escape from immune recognition by natural killer (NK) cells and cooperates with p53 inactivation to bypass senescence. In a mouse lymphoma model, NF-κB inhibition bypasses treatment-induced senescence, producing drug resistance, early relapse, and reduced survival. Our results demonstrate that NF-κB controls both cell-autonomous and non-cell-autonomous aspects of the senescence program and identify a tumor-suppressive function of NF-κB that contributes to the outcome of cancer therapy.


[Long-term follow-up results of eleven cases after resection of hepatic metastases from colorectal cancer].
Eleven patients with hepatic metastases from colorectal cancer survived more than 5 years after the resection were reviewed. There were 3 (27.3%) disease-free survivors, the longest survival period was 7 years and 2 months. Compared with 41 survivors of less than 5-year duration after resection, it was shown that close follow-up after resection of the primary cancer, detecting early subclinical hepatic metastases, preoperative lower level of CEA, tumor less or equal to 5 cm in size, single metastatic nodule and radical resection were important factors influening long-term survival (P < 0.05). It is of the opinion that early diagnosis, early resection and re-resection after detecting subclinical local recurrence and metastases play important role in improving long-term response.


Differences in sleep quality and health-related quality of life in young adults with allergies and asthma and their healthy peers.
The current study examined the relationship between sleep quality and health-related quality of life (HRQOL). Participants were 501 undergraduate students with allergies (167), asthma + allergies (167), or with no history of a chronic illness (167) completed study measures from August 2011 to April 2012. The undergraduate students completed questionnaires online as part of a larger study of psychosocial adjustment of young adults. Young adults with allergies and asthma + allergies reported significantly worse sleep quality and HRQOL than healthy peers. Additionally, those with allergies and asthma + allergies had significantly more sleep disturbances and used sleeping medication significantly more often in the previous month than healthy peers. These results highlight concerns regarding quality of life and sleep problems in an often-overlooked population. Importantly, sleep difficulties can result in difficulties in daily living and impairment in academic functioning.


This article describes the construction of a documentary archive for the Eunice Weaver School, part of the Educandário/Preventório Afrânio de Azevedo Training Complex (inaugurated in Goiânia in 1943). We stress the importance of creating similar archives to provide access to the memories of those subjected to policies related to preventing Hansen's disease (leprosy). The documentation covers the period 1945-1990, depicting the everyday lives of blameless children who were institutionalized as part of state policies to prevent this disease. The material is regionally focused, expanding the number of known sources for the history of institutions and this disease in the state of Goiás, and served as a potential resource for patients attempting to gain release.


Biomechanical evaluation of three different configurations of external fixators for treating distal third tibia fracture: Finite element analysis in axial, bending and torsion load.
External fixators have been widely used in treating open fractures and have produced excellent outcomes, as they could successfully heal bones. The stability of external fixators lies greatly in their construction. Factors that associated with the stability of the external fixators includes stress, displacement, and relative micromotion. Three-dimensional (3D) models of bone and external fixators were constructed by using 3D modelling software, namely Materialise and SolidWorks, respectively. Three different configurations of external fixators namely Model 1, Model 2, and Model 3 were analysed. Three load cases were simulated to assess the abovementioned factors at the bone, specifically at the fracture site and at the external fixator. Findings showed that the double-cross configuration (Model 3) was the most promising in axial, bending, and torsion load cases as compared to the other two configurations. The no-cross configuration (Model 1) had the highest risk of complication due to high stress, relative micromotion, and displacement in the bending and torsion load cases. On the other hand, the single-cross configuration (Model 2) had the highest risk of complication when applied with axial load. In conclusion, the double-cross locking construct (Model 3) showed the biggest potential to be a new option for medical surgeons in treating patients associated with bone fracture. This new double-cross locking construct showed superior biomechanical stability as compared to single-cross and no-cross configurations in the axial, bending, and torsion load cases.


Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT(1) antagonist, pranlukast, in Japanese patients with moderate asthma.
CysLT(1) antagonists are effective for a subset of patients with asthma; however, there has been no good way to predict a given patient's response. We examined the interaction between the clinical response to a cysLT(1) antagonist, pranlukast, and DNA sequence variant A(-444)C in leukotriene C(4) synthase (LTC(4) S) gene in Japanese patients with moderate asthma. The frequency of LTC(4) S C(-444) allele was 21.6% in the Japanese general population (n = 171) and 19.4% in the asthmatic subjects ( n= 349). A 4-week prospective, open trial of pranlukast (225 mg twice daily) was performed in 50 patients with moderate asthma who had been well controlled with inhaled corticosteroid (beclomethasone 400-800 microg/day or fluticasone 200-400 microg/day). The C(-444) allele carriers (n = 16) responded better to pranlukast compared to the A(-444) allele homozygotes ( n= 31) [14.3 5.3% vs. 3.1 2.4% improvement of forced expiratory volume in one second (FEV(1) ), 0.01], while LTC(4) S genotype-stratified response to inhaled beta-agonist salbutamol (200 microg) was not observed (17.5 2.1% vs. 18.7 2.2% improvement of FEV(1) ). Univariate analysis demonstrated that the better response to pranlukast (more than 10% improvement of FEV(1) ) was correlated with LTC(4) S genotype (P < 0.01) and pretreatment airway reversibility to salbutamol (P < 0.01), but not with sex, age, atopic status, urinary leukotriene E(4) excretion rate, or daily dose of inhaled corticosteroid. Furthermore, multivariate regression analysis suggested that LTC(4) S genotype and the bronchodilatory effect of salbutamol were independent variables to predict the clinical response to pranlukast (P < 0.05). We conclude that LTC(4) S genotype is predictive of the clinical response to a cysLT(1) antagonist, pranlukast, in Japanese patients with moderate asthma.


The influence of spinal cord injury on coping styles and self-perceptions: a controlled study.
Well-controlled research investigating psychological responses following Spinal Cord Injury (SCI) is lacking. In addition, much of the literature is based on depression following SCI and is dominated by data from the USA. The effects of SCI on perceptions of control, self-esteem and coping styles over the first year of SCI were investigated. Forty-one acute spinal injured patients and 41 able-bodied controls matched for age, sex and education completed a variety of standardised questionnaires on three occasions over one year. The instruments included the Locus of Control of Behaviour Scale, Rosenberg's Self-Esteem Scale, and an adapted Mental Adjustment to Cancer (MAC) Scale which measures coping styles, including fighting spirit, helplessness/hopelessness and fatalism. The SCI group were found to be more external in their perceptions of control, lower in self-esteem, and more helpless/hopeless and fatalistic in attitude than the controls. The majority of the SCI group had scores reflecting adaptive coping styles and intact levels of self-esteem but there were still a substantial proportion who displayed maladaptive coping styles (e.g. external locus of control, fatalism, helplessness). No differences in scores across time were found for either group. Implications for psychological rehabilitation are discussed.


Development and validation of the Fatalistic Causal Attributions of Cancer Questionnaire: A three-phase study.
Tools have been developed to assess the existence and intensity of fatalistic beliefs. Causal attributions of cancer, referring to the foundation for fatalistic views of cancer as being predetermined or reflecting an unavoidable death, are lacking. The aim was to develop and validate the Fatalistic Causal Attributions of Cancer Questionnaire, a measurement tool for studying the causal attributions of cancer. Three-phase study. Phase I: Item extraction and development based on focus groups (N = 30) and assessment of content validity. Phase II: Assessment of quality of items and construct validity (exploratory factor analysis, confirmatory factor analysis, and convergent validity) of data from 252 participants (aged 50-75). Phase III: Confirmatory factor analysis and assessment of the discriminant validity and reliability of the questionnaire with 127 online respondents (aged 20-70). In Phase I, an initial questionnaire was constructed. In Phase II, four factors were identified: Belief in divine providence, belief in personal resilience as a protective factor, belief in chance or luck, and belief in inevitable environmental or genetic factors. The factorial structure of an 18-item version that emerged in the confirmatory factor analysis had good fit indexes and reliability measures. In Phase III, the 18-item questionnaire and its factorial structure and reliability were confirmed. The findings show acceptable psychometric properties for the questionnaire. We suggest that this questionnaire should be used with an existing questionnaire that assesses the intensity of fatalistic perceptions for a more comprehensive assessment of fatalism in research and in promoting adherence to screening.


Sustaining pattern of phenformin hydrochloride using various polymers and waxes.
The present study was carried out to formulate matrix tablets of phenformin hydrochloride. Granules of phenformin HCl were prepared by using ethyl cellulose, eudragit RS 100, gum acacia, carnauba wax, stearyl alcohol, glyceryl monostearate and triethanol amine. Thus the granules were compressed and fourteen tablets formulations were prepared. All the physical parameters of granules and matrix tablets were studied including compatibility study. One commercial timed disintegration capsule was also included for study and comparison. The results of in vitro studies showed that sustained release matrix tablet might be prepared using carnauba wax, stearyl alcohol, triethanol amine and magnesium stearate.


Distinctive structure, composition and biomechanics of collagen fibrils in vaginal wall connective tissues associated with pelvic organ prolapse.
Collagen is the predominant structural protein within connective tissues. Pelvic organ prolapse (POP) is characterized by weakening of the pelvic floor connective tissues and loss of support for pelvic organs. In this study, we examined the multiscale structure, molecular composition and biomechanics of native collagen fibrils in connective tissues of the posterior vaginal fornix collected from healthy women and POP patients, and established the correlation of these properties with clinical POP quantification (POP-Q) scores. The collagen characteristics, including collagen amount, ratio of Collagen I and Collagen III, collagen fibril d-period, alignment and stiffness, were found to change progressively with the increase of the clinical measurement of Point C, a measure of uterine descent and apical prolapse. The results imply that a severe prolapse is associated with stiffer collagen fibrils, reduced collagen d-period, increased fibril alignment and imbalanced collagen synthesis, degradation and deposition. Additionally, prolapse progression appears to be synchronized with deterioration of the collagen matrix, suggesting that a POP-Q score obtained via a non-invasive clinical test can be potentially used to quantitatively assess collagen abnormality of a patient's local tissue. STATEMENT OF SIGNIFICANCE: Abnormal collagen metabolism and deposition are known to associate with connective tissue disorders, such as pelvic organ prolapse. Quantitative correlation of the biochemical and biophysical characteristics of collagen in a prolapse patient's tissue with the clinical diagnostic measurements is unexplored and unestablished. This study fills the knowledge gap between clinical prolapse quantification and the individual's cellular and molecular disorders leading to connective tissue failure, thus, provides the basis for clinicians to employ personalized treatment that can best manage the patient's condition and to alert pre-symptomatic patients for early management to avoid unwanted surgery.


Determination of calcium phosphate inhibitor activity. Critical assessment of the methodology.
A method is described which determines the amount of calcium phosphate inhibitor activity in solutions with ionic compositions similar to that of undiluted plasma or serum. Constant supersaturations were obtained for the inhibitor analysis by equilibrating an aliquot of sample with dicalcium phosphate dihydrate (DCPD) and it was shown that the ion activity product of the equilibrated solutions was similar to the solubility product of DCPD. The amount of inhibitor activity in solution is assessed by determining the amount of hydroxylapatite seed needed for a predetermined rate of crystal growth. It was shown that the Langmuir adsorption isotherm is an appropriate model for describing the inhibitor data and provides a convenient linear-regression means for computing inhibitor activities. When tested at its normal physiological concentrations in plasma, albumin was the most important of the known calcium phosphate inhibitors.


A Traditional Chinese Medicine for the Treatment of Endometrial Hyperplasia via Regulating the HPO Axis in Rats.
Dysfunctional uterine bleeding, accompanied by endometrial hyperplasia (EH), is a common gynecological disease that seriously affects female physical and mental health. Some drugs have been prompted to cure the disease, but most medications have certain side effects and limitations. In the present study, we demonstrated an unexploited Chinese traditional medicine, a combination of Saururus chinensis, Celosia cristata, and Spatholobus suberectus (SCS), which could be used for the treatment of EH and associated complications in rats. We identified the active components from the three Chinese herbs via thin-layer chromatography and high-performance liquid chromatography methods. In addition, serum biochemical indexes and histologic section results found that acute high-dose SCS exerted no adverse impacts on the rats. We then showed that SCS shortened coagulation time (p=0.018) and degree of swelling (p=0.021) on rats at 30 min compared to blank control. Further studies proved that recovered endometrial thickness was associated with the modulation of four hormones (follicle-stimulating hormone, luteinizing hormone, estrogen, and progesterone). Specifically, follicle-stimulating hormone and progesterone contents increased gradually with time, and estrogen was decreased, whereas luteinizing hormone content was returned to normal after a short-term elevation (p < 0.05). Besides, SCS increased uterine endometrium's mRNA expression levels of matrix metalloproteinase-1 (p < 0.001) and tissue inhibitor of matrix metalloproteinase-1 (p < 0.001), promoting the repair of proliferating endometrium in the rats. Collectively, our study indicates that SCS harbors a profoundly curative effect on the treatment of EH and relative complications and uncovers the mechanism at molecular and gene expression levels.


Remote effects of dry needling on the irritability of the myofascial trigger point in the upper trapezius muscle.
To investigate the remote effect of dry needling on the irritability of a myofascial trigger point in the upper trapezius muscle. Thirty-five patients with active myofascial trigger points in upper trapezius muscles were randomly divided into two groups: 18 patients in the control group received sham needling, and 17 patients in the dry-needling group received dry needling into the myofascial trigger point in the extensor carpi radialis longus muscle. The subjective pain intensity, pressure pain threshold, and range of motion of the neck were assessed before and immediately after the treatment. Immediately after dry needling in the experimental group, the mean pain intensity was significantly reduced, but the mean pressure threshold and the mean range of motion of cervical spine were significantly increased. There were significantly larger changes in all three parameters of measurement in the dry-needling group than that in the control group. This study demonstrated the remote effectiveness of dry needling. Dry needling of a distal myofascial trigger point can provide a remote effect to reduce the irritability of a proximal myofascial trigger point.


How to measure what matters: development and application of guiding principles to select measurement instruments in an epidemiologic study on functioning.
The purpose of this article was to describe and to apply a comprehensive set of guiding principles in the selection of measurement instruments for a longitudinal epidemiologic study focusing on functioning using the International Classification of Functioning, Disability, and Health (ICF) as reference framework. Based on the literature, the ICF linkage rules, and the definition of ICF categories to be measured, the following guiding principles for selecting measurement instruments are defined: redundancy, efficiency, level of detail of information, comparability, feasibility, and truth and discrimination. Examples illustrate that the application of guiding principles allows for a systematic and reasoned process of measurement instrument selection and thus offers a potential solution for the multifaceted challenges that one encounters in the selection of measurement instruments. It is transparently demonstrated how the ICF linkage rules enable researchers to address issues such as efficiency, comparability, and redundancy and how the definition of a set of ICF categories to be measured allows assessing inefficiencies in measurement instruments. Because of the ICF linkage rules and the definition of ICF categories to be measured, new guiding principles for selecting measurement instruments emerge. The main challenges lie in the difficulty to quantify and prioritize the applicability of guiding principles and the fact that they strongly interact. Notably, the prioritization and application of guiding principles must be defined considering the specific characteristics and aims of the specific study.


Antioxidant supplementation improves platelet membrane fluidity in idiopathic retinal periphlebitis (Eales' disease).
Oxidative damage to cellular membranes plays an important role in the pathobiology of tissue injury. Retinal photoreceptors and platelets are an easy target of oxidants because of high proportion of polyunsaturated fatty acids. A tertiary-care center-based prospective study was undertaken to study the effect of antioxidant supplementation over membrane fluidity in platelets in idiopathic retinal periphlebitis (Eales' disease) for the first time. Assay of thiobarbituric acid reactive substances (TBARS) levels was done following a standard protocol and membrane fluidity in platelets was estimated using a fluorescent probe, 1,6-diphenyl-1,3,5-hexatrience, in 15 cases and 12 healthy controls. Prednisolone (1 mg/kg) in a weekly tapering dose for 6 weeks and a commercially available antioxidant preparation [lutein 3.2 mg (containing zeaxanthin 256 mcg), L-glutathione 5 mg, vitamin E 15 IU, vitamin C 150 mg, zinc 40 mg, copper 2 mg, selenium 40 mcg, and manganese 5 mg] was administered once a day for 3 months to all the cases. Pre- and postantioxidant supplementation platelet TBARS and membrane fluidity levels were assessed in all the cases. Significant increase was observed in TBARS levels in the cases when compared with controls (P = 0.01). Platelet fluorescence polarization was significantly higher in cases, indicating decreased membrane fluidity, when compared with controls (P = 0.005). Antioxidant supplementation led to marked decrease in TBARS levels (P = 0.01) and improved levels of platelet membrane fluidity (P = 0.001). Antioxidant supplementation leads to significant decrease in oxidative stress and a significant improvement in platelet membrane fluidity, thereby helping to prevent retinal photoreceptor dysfunction.


Abnormal kainate receptor expression in prefrontal cortex in schizophrenia.
Abnormalities of molecules associated with the glutamate synapse have been implicated in the pathophysiology of schizophrenia. Of the many glutamate receptors, those most commonly suggested to be involved in schizophrenia are the ionotropic subtypes, the NMDA, AMPA, and kainate receptors. Both the NMDA and AMPA subtypes have been extensively studied in postmortem brains of individuals with schizophrenia, but relatively little is known about the expression of the kainate subtype of glutamate receptor. In this study, we have determined cortical and striatal kainate receptor expression in brains from persons with schizophrenia and a comparison group, using both in situ hybridization and receptor autoradiography. At the level of subunit mRNA expression, a shift in subunit stoichiometry was evident in multiple regions of the prefrontal cortex, with increased expression of gluR7 mRNA and decreased expression of KA2 mRNA. Decreased kainate receptor binding was also observed in the subjects with schizophrenia, but was restricted to infragranular laminae of the prefrontal cortex. No differences in kainate receptor binding or subunit mRNA levels were found in striatum or occipital cortex, suggesting that these findings may be restricted to association cortex. These data add to the growing literature implicating ionotropic glutamate receptor disturbances in schizophrenia, and indicate that in addition to AMPA and NMDA receptors, the kainate receptors are also abnormally expressed in this illness.


Myeloid-derived suppressor cells contribute to oral cancer progression in 4NQO-treated mice.
Abnormal myelopoiesis especially the expansion of myeloid-derived suppressor cells (MDSCs) is increasingly recognized as an important reason for the escape of tumor from immune surveillance. This study aims to investigate the role of this specific population of cells in oral cancer progression. 4-Nitroquinoline 1-oxide (4NQO) was used to induce oral cancer in C57BL/6 mice. The tongue mucosa was examined by hematoxylin and eosin staining. The distribution of MDSCs in the spleen and peripheral blood and T cell subsets in the spleen was analyzed by flow cytometry. The expression of MDSCs in the tongue tissues was investigated by immunohistochemical staining, and the expression of arginase-1 (ARG-1) and NOS-2 in the tongue tissues was detected by real-time PCR. We found that during tumor progression, significantly increased frequency of MDSCs was observed in the spleens and peripheral blood of 4NQO-treated mice, and the frequency of MDSCs in the spleens was positively correlated with systemic CD3(+) CD8(+) T cells. Moreover, 4NQO-treated mice showed significantly higher MDSCs infiltration and ARG-1 mRNA level in the tumor site. Myeloid-derived suppressor cells contribute to oral tumor progression and represent a potential target for immunotherapy of oral cancer.


Molecular Profiling of Malignant Pleural Effusions with Next Generation Sequencing (NGS): Evidence that Supports Its Role in Cancer Management.
Malignant pleural effusions (MPEs) often develop in advanced cancer patients and confer significant morbidity and mortality. In this review, we evaluated whether molecular profiling of MPEs with next generation sequencing (NGS) could have a role in cancer management, focusing on lung cancer. We reviewed and compared the diagnostic performance of pleural fluid liquid biopsy with other types of samples. When applied in MPEs, NGS may have comparable performance with corresponding tissue biopsies, yield higher DNA amount, and detect more genetic aberrations than blood-derived liquid biopsies. NGS in MPEs may also be preferable to plasma liquid biopsy in advanced cancer patients with a MPE and a paucicellular or it could be difficult to obtain tissue/fine-needle aspiration biopsy. Of interest, post-centrifuge supernatant NGS may exhibit superior results compared to cell pellet, cell block or other materials. NGS in MPEs can also guide clinicians in tailoring established therapies and identifying therapy resistance. Evidence is still premature regarding the role of NGS in MPEs from patients with cancers other than lung. We concluded that MPE processing could provide useful prognostic and theranostic information, besides its diagnostic role.


The calreticulin-binding sequence of thrombospondin 1 regulates collagen expression and organization during tissue remodeling.
Amino acids 17-35 of the thrombospondin1 (TSP1) N-terminal domain (NTD) bind cell surface calreticulin to signal focal adhesion disassembly, cell migration, and anoikis resistance in vitro. However, the in vivo relevance of this signaling pathway has not been previously determined. We engineered local in vivo expression of the TSP1 calreticulin-binding sequence to determine the role of TSP1 in tissue remodeling. Surgical sponges impregnated with a plasmid encoding the secreted calreticulin-binding sequence [NTD (1-35)-EGFP] or a control sequence [mod NTD (1-35)-EGFP] tagged with enhanced green fluorescent protein were implanted subcutaneously in mice. Sponges expressing NTD (1-35)-EFGP formed a highly organized capsule despite no differences in cellular composition, suggesting stimulation of collagen deposition by the calreticulin-binding sequence of TSP1. TSP1, recombinant NTD, or a peptide of the TSP1 calreticulin-binding sequence (hep I) increased both collagen expression and matrix deposition by fibroblasts in vitro. TSP1 stimulation of collagen was inhibited by a peptide that blocks TSP1 binding to calreticulin, demonstrating the requirement for cell surface calreticulin. Collagen stimulation was independent of TGF-β activity and Smad phosphorylation but was blocked by an Akt inhibitor, suggesting that signaling through the Akt pathway is important for regulation of collagen through TSP1 binding to calreticulin. These studies identify a novel function for the NTD of TSP1 as a mediator of collagen expression and deposition during tissue remodeling.


Three-component Biginelli cyclocondensation reaction using C-glycosylated substrates. Preparation of a collection of dihydropyrimidinone glycoconjugates and the synthesis of C-glycosylated monastrol analogues.
The aldehyde-ketoester-urea cyclocondensation reaction has been revisited using C-glycosylated reagents with the aim of exploring a potential entry to a library of dihydropyrimidinone glycoconjugates. A collection of 13 mono- and bis-C-glycosylated dihydropyrimidinones has been prepared by a parallel synthesis approach using the three-component promoter CuCl/AcOH/BF(3) x Et(2)O. The sugar residues have been installed at either N1, C4, or C6 in the monoglycosylated derivatives and at both the C4 and C6 in the bisglycosylated products. The mono- and bisglycosylated products at C4 and C6 were obtained as mixtures of diastereoisomers with good to excellent selectivities due to the asymmetric induction by the sugar residue in the formation of the C4 stereocenter of the dihydropyrimidinone ring. Individual stereoisomers were isolated as pure compounds and their structures assigned with the aid of X-ray crystallography and chiroptical properties. As a demonstration of this new concept in the Biginelli reaction, the synthesis of two C4 epimer monastrol analogues bearing the ribofuranosyl moiety at C6 has been described.


Maternal corticosteroid use and hypospadias.
To explore whether women who reported corticosteroid use during pregnancy were more likely to deliver an infant with hypospadias than women who did not. The analysis encompassed data on deliveries with an estimated due date between 1997 and 2004 from the National Birth Defects Prevention Study, a large population-based, case-control study conducted in the United States. Included were 1165 cases of moderate to severe hypospadias and 3000 nonmalformed male controls. The mothers of 39 cases (3.3%) and 62 controls (2.1%) reported using a corticosteroid medication during the period extending from 4 weeks before conception to 14 weeks after conception. The odds ratio (OR) for any corticosteroid exposure versus no corticosteroid exposure was 1.6 (95% confidence interval [CI] = 1.1 to 2.5); after adjustment for maternal race/ethnicity, education, age, and study site, it was 1.3 (95% CI = 0.8 to 2.0). Analyses by route of administration and specific component suggest that elevated ORs occurred only for nasal spray/inhaled corticosteroids (OR = 1.5; 95% CI = 0.9 to 2.6). Maternal use of corticosteroid medications was weakly associated with risk of hypospadias, but the association was negligible after adjustment for potential confounders.


The academic prince.
The author presents advice to deans and chairs of academia by imagining what Machiavelli might recommend were he to write a modern version of The Prince for academics. "Machiavelli" cautions that since modern academic "princes" have little power (except, perhaps, over teaching and laboratory space), the success of their rule depends upon respect. Regarding the choice of an academic prince, find someone who can be a good role model, set standards, and reward academic excellence, and who will, above all, be respected. Avoid choosing a prince who is a nice, nonthreatening candidate with "good human relations" and "good executive skills." Choose candidates who are already successful and fulfilled and who will see the new post not as a promotion or a balm for their insecurity, but as an intrusion into their academic lives. Fill empty positions as quickly as possible-better a weak prince than no prince at all. Seek short terms for princes, both because respected academics will want to return to their normal lives as soon as possible, and because with short mandates, greater chances can be taken with young, unproved, but promising candidates. At the same time, the appointment of aging administrators who have lost their academic skills is to be avoided. Above all, respect the throne-i.e., the position of chair or dean-even if the person holding the position may not deserve the respect, since when the prince retires with honor, the position becomes more attractive to future good candidates.


Reproductive disorders affecting fertility in endometriosis.
The classical concept of endometriosis as a cause of infertility is challenged. Traditionally, both surgical and medical therapy of endometriosis-associated infertility has focused on eliminating or reducing the visible implants. The classic 6-month medical approach has been a failure, and surgery may moderately enhance fertility, but its benefit in the absence of adhesions is still doubtful. Recent studies have shown that endometriosis is characterized by an aberrant response to sex steroid hormones, resulting in pleiotropic dysfunctions of the reproductive system involving the uterine, peritoneal and ovarian micro-environment. Studies on endometriosis and IVF have been highly relevant in revealing the pleiotropic dysfunctions in patients with endometriosis, although the results should be interpreted with caution. The conclusion seems to support the view that infertility in patients with endometriosis is primarily dysfunctional, rather than lesional, in origin. It is concluded that the place of medical therapy in endometriosis should be reviewed and that the surgical approach needs to be complemented by appropriate medical therapy to restore fertility.


Renoprotective effects of long-term oral nicotine in a rat model of spontaneous proteinuria.
Many proteinuric renal conditions are accompanied by renal inflammation. Nicotine is known to have anti-inflammatory properties and is used in oral form to help subjects quit smoking. A potential anti-inflammatory role of nicotine in proteinuric renal diseases has not been investigated to date. We therefore evaluated the effects of oral nicotine in a rat model of proteinuria-induced renal inflammation. We used a well-established model of adult (24 wk of age) male Munich-Wistar-Frömter rats. Animals were given three different physiological doses of nicotine in drinking water for 28 wk until 52 wk of age (long term). A group without nicotine served as a parallel control. At 52 wk of age, the control group had a 2.1 times reduction in creatinine clearance, 3.2 times increase in urinary protein excretion, an increased focal glomerulosclerosis (FGS) score, increased glomerular desmin deposition, decreased glomerular podocin, and a higher accumulation of macrophages and myofibroblasts compared with 24-wk-old animals. Oral treatment with nicotine dose dependently preserved renal function and halted proteinuria progression, which were independent of blood pressure reduction. It also reduced FGS, desmin deposition, podocin loss, and density of renal macrophages and myofibroblasts. Nicotine also reduced the level of gene expression of the renal inflammatory markers monocyte chemoattractant protein and vascular cell adhesion molecule-1. In conclusion, long-term oral nicotine preserved kidney function, reduced proteinuria, reduced renal inflammation, and protected progression of renal structural damage in a rat model of proteinuria. We further suggest evaluating nicotine as a potential additional therapeutic option for treating proteinuric kidney diseases.


Anti-GD1a ganglioside antibodies in peripheral motor syndromes.
High titers of anti-GD1a antibodies have been found in patients with Guillain-Barre syndrome or motor neuropathy. To determine the possible diagnostic relevance of these antibodies, we measured serum anti-GD1a IgG and IgM antibodies by enzyme-linked immunosorbent assay in 195 patients with different motor syndromes and in 335 control subjects. Moderately high antibody titers (1/1,280-1/5,120) were occasionally found in patients with chronic inflammatory demyelinating polyneuropathy (5%), multifocal motor neuropathy (18%), lower motor neuron disease (3.8%), or amyotrophic lateral sclerosis (1.8%) and in immunological control subjects (1.2%), while titers of 1/20,480 or higher were only found in 2 patients with Guillain-Barre syndrome (IgG in both) and 2 with motor neuropathy and IgM lambda monoclonal gammopathy improving with immunotherapy. In both motor neuropathy patients and the Guillain-Barre syndrome patient who were retested during recovery, anti-GD1a titers decreased concomitantly with clinical improvement. High anti-GD1a antibody titers may be found in several motor syndromes but only markedly increased anti-GD1a titers are strictly associated with potentially treatable dysimmune neuropathies.


Temporal repolarization lability in hypertrophic cardiomyopathy caused by beta-myosin heavy-chain gene mutations.
Certain genetic mutations associated with hypertrophic cardiomyopathy (HCM) carry an increased risk of sudden death. QT variability identifies patients at a high risk for sudden death from ventricular arrhythmias. We tested whether patients with HCM caused by beta-myosin heavy-chain (beta-MHC) gene mutations exhibit labile ventricular repolarization using beat-to-beat QT variability analysis. We measured the QT variability index and heart rate-QT interval coherence from Holter monitor recordings in 36 patients with HCM caused by known beta-MHC gene mutations and in 26 age- and sex-matched controls. There were 7 distinct beta-MHC gene mutations in these 36 patients; 9 patients had HCM caused by the malignant Arg(403)Gln mutation and 8 patients had HCM caused by the more benign Leu(908)Val mutation. The QT variability index was higher in HCM patients than in controls (-1.24+/-0.17 versus -1. 58+/-0.38, P<0.01), and the greatest abnormality was detected in patients with the Arg(403)Gln mutation (-0.99+/-0.49 versus -1. 46+/-0.43 in controls, P<0.05). In keeping with this finding, coherence was lower for the entire HCM group than for controls (P<0. 001). Coherence was also significantly lower in patients with the Arg(403)Gln mutation compared with controls (P<0.05). These findings suggest that (1) patients with HCM caused by beta-MHC gene mutations exhibit labile repolarization quantified by QT variability analysis and, hence, may be more at risk for sudden death from ventricular arrhythmias, and (2) indices of QT variability may be particularly abnormal in patients with beta-MHC gene mutations that are associated with a poor prognosis.


Nano-corrugated Nanochannels for In Situ Tracking of Single-Nanoparticle Translocation Dynamics.
Dynamic motions of materials in liquid present a wealth of information concerning their physical properties. While fluorescence microscopy has been widely utilized for single-particle observations, the method cannot be used for characterizing fast motions of nanoscale objects due to the limited spatiotemporal resolution. Here, we report on a nanostructure strategy for nanoscale tracking of single nanoparticles. We fabricated a straight conduit in a SiO2 layer on a Si wafer with lithographically defined 30 nm-sized protrusions formed on the side walls. We performed resistive pulse measurements at a 1 MHz sampling rate wherein we found n-stepped current traces signifying n number of nanoparticles moving concurrently inside the nanochannel. Ensemble average of the ionic current signals revealed a peculiar feature reflecting the slightly stronger ion blockage at the nanoconstrictions between the protrusions, thereby proving the ability of nano-corrugation as physical gates to signify the precise positions of objects inside the nanofluidic channel. This in situ tracking approach elucidated steady-state motions of the nanoparticles moving at a constant speed under the counter-balanced electrophoretic and viscous drag forces, which also allowed estimations of their surface charge densities. The present method can be utilized as a speedometer for nanoscale objects of virtually any size as long as they are able to be put through the sensing zones with potential applications for single-molecule time-of-flight mass spectrometry.


Mental health. Drawing the line.
Employing community psychiatric nurses to assess clients referred to community psychiatric teams can help target resources. The assessment nurses deal both with routine and emergency referrals. Some GPs were initially concerned about nurses undertaking assessments previously carried out by psychiatrists.


The Virome of Piper nigrum: Identification, Genomic Characterization, Prevalence, and Transmission of Three New Viruses of Black Pepper in China.
Viral diseases are one of the main categories of diseases that cause substantial yield losses in black pepper. Disease symptoms in black pepper are generally complex and are often caused by both known and undescribed viruses. To identify and clarify the etiology of viral diseases in black pepper in Hainan, China, we conducted high-throughput sequencing (HTS) by targeting purified double-stranded RNA (dsRNA) and ribosomal RNA depleted total RNA (rRNA-depleted totRNA). Analysis of the data revealed the presence of one known virus, piper yellow mottle virus (PYMoV), and three newly identified viruses: black pepper virus F (BPVF) in the genus Fabavirus, black pepper virus E (BPVE) in the genus Enamovirus, and black pepper virus B (BPVB) in the genus Badnavirus. The dominant viruses in P. nigrum sampled in Hainan are PYMoV, with an incidence of 100%, followed by BPVF (84%, 133 of 158) and BPVB (66%, 105 of 158). Mechanical inoculation of sap extracts from source plants containing PYMoV, BPVF, and BPVB gave negative results on both herbaceous and woody host plants 60 days postinoculation (dpi). BPVF and PYMoV were successfully transmitted to virus-free seedlings of black pepper through bark grafting, while BPVB was experimentally undetectable up to 150 dpi. Seed transmission experiments showed that no target viruses were present in all 59 germinated seedlings. This study provides information on diagnosis, prevalence, and transmission of black-pepper-associated viruses.


Coloring random graphs.
We study the graph coloring problem over random graphs of finite average connectivity c. Given a number q of available colors, we find that graphs with low connectivity admit almost always a proper coloring, whereas graphs with high connectivity are uncolorable. Depending on q, we find the precise value of the critical average connectivity c(q). Moreover, we show that below c(q) there exists a clustering phase c in [c(d),c(q)] in which ground states spontaneously divide into an exponential number of clusters and where the proliferation of metastable states is responsible for the onset of complexity in local search algorithms.


Localization of the Ethylene-synthesizing System in Apple Tissue.
Apple (Malus sp.) slices gradually lost the ability to synthesize ethylene when incubated with a mixture of enzymes that digest cell walls. The released protoplasts did not produce ethylene. The release of protoplasts was faster from climacteric fruit slices than from preclimacteric tissue. In protoplast suspension culture, as new cell wall was deposited (as judged by the intensity of fluorescence of regenerating protoplasts stained with Calcofluor White and the incorporation of labeled myo-inositol into their ethanol-insoluble residue), ethylene synthesis was gradually regained. Restored ethylene synthesis reached a maximum after 80 hours in protoplasts from preclimacteric fruit and in 120 hours in those from climacteric tissue. Addition of methionine (1 mm) to the culture medium was essential for appreciable synthesis of ethylene; and this synthesis was inhibited by the aminoethoxy analogue of rhizobitoxine and by propyl gallate, inhibitors of ethylene synthesis in higher plants. We suggest that the ethylene-synthesizing enzyme system is highly structured in the apple cell and is localized in a cell wall-cell membrane complex.


A two-site enzyme-linked immunosorbent assay for inhibin.
The investigation of the role of inhibin in the regulation of fertility is hindered by the lack of a routine, specific assay. The pituitary cell bioassay is time-consuming and the existing RIAs, based on either purified bovine 32-kDa inhibin or synthetic alpha-subunit peptides, are not specific for the biologically active inhibin molecules. We have used monoclonal antibodies, one specific for the N-terminal region of the human inhibin alpha chain, and the other raised to a peptide sequence close to the C-terminal of the human beta A-inhibin chain, to create a two-site sandwich ELISA specific for alpha beta-inhibin molecules. This was used to estimate levels of inhibin in crude bovine and human follicular fluids and fractions concentrated from them. Comparison of the values obtained with the ELISA and those obtained with the pituitary cell bioassay, suggests that the ELISA measures biologically active inhibin. Compared with the peptide-based RIA, the ELISA gave much lower (as little as 100-fold lower) values for the inhibin content of these samples, e.g., bovine follicular fluid 0.375 micrograms/ml (ELISA) compared with 41.0 micrograms/ml (RIA). Such large differences, possibly due to the presence of relatively large amounts of biologically inactive forms of inhibin such as the pro-alpha c or free alpha forms, suggest that those RIAs, which essentially measure the level of alpha-inhibin, considerably overestimate the levels of the active forms of inhibin in the samples and that results obtained using these assays may need reinterpretation.


A Systematically Assembled Signature of Genes to be Deep-Sequenced for Their Associations with the Blood Pressure Response to Exercise.
:Background: Exercise is one of the best nonpharmacologic therapies to treat hypertension. The blood pressure (BP) response to exercise is heritable. Yet, the genetic basis for the antihypertensive effects of exercise remains elusive. Methods: To assemble a prioritized gene signature, we performed a systematic review with a series of Boolean searches in PubMed (including Medline) from earliest coverage. The inclusion criteria were human genes in major BP regulatory pathways reported to be associated with: (1) the BP response to exercise; (2) hypertension in genome-wide association studies (GWAS); (3) the BP response to pharmacotherapy; (4a) physical activity and/or obesity in GWAS; and (4b) BP, physical activity, and/or obesity in non-GWAS. Included GWAS reports disclosed the statistically significant thresholds used for multiple testing. Results: The search yielded 1422 reports. Of these, 57 trials qualified from which we extracted 11 genes under criteria 1, 18 genes under criteria 2, 28 genes under criteria 3, 27 genes under criteria 4a, and 29 genes under criteria 4b. We also included 41 genes identified from our previous work. Conclusions: Deep-sequencing the exons of this systematically assembled signature of genes represents a cost and time efficient approach to investigate the genomic basis for the antihypertensive effects of exercise.


A pilot clinical trial to determine the safety and efficacy of aerosolized hyaluronan as a treatment for COPD.
A novel therapy for COPD involving the use of aerosolized hyaluronan (HA) was tested on a small cohort of COPD patients to determine both its safety and efficacy in reducing levels of desmosine and isodesmosine (DID), biomarkers for elastin degradation. In a 2-week, randomized, double-blind trial, 8 patients receiving 150 kDa HA (mean molecular weight) and 3 others given placebo did not show significant adverse effects with regard to spirometry, electrocardiograms, and hematological indices. Furthermore, measurements of DID in plasma from HA-treated patients indicated a progressive decrease over a 3-week period following initiation of treatment (r=-0.98; p=0.02), whereas patients receiving placebo showed no reduction in DID (r=-0.70; p=0.30). Measurements of sputum in the HA-treated group also revealed a progressive decrease in DID (r=-0.97; p=0.03), but this finding was limited by the absence of similar measurements in the placebo group. Nevertheless, the results of this small, pilot study support a longer-term trial of HA in a larger population of COPD patients.


Anatomical pathways for auditory memory in primates.
Episodic memory or the ability to store context-rich information about everyday events depends on the hippocampal formation (entorhinal cortex, subiculum, presubiculum, parasubiculum, hippocampus proper, and dentate gyrus). A substantial amount of behavioral-lesion and anatomical studies have contributed to our understanding of the organization of how visual stimuli are retained in episodic memory. However, whether auditory memory is organized similarly is still unclear. One hypothesis is that, like the "visual ventral stream" for which the connections of the inferior temporal gyrus with the perirhinal cortex are necessary for visual recognition in monkeys, direct connections between the auditory association areas of the superior temporal gyrus and the hippocampal formation and with the parahippocampal region (temporal pole, perhirinal, and posterior parahippocampal cortices) might also underlie recognition memory for sounds. Alternatively, the anatomical organization of memory could be different in audition. This alternative "indirect stream" hypothesis posits that, unlike the visual association cortex, the majority of auditory information makes one or more synapses in intermediate, polymodal areas, where they may integrate information from other sensory modalities, before reaching the medial temporal memory system. This review considers anatomical studies that can support either one or both hypotheses - focusing on anatomical studies on the primate brain, primarily in macaque monkeys, that have reported not only direct auditory association connections with medial temporal areas, but, importantly, also possible indirect pathways for auditory information to reach the medial temporal lobe memory system.


Management of transient cerebral ischemic attacks.
Transient ischemic attacks (TIAs) are brief reversible episodes of neurological dysfunction due to temporary focal cerebral ischemia. Angiography should be performed only when operation is indicated or when the diagnosis is in doubt. Surgical treatment is recommended when the patient is a good surgical risk, when the stenosis is more than 70 per cent in the appropriate vessel and in certain patients with less severe stenotic lesions that appear to be a probable source of emboli. Anticoagulant therapy is indicated when there are recurrent TIAs, when the patient is not a good surgical candidate and when no appropriate surgically remediable lesion is found by angiography. If there is any significant contraindication to anticoagulants they should not be given. Discontinuance of anticoagulant therapy when the patient has been symptom-free for six months is recommended. In the experience of the authors the TIA syndrome is more benign in its course than was originally suspected and a conservative approach to surgical and anticoagulant therapy is recommended.


Self-Healing Mechanism and Conductivity of the Hydrogel Flexible Sensors: A Review.
Sensors are devices that can capture changes in environmental parameters and convert them into electrical signals to output, which are widely used in all aspects of life. Flexible sensors, sensors made of flexible materials, not only overcome the limitations of the environment on detection devices but also expand the application of sensors in human health and biomedicine. Conductivity and flexibility are the most important parameters for flexible sensors, and hydrogels are currently considered to be an ideal matrix material due to their excellent flexibility and biocompatibility. In particular, compared with flexible sensors based on elastomers with a high modulus, the hydrogel sensor has better stretchability and can be tightly attached to the surface of objects. However, for hydrogel sensors, a poor mechanical lifetime is always an issue. To address this challenge, a self-healing hydrogel has been proposed. Currently, a large number of studies on the self-healing property have been performed, and numerous exciting results have been obtained, but there are few detailed reviews focusing on the self-healing mechanism and conductivity of hydrogel flexible sensors. This paper presents an overview of self-healing hydrogel flexible sensors, focusing on their self-healing mechanism and conductivity. Moreover, the advantages and disadvantages of different types of sensors have been summarized and discussed. Finally, the key issues and challenges for self-healing flexible sensors are also identified and discussed along with recommendations for the future.


Disease-associated prion protein in vessel walls.
Human prion diseases like Creutzfeldt-Jakob disease are infectious, inherited, or sporadic neurodegenerative disorders, characterized by the accumulation of an abnormal isoform of the host-encoded prion protein. This affects nervous tissue in sporadic Creutzfeldt-Jakob disease and, additionally, in lymphoid tissue in bovine spongiform encephalopathy-linked variant Creutzfeldt-Jakob disease. Experimental studies have established the involvement of cells of the lymphoid and peripheral nervous system in the transport of prions to their target central nervous system tissue. To evaluate the role of vessel wall-associated mobile cells, we obtained formalin-fixed tissue blocks from various brain regions and/or basal arteries from sporadic, variant and iatrogenic Creutzfeldt-Jakob disease, and unselected control cases. We demonstrate disease-associated prion protein deposits in intracranial vessel walls, in sporadic and variant Creutzfeldt-Jakob disease by performing immunohistochemical staining and paraffin-embedded tissue blotting. Using double immunofluorescence, these deposits co-localize with HLA-DR and S-100 immunoreactive cells in the intima, which are components of the vascular-associated dendritic cell network, as well as with HLA-DR and CD-68 immunopositive macrophages of the intima and media. We conclude that mobile cells in vessel walls like dendritic and monocyte/macrophage lineage cells may be involved in spread of disease-associated prion protein and possibly also of infectivity.


Genetic evidence supports demic diffusion of Han culture.
The spread of culture and language in human populations is explained by two alternative models: the demic diffusion model, which involves mass movement of people; and the cultural diffusion model, which refers to cultural impact between populations and involves limited genetic exchange between them. The mechanism of the peopling of Europe has long been debated, a key issue being whether the diffusion of agriculture and language from the Near East was concomitant with a large movement of farmers. Here we show, by systematically analysing Y-chromosome and mitochondrial DNA variation in Han populations, that the pattern of the southward expansion of Han culture is consistent with the demic diffusion model, and that males played a larger role than females in this expansion. The Han people, who all share the same culture and language, exceed 1.16 billion (2000 census), and are by far the largest ethnic group in the world. The expansion process of Han culture is thus of great interest to researchers in many fields.


Exhaled nitric oxide and bronchial responsiveness to adenosine 5'-monophosphate in subjects with allergic rhinitis.
To determine differences in exhaled nitric oxide (ENO) between subjects with allergic rhinitis with and without increased responsiveness to direct and indirect bronchoconstrictor agents. Cross-sectional study with the order of challenge tests randomized. Specialist allergy unit in a university hospital. Thirty-eight subjects without asthma with allergic rhinitis and 10 healthy nonatopic control subjects. Participants were challenged with increasing concentrations of adenosine 5'monophosphate (AMP) and methacholine. ENO was measured with the single-exhalation method. A positive response to both bronchoconstrictor agents was detected in nine subjects with allergic rhinitis, whereas four subjects showed increased responsiveness to AMP but not to methacholine. The geometric mean (range) ENO values were significantly higher in subjects with allergic rhinitis with increased responsiveness to either methacholine or AMP than in subjects with normal responsiveness to both agonists: 51.3 parts per billion (ppb) [22.0 to 108.5 ppb] vs 25.1 ppb (5.7 to 102.9 ppb, respectively; p = 0.007) and healthy control subjects (11.2 ppb [5.0 to 31.9 ppb], p < 0.001). Subjects with allergic rhinitis with normal responsiveness to both agonists also had higher concentrations of ENO than healthy control subjects (p = 0.007). No correlation was found between ENO and either of the provocative concentrations of methacholine or AMP causing a 20% fall in FEV(1). In subjects without asthma but with allergic rhinitis, the presence of bronchoconstriction in response to methacholine or AMP is associated with increased ENO concentrations. However, elevated concentrations of ENO are detected even in subjects with allergic rhinitis without airway hyperresponsiveness. These results suggest that the presence of airway hyperresponsiveness is not the only factor that determines the increased NO levels detected in subjects with allergic rhinitis.


Seroprevalence of Anti-SARS-CoV-2 IgG Antibodies among HIV Infected Individuals Attending ART Centre at Pune: A Cross-Sectional Study.
Background: We aimed to determine the anti-SARS-CoV-2 IgG antibodies among people living with HIV (PLHIV) in Pune, India. Methods: This cross-sectional study was conducted between March 2021 and June 2021. Demographic and clinical information related to coronavirus disease 2019 (COVID-19) were recorded on structured questionnaires. Blood samples were collected and tested for anti-SARS-CoV-2 IgG antibodies using commercial ELISA. Results: Of the 405 HIV infected individuals enrolled in the study, 223(55.1%) were females. Mean age and CD4 count of participants were 42 years (SD: 10) and 626 cells/mm3 (SD: 284) respectively. A total of 382 (95%) PLHIV were virologically suppressed. The seropositivity against SARS-CoV-2 was found in 221 PLHIV (54.6%, 95% CI: 49.7-59.4). No significant association was found between demographic or clinical factors and seropositivity. Conclusion: A high prevalence of anti-SARS-CoV-2 IgG antibodies was found among PLHIV attending ART centre indicating an exposure to the virus among them.


Selected Livestock-Associated Zoonoses as a Growing Challenge for Public Health.
The aim of this paper is to review the most significant livestock-associated zoonoses. Human and animal health are intimately connected. This idea has been known for more than a century but now it has gained special importance because of the increasing threat from zoonoses. Zoonosis is defined as any infection naturally transmissible from vertebrate animals to humans. As the frequency and prevalence of zoonotic diseases increase worldwide, they become a real threat to public health. In addition, many of the newly discovered diseases have a zoonotic origin. Due to globalization and urbanization, some of these diseases have already spread all over the world, caused by the international flow of goods, people, and animals. However, special attention should be paid to farm animals since, apart from the direct contact, humans consume their products, such as meat, eggs, and milk. Therefore, zoonoses such as salmonellosis, campylobacteriosis, tuberculosis, swine and avian influenza, Q fever, brucellosis, STEC infections, and listeriosis are crucial for both veterinary and human medicine. Consequently, in the suspicion of any zoonoses outbreak, the medical and veterinary services should closely cooperate to protect the public health.


Simian virus 40 large T antigen binds to topoisomerase I.
Binding of simian virus 40 (SV40) large T antigen to human and calf thymus topoisomerase I (topo I) was readily detected by using modified enzyme-linked immunosorbent assays and immunoblots. In addition to WT T antigen, binding could also be readily demonstrated with T antigen fragments from the amino-terminal region as well as with fragments missing this region, but much less so with small t antigen or with human p53. Antibody-blocking experiments showed that a monoclonal antibody that binds to the N-terminal region and several antibodies that recognize the central region of T antigen interfere with the binding to topo I. Our data are consistent with the existence of two separate topo I-binding regions in T antigen, one mapping within residues 82 to 246 and an apparently weaker one present after residue 246. By comparing the binding of T antigen to topo I with that of T antigen to DNA polymerase alpha or RPA, a single-stranded DNA-binding protein, it was determined that the T antigen-topo I interaction is much stronger and that the binding sites for topo I and DNA polymerase overlap, whereas the one for RPA differs. Several unwinding-defective mutants of T antigen were partially defective in their binding to topo I, suggesting that the binding to topo I is required for unwinding circular DNA. Finally, immunoprecipitation experiments demonstrated that T antigen can interact with DNA-bound topo I, indicating that such an interaction may take place during SV40 DNA replication.


The First Decade of Web-Based Sports Injury Surveillance: Descriptive Epidemiology of Injuries in US High School Girls' Volleyball (2005-2006 Through 2013-2014) and National Collegiate Athletic Association Women's Volleyball (2004-2005 Through 2013-2014).
The advent of Web-based sports injury surveillance via programs such as the High School Reporting Information Online system and the National Collegiate Athletic Association Injury Surveillance Program has aided in the acquisition of girls' and women's volleyball injury data. To describe the epidemiology of injuries sustained in high school girls' volleyball in the 2005-2006 through 2013-2014 academic years and collegiate women's volleyball in the 2004-2005 through 2013-2014 academic years using Web-based sports injury surveillance. Descriptive epidemiology study. Online injury surveillance from high school girls' (annual average = 100) and collegiate women's (annual average = 50) volleyball teams. Girls' and women's volleyball players who participated in practices and competitions during the 2005-2006 through 2013-2014 academic years in high school and the 2004-2005 through 2013-2014 academic years in college. Athletic trainers collected time-loss (≥24 hours) injury and exposure data. Injury rates per 1000 athlete-exposures (AEs), injury rate ratios (IRRs) with 95% confidence intervals (CIs), and injury proportions by body site and diagnosis were calculated. The High School Reporting Information Online system documented 1634 time-loss injuries during 1 471 872 AEs; the National Collegiate Athletic Association Injury Surveillance Program documented 2149 time-loss injuries during 563 845 AEs. The injury rate was higher in college than in high school (3.81/1000 versus 1.11/1000 AEs; IRR = 3.43; 95% CI = 3.22, 3.66), and higher in high schools with ≤1000 students than in those with >1000 students (IRR = 1.35; 95% CI = 1.23, 1.49). Injury rates did not vary by collegiate division. The injury rate was higher during competitions than practices for high school (IRR = 1.23; 95% CI = 1.12, 1.36) but not for college (IRR = 1.01; 95% CI = 0.92, 1.10). Ankle sprains were common in both the high school and collegiate setting. However, liberos had a high incidence of concussion. Injury rates were higher among collegiate than high school players. However, injury rates differed by event type in high school, unlike college. Concussion injury patterns among liberos varied from those for other positions. These findings highlight the need for injury-prevention interventions specific to setting and position.


The Schizosaccharomyces pombe replication inhibitor Spd1 regulates ribonucleotide reductase activity and dNTPs by binding to the large Cdc22 subunit.
Ribonucleotide reductase (RNR) is an essential enzyme that provides the cell with a balanced supply of deoxyribonucleoside triphosphates for DNA replication and repair. Mutations that affect the regulation of RNR in yeast and mammalian cells can lead to genetic abnormalities and cell death. We have expressed and purified the components of the RNR system in fission yeast, the large subunit Cdc22p, the small subunit Suc22p, and the replication inhibitor Spd1p. It was proposed (Liu, C., Powell, K. A., Mundt, K., Wu, L., Carr, A. M., and Caspari, T. (2003) Genes Dev. 17, 1130-1140) that Spd1 is an RNR inhibitor, acting by anchoring the Suc22p inside the nucleus during G1 phase. Using in vitro assays with highly purified proteins we have demonstrated that Spd1 indeed is a very efficient inhibitor of fission yeast RNR, but acting on Cdc22p. Furthermore, biosensor technique showed that Spd1p binds to the Cdc22p with a KD of 2.4 microM, whereas the affinity to Suc22p is negligible. Therefore, Spd1p inhibits fission yeast RNR activity by interacting with the Cdc22p. Similar to the situation in budding yeast, logarithmically growing fission yeast increases the dNTP pools 2-fold after 3 h of incubation in the UV mimetic 4-nitroquinoline-N-oxide. This increase is smaller than the increase observed in budding yeast but of the same order as the dNTP pool increase when synchronous Schizosaccharomyces pombe cdc10 cells are going from G1 to S-phase.


Targeting the mitochondrial permeability transition pore for drug discovery: Challenges and opportunities.
Several drug targets have been amenable to drug discovery pursuit not until the characterization of the mitochondrial permeability transition pore (MPTP), a pore with an undefined molecular identity that forms on the inner mitochondrial membrane upon mitochondrial permeability transition (MPT) under the influence of calcium overload and oxidative stress. The opening of the pore which is presumed to cause cell death in certain human diseases also has implications under physiological parlance. Different models for this pore have been postulated following its first identification in the last six decades. The mitochondrial community has witnessed many protein candidates such as; voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT), Mitochondrial phosphate carrier (PiC), Spastic Paralegin (SPG7), disordered proteins, and F1Fo ATPase. However, genetic studies have cast out most of these candidates with only F1Fo ATPase currently under intense argument. Cyclophilin D (CyPD) remains the widely accepted positive regulator of the MPTP known to date, but no drug candidate has emerged as its inhibitor, raising concern issues for therapeutics. Thus, in this review, we discuss various models of MPTP reported with the hope of stimulating further research in this field. We went beyond the classical description of the MPTP to ascribe a 'two-edged sword property' to the pore for therapeutic function in human disease because its inhibition and activation have pharmacological relevance. We suggested putative proteins upstream to CyPD that can regulate its activity and prevent cell deaths in neurodegenerative disease and ischemia-reperfusion injury.


AG8 cells, which are highly resistant to hydrogen peroxide, display collateral sensitivity to the combination of hydrogen peroxide and L-histidine.
The results obtained in the present study indicate that AG8 cells, which are highly resistant to H2O2, are not cross-resistant to the combination of H2O2/L-histidine. In fact, once the influence of elevated catalase on the AG8 pheno-type has been circumvented (by treatment of AG8 cells with aminotriazole), AG8 cells display essentially no cross-resistance to the H2O2/L-histidine cocktail while retaining considerable resistance to H2O2 alone (when compared to wild-type AA8 cells). Although H2O2 alone dose not produce DNA double strand breaks (DSBs), this type of lesion was readily detected upon exposure of sensitive or resistant cells to the oxidant in the presence of the amino acid. Interestingly, similar levels of DNA DSBs were detected in AA8 and catalase-depleted AG8 cells. An excellent correlation was found when the cytotoxicity and the level of DNA DSBs obtained in sensitive and resistant cells (with normal or reduced catalase levels) challenged with the cocktail H2O2/L-histidine were compared. This would suggest that DSBs produced on a per cell basis always result in an equal level of toxicity, regardless of the cell type (resistant versus sensitive cell line), the lethality of each of these cell lines being dependent on the number of induced DSBs. In conclusion, the results presented here provide further evidence in support of the hypothesis that cell killing elicited by the combination of H2O2/L-histidine involves a mechanism distinct from that following treatment with H2O2 alone. The fact that H2O2-resistant AG8 cells, which are not cross-resistant to agents promoting cell death via DNA DSB-induction, display collateral sensitivity to the cocktail H2O2/L-histidine, strongly suggests that cell killing triggered by this treatment is mediated by DNA double strand breakage.


Balanopreputial sac and urine microbiota in patients with male genital lichen sclerosus.
Male genital lichen sclerosus (MGLSc) is a chronic inflammatory scarring dermatosis associated with penile carcinoma. The prepuce is pivotal in its etiology. Other proposed etiological factors are the subject of dispute and include occluded urinary exposure, autoimmunity, immunodysregulation, and infectious agents. To determine whether the bacterial microbiota of the balanopreputial sac and urine are associated with MGLSc. Twenty uncircumcised patients with MGLSc and 20 healthy uncircumcised males were enrolled in a prospective case-control study. Balanopreputial swabs and urine specimens were subjected to 16S rRNA gene amplicon sequencing. Microbiota analysis indicated differences between the groups. In the balanopreputial sac, the median relative abundance of Finegoldia spp. was lower (9% [range 0-60%]) in MGLSc patients than in controls (28% [range 0-62%]). Conversely, the median relative abundance of Fusobacterium spp. was higher in MGLSc patients (4% [range 0-41%]) than in controls (0% [range 0-28%]). In the urine, the median relative abundance of Finegoldia spp. was comparable between groups, whereas that of Fusobacterium spp. was higher in MGLSc patients (0% [range 0-18%] vs. 0% [range 0-5%]). There was a strong association between the microbiota composition of the balanopreputial sac and urine in MGLSc. Dysbiosis could be involved in the etiopathogenesis of MGLSc. Further studies are required to confirm the association suggested herein and to determine its nature.


A new aphid genus Neoaulacorthum (Hemiptera: Aphididae: Macrosiphini), determined by molecular and morphometric analyses.
We performed molecular and morphological analyses to determine the generic limit of the genus Aulacorthum, including several species with controversial taxonomic histories. The sequences of four mitochondrial genes, COI, COII, srRNA and lrRNA, and one nuclear gene, EF1a, implied that Aulacorthum is not monophyletic, with Aulacorthum magnoliae and Aulacorthum nipponicum forming a clade that is not sister to other currently recognized Aulacorthum species. Morphometric analysis based on 20 morphological characters also showed that A. magnoliae and A. nipponicum exhibited morphological characteristics distinct from congeneric species. Based on these results, we propose a new genus, Neoaulacorthum ge. n., for A. magnoliae and A. nipponicum.


Magnetic resonance imaging of the fetal brain.
US remains the key imaging technique for prenatal screening of CNS pathology. However, MR imaging of the fetal brain is a powerful tool to further characterize CNS anomalies, especially during the third trimester. The prognosis of CNS anomalies detected at fetal MR imaging is not always known. As such, management may be problematic with regards to medical interruption of pregnancy. A multidisciplinary approach is essential in order to insure comprehensive evaluation and management of the pregnancy.


[Non-erythrocyte blood products transfusion in very preterm and extremely preterm infants in Chinese neonatal intensive care units].
Objective: To describe the use of non-erythrocyte blood products transfusion in very preterm and extremely preterm infants in the neonatal intensive care units (NICU) of the Chinese Neonatal Network (CHNN) in 2019, to explore the disparity between different centers, and to further investigate the rationality and standardability of non-erythrocyte blood products transfusion. Methods: This was a cross-sectional study based on the CHNN cohort of very preterm and extremely preterm infants. All 6 598 infants with gestational age (GA)<32 weeks and admitted to the 57 NICU of CHNN within 24 h of life in 2019 were enrolled. Non-erythrocyte blood products included platelet, plasma, albumin, immunoglobulin, cryoprecipitate and prothrombin complex. Infants who received at least one type of non-erythrocyte blood products were defined in transfusion group. The comparison between infants with and without transfusion was done by t-test, rank-sum test or χ2 test as appropriate. Linear regression model was used to generate adjusted transfusion rate of each center, and to investigate the correlation between adjusted rate and center-level characteristics. Results: A total of 6 598 infants were enrolled in the study, with gestational age of 30.0 (28.7, 31.0) weeks and birth weight of (1 353±312) g, and 43.6 % (2 877) of them were female. Among them, 42.7% (2 816) infants were enrolled in transfusion group, with the times of transfusion as 3 (1, 6) times. Compared to the infants without any transfusion of non-erythrocyte blood products, those infants received transfusion had lower gestational age (Z=17.62, P<0.01), lower birth weight (t=18.64, P<0.01), higher proportion of small-for-gestation age (χ2=31.06, P<0.01), multiple birth (χ²=12.82, P<0.01) and intensive resuscitation in delivery room (χ²=287.52, P<0.01), as well as lower proportion of females (χ²=10.68, P<0.01) and even lower proportion of infants born in this hospital (χ²=78.23, P<0.01). Among the entire study population, albumin (25.4%, 1 674 cases), immunoglobulin (21.5%, 1 417 cases) and plasma (18.9%, 1 245 cases) were the most commonly used non-erythrocyte blood products. Overall, 60.4% (544/901) infants with gestational age <28 weeks received transfusion 4 (2, 8) times. A total of 39.9% (2 272/5 697) infants between 28-31weeks received non-erythrocyte blood products 3 (1, 6) times. The non-erythrocyte blood products transfusion rates of critically-ill and non-critically-ill infants were 62.2% (1 693/2 723) and 29.0% (1 123/3 875) respectively, and the transfusion times were 4 (2,7) and 2 (1,4) times. The transfusion rates varied significantly among different NICU, and the disparities remained obvious after adjustment (adjusted χ²=153.48, P<0.01). Conclusion: Near half of very preterm and extremely preterm infants admitted to Chinese NICU in 2019 receive non-erythrocyte blood products during hospitalization with significant disparities among different hospitals.


Endocrine, neural, and immune control of secretory component output by lacrimal gland acinar cells.
Androgens regulate the synthesis and secretion of secretory component (SC), the IgA antibody receptor, by acinar cells from the lacrimal gland. However, this hormone action may be susceptible to significant modification by other agents from the endocrine, nervous, or immune systems. To investigate the nature of this neuroimmunoendocrine interaction, the present study examined the impact of hormones, neurotransmitters, and lymphokines on basal and androgen-induced SC production by lacrimal gland acinar cells in vitro. Our results demonstrated that vasoactive intestinal peptide, the beta-adrenergic agonist, isoproterenol, PGE2, IL-1 alpha, IL-1 beta, and TNF-alpha significantly increased media SC levels in control or androgen-containing cell cultures. In contrast, the cholinergic agonist, carbachol, significantly decreased cellular SC output. These effects may be mediated through the agents' known capacity to alter intracellular cAMP levels. In support of this hypothesis, exposure of acinar cells to stimulators or analogues of cAMP resulted in a significant enhancement of SC production. Thus, these findings indicate that SC output in lacrimal tissue may be modulated by interactions between the endocrine, nervous and immune systems.


The stability of many-body systems.
We apply the pair interaction stability criteria of Fisher and Ruelle (1966 J. Math. Phys. 7 260) to establish the range of thermodynamic stability for a number of simple analytic potential forms used for condensed matter theory and modelling in the literature. We identify the ranges of potential parameters where, for a given potential, the system is thermodynamically stable, unstable and of uncertain stability. This was further explored by carrying out molecular dynamics simulations on the double Gaussian potential in the stable and unstable regimes. We show that, for example, the widely used exponential-6 and Born-Mayer-Huggins alkali halide potentials produce many-particle systems that are thermodynamically unstable.


IQGAP3 Overexpression Correlates With Poor Prognosis and Radiation Therapy Resistance in Breast Cancer.
Background: IQ motif-containing GTPase activating protein 3 (IQGAP3), the latest identified member of the IQGAP family, may act as a crucial factor in cancer development and progression; however, its clinical value in breast cancer remains unestablished. We explored the correlation between IQGAP3 expression profile and the clinicopathological features in breast cancer. Methods: IQGAP3 mRNA and protein levels were detected in breast cancer cell lines and tumor tissues by real-time PCR and western blotting and compared to the normal control groups. Protein expression of IQGAP3 was also evaluated immunohistochemically in archived paraffin-embedded specimens from 257 breast cancer patients, and the associations between IQGAP3 expression level, clinical characteristics, and prognosis were analyzed. We assessed the relationship between IQGAP3 expression and sensitivity to radiation therapy which was determined by subgroup analysis. Results: IQGAP3 was significantly upregulated in breast cancer cell lines and human tumor tissues at both the mRNA and protein level compared to controls. Additionally, high levels of IQGAP3 expression were detected in 110/257 (42.8%) of archived paraffin-embedded breast cancer specimens. High IQGAP3 expression level was significantly related to clinical stage (p = 0.001), T category (p = 0.002), N category (p = 0.001), locoregional recurrence (p = 0.002), distant metastasis (p = 0.001), and vital status (p = 0.001). Univariate and multivariate statistical analysis showed that IQGAP3 expression was an independent prognostic factor among all 257 breast cancer patients in our cohort (p = 0.003, p = 0.001). Subgroup analysis revealed IQGAP3 expression correlated with radioresistance and was also an independent predictor of radiotherapy outcome. Conclusion: Our findings suggest that high IQGAP3 expression predicts poor prognosis and radioresistance in breast cancer. Therefore, IQGAP3 may be a reliable prognostic biomarker in breast cancer and could be used to identify patients who may benefit from radiotherapy.


Stability of Hydrocortisone Preservative-Free Oral Solutions.
The physical and chemical stability of a preservative-free oral solution of hydrocortisone succinate was studied at different pH values and storage temperatures. Oral solutions of hydrocortisone 1 mg/mL were prepared by dissolving hydrocortisone succinate powder in citrate buffers at pH 4.0, 5.5, and 6.5, or with sterile water (pH 7.4) stored in amber glass vials. Three identical samples of the formulations were prepared and stored under refrigeration (3-7°C), ambient temperature (20-22°C) and high temperature (29-31°C). A 200-μL sample was withdrawn from each of the 3 samples immediately after preparation and at 1, 7, 14, 21, and 35 days. Samples were assayed in duplicate using stability-indicating liquid chromatography. Stability was determined by evaluating the percentage of the initial concentration remaining at each time point; stability was defined as the retention of at least 90% of the initial concentration of hydrocortisone succinate. At least 92% of the initial hydrocortisone succinate concentration in solutions pH 5.5, 6.5, and 7.4 remained throughout the 14-day study period under refrigeration. There were no detectable changes in color, odor, or pH and no visible microbial growth in these samples. In other storage conditions, hydrocortisone succinate was rapidly degraded. The hydrocortisone succinate preservative-free oral solutions at pH 5.5, 6.5, or 7.4 are chemically stable when stored under refrigeration for at least 14 days. They provide flexible and convenient dosage forms without any preservatives for pediatric patients.


Proflavin suppresses the growth of human osteosarcoma MG63 cells through apoptosis and autophagy.
Proflavin is one of the novel acridine derivatives that possess various pharmacological effects. Although numerous studies have been performed to investigate proflavin, its effects have not been investigated on the human osteosarcoma MG63 cell line. The core aim of the present study was to test the effects of proflavin on the viability of MG63 cells and the induction of apoptosis and autophagy in MG63 cells. The induction of apoptosis was examined by measuring the changes in the expression of the B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein mRNA and proteins. Apoptotic cell death was identified by the proteolytic cleavage of poly (adenosine diphosphate-ribose) polymerase and caspase-3 and caspase-9. In addition, the autophagic effects of proflavin were examined by the quantitation of the mRNA expression of autophagy protein 5 and Beclin 1, in addition to the identification of the accumulation of microtubule-associated protein 1 light chain 3-II. The present results revealed that proflavin inhibited the proliferation of MG63 cells in a dose-dependent manner. Proflavin-induced cell death was attributed to apoptosis and autophagy. Overall, the present results indicated that the antiseptic agent proflavin exerts anticancer potential through the synergistic activity of apoptosis and autophagy.


Comparison of Salivary Antioxidants and Oxidative Stress Status in Gestational Diabetes Mellitus and Healthy Pregnant Women.
One of the most common complications of pregnant women is gestational diabetes mellitus (GDM). Oxidative stress can play an important role in GDM. The aim of this study was to evaluate salivary antioxidants and oxidative stress markers in GDM. Twenty pregnant women with GDM and 20 healthy pregnant women with normal blood glucose test participated in this study. Five mL of unstimulated saliva samples were collected. Spectrophotometric assay was carried out for sialo-chemical analysis. Stata software was used for data analysis. The GDM group exhibited no significant difference in salivary total antioxidant capacity and malondialdehyde compared to the healthy control group. All antioxidants markers, the uric acid, total antioxidant, peroxidase and catalase, decreased in GDM group that the difference of peroxidase and catalase was statistically significant. All of oxidative stress markers, the salivary malondialdehyde, total oxidative stress and total thiol, increased in GDM group. GDM group exhibited significantly higher salivary total oxidative stress levels. Catalase level was significantly lower and total oxidative stress was significantly higher. These two markers might have significant importance and might exhibit early changes compared to other factors in GDM. Some salivary antioxidants might have diagnostic, prognostic or therapeutic implications in GDM. Other studies with large sample size on salivary and blood samples need to be done to confirm these properties and salivary samples using instead of blood samples in GDM biomarkers changes.


Body iron stores and glucose intolerance in premenopausal women: role of hyperandrogenism, insulin resistance, and genomic variants related to inflammation, oxidative stress, and iron metabolism.
OBJECTIVE Increased serum ferritin levels and iron stores may be involved in the development of abnormal glucose tolerance in women presenting with obesity and/or polycystic ovary syndrome (PCOS). We aimed to study the determinants of serum ferritin levels in premenopausal women among indexes of insulin resistance, adiposity, hyperandrogenism, and genotypes pertaining to inflammation, oxidative stress, and iron metabolism. RESEARCH DESIGN AND METHODS A total of 257 premenopausal women, classified depending on the presence or absence of PCOS, obesity, and/or abnormal glucose tolerance, underwent a complete metabolic evaluation, serum ferritin, haptoglobin, and C-reactive protein (CRP) measurements, and genotyping for proinflammatory and prooxidant variants and mutations in the HFE gene. RESULTS Serum ferritin concentrations were increased in women presenting with PCOS and/or abnormal glucose tolerance, independent of obesity. A stepwise multivariate linear regression analysis (R(2) = 0.18, P < 0.0001) retained menstrual dysfunction (beta = 0.14, P = 0.035), free testosterone (beta = 0.14, P = 0.052), insulin sensitivity index (beta = -0.12, P = 0.012), the His63Asp variant in HFE (beta = 0.16, P = 0.008), and abnormal glucose tolerance (beta = 0.15, P = 0.015) as significant predictors of the logarithm of ferritin levels, whereas CRP, haptoglobin, waist-to-hip ratio, or variants in the TNFalpha, TNFRSF1B, IL6, IL6ST, IL6Ralpha, PON1, and HFE Cys282Tyr mutation exerted no influence. CONCLUSIONS Androgen excess (partly because of hyperandrogenemia and partly because of menstrual dysfunction), insulin resistance, abnormal glucose tolerance, and the HFE His63Asp variant correlate with ferritin levels in premenopausal women.


Predicting Outcomes in Sporadic and Hereditary Medullary Thyroid Carcinoma over Two Decades.
Background: Medullary thyroid cancer (MTC) can be associated with significant morbidity and mortality in advanced cases. Hence, we aimed to identify factors at the time of MTC surgery that predict overall survival (OS), disease-specific survival (DSS), locoregional recurrence/persistence (LR), and distant metastases (DM). Methods: We performed a retrospective study of clinicopathologic, radiological, and laboratory data in MTC patients who underwent thyroidectomy at Mayo Clinic from January 1995 to December 2015. Results: We identified 163 patients (mean age 48.4 years, 48% males), 102 with sporadic MTC and 61 with hereditary disease (n = 46 multiple endocrine neoplasia [MEN] 2A, n = 3 MEN 2B, n = 12 familial MTC) with a median follow-up time of 5.5 years. On univariate analysis, age >55 years, male sex, DM at the time of surgery (M1), lateral neck lymph node (LN) involvement (N1b), gross extrathyroidal extension (ETE), American Joint Committee on Cancer (AJCC) stage 3/4, tumor size (T) 3/4, tumor size, and postoperative calcitonin (Ctn) and carcinoembryonic antigen (CEA) were significant predictors of worse OS and DSS. On multivariable analysis, both gross ETE (hazard ratio [HR] 4.62, 6.58) and M1 (HR 5.11, 10.45) remained significant predictors of worse OS as well as DSS, while age >55 years (HR 3.21), male sex (HR 2.42), and postoperative Ctn (HR 1.002 for every 100 pg/mL increase) were significant only for worse OS. On univariate analysis, male sex, M1, N1b, gross ETE, stage 3/4, T 3/4, tumor size, number of LNs involved, and postoperative Ctn were significant predictors of LR and DM; age >55 years was additionally significant for DM. On multivariable analysis, gross ETE (HR 3.16, 5.93) and N1b (HR 4.31, 4.64) remained significant predictors of LR and DM; ratio of resected/involved LN (HR 10.91) was additionally predictive for LR and postoperative Ctn (HR 1.003 for every 100 pg/mL increase) for DM. Conclusions: Disease burden at initial surgery, especially gross ETE, lateral neck LN involvement, and DM, as well as the biochemical response to surgery appear to be more important than demographic factors in terms of MTC prognosis. These findings highlight the importance of rigorous perioperative assessment to better predict MTC outcomes.


Synergistic action of two sources of avian growth factors on proliferative differentiation of chick embryonic hematopoietic cells.
During embryonic development, the components of the avian immune system undergo ontogeny in several distinct organs, including the bone marrow, spleen, thymus, and bursa of Fabricius. This process is regulated and controlled by the complex interactions of various cytokines and colony-stimulating factors (CSF). The objective was to examine the action of two different sources of hematopoietic growth factors, spleen-conditioned media (SCM) and chick embryo extract (CEE), on the proliferation of hematopoietic cells from various organs and on the differentiation of progenitor cells in semi-solid culture. Spleen and bone marrow cells obtained at Day 16 of incubation responded in a dose-dependent manner to the addition of SCM and CEE alone or in combination. No proliferative effect of SCM was observed on cells obtained from embryonic thymus or bursa. Clonal analysis of bone marrow and spleen cells suggested that CEE may contain the avian equivalents of stem cell factor, interleukin-3, granulocyte-macrophage CSF, granulocyte-CSF, and macrophage-CSF. Clonal analysis of SCM cultures suggested that in addition to myelomonocytic growth factor, which affects primarily macrophage-granulocyte lineages, a thrombocyte-CSF-like activity was also apparent. The SCM alone tended to act upon committed late progenitors. The combination of CEE and SCM amplified the size and the total number of colonies obtained and appeared to act synergistically upon progenitors with a high level of proliferative potential. This response on young progenitors was confirmed when cells were cultured in CEE and SCM prior to clonal analysis. These results document the presence of thrombocyte CSF in SCM and the effect of both CEE and SCM on the proliferative differentiation of avian embryonic hematopoietic progenitors.


[Hearing status of Robin sequence patients].
To determine wether Robin sequence is a risk factor for conductive and/or sensorineural hearing loss. 13 children with type III Robin sequence, admitted in our institution between 1984 and 1997 for tracheotomy were enrolled in this retrospective study. Each child had several audiological evaluations including subjective and objective methods adapted to their age. Subjective methods were audiometric tests, objective methods were Click Evoqued Otoacoustic Emissions and Auditory Brainstem Response. 3 children had normal hearing, 10 children had a conductive hearing loss caused by middle ear effusion, 4 patients had also a congenital permanent sensorineural evolutive hearing loss. Among the 4 infants with a sensorineural hearing loss, 2 had a polymalformative syndrome, and 2 had an isolated Robin sequence. Robin sequence is a risk factor for sensorineural hearing loss and conductive hearing loss. This hearing loss should be assessed as soon as possible after birth by otoscopy, click-evoqued otoacoustic emissions, auditory brainstem response and audiometric tests.


Scarce evidence of efficacy of hyperbaric oxygen therapy in necrotizing soft tissue infection: a systematic review.
Background: Necrotizing soft tissue infection (NSTI) is a rare and potentially life-threatening disease. Rapid surgical intervention, antibiotics and intensive care are the mainstay of treatment. Hyperbaric oxygen therapy (HBOT) is used as adjuvant therapy in some centres but there is a lack of research-based evidence of efficacy. Methods: Following the PRISMA guideline we conducted a systematic review on the efficacy of HBOT on NSTI with mortality as primary outcome. Through January 2019 major databases were searched and relevant literature assessed. The criteria for study inclusion were research of any design and any period of time comparing HBOT vs. non-HBOT in a population of NSTI-patients. Studies were analysed using the modified Delphi method and risk of bias in non-randomized studies - of interventions tool. Relative risk (RR) on mortality was calculated for each study individually. Results: A number of 1733 studies were identified through database search. Ultimately, 21 studies were included of which 19 were case series with a control group. The majority of the studies performed poor in quality assessment and all featured a high to critical risk of bias. The association of HBOT on mortality was generally reported as positive, however, the results should be considered with great scepticism. Conclusions: The evidence of HBOT in NSTI is poor and biased. There is a strong need for randomized controlled trials (RCTs) to shed light on a potential life-saving treatment.