Temperature inhomogeneities cause the abundance discrepancy in H II regions.

H II regions are ionized nebulae surrounding massive stars. They exhibit a wealth of emission lines that form the basis for estimation of chemical composition. Heavy elements regulate the cooling of interstellar gas, and are essential to the understanding of several phenomena such as nucleosynthesis, star formation and chemical evolution1,2. For over 80 years3, however, a discrepancy exists of a factor of around two between heavy-element abundances derived from collisionally excited lines and those from the weaker recombination lines, which has thrown our absolute abundance determinations into doubt4,5. Here we report observational evidence that there are temperature inhomogeneities within the gas, quantified by t2 (ref. 6). These inhomogeneities affect only highly ionized gas and cause the abundance discrepancy problem. Metallicity determinations based on collisionally excited lines must be revised because these may be severely underestimated, especially in regions of lower metallicity such as those recently observed with the James Webb Space Telescope in high-z galaxies7-9. We present new empirical relations for estimation of temperature and metallicity, critical for a robust interpretation of the chemical composition of the Universe over cosmic time.

Next-generation sequencing clarified why first-line treatment with osimertinib was ineffective in an autopsied case of EGFR-mutated lung squamous cell carcinoma.

Epidermal growth factor receptor (EGFR)-mutated squamous cell carcinoma (SCC) is less common than adenocarcinoma. The third-generation EGFR-tyrosine kinase inhibitor, osimertinib, is effective in EGFR-mutated lung adenocarcinoma, but its efficacy in EGFR-mutated lung SCC is unclear. The patient was an 83-year-old male. He was diagnosed with SCC of the lung, and molecular analysis revealed that the tumor was positive for EGFR exon19 deletion. He was treated with osimertinib 80 mg/day. No adverse events were observed, but after 18 days of therapy, he complained of dyspnea, and a computed tomography scan showed enlarged lung cancer. The case was categorized as a progressive disease. The patient died 3 weeks later. The autopsy findings confirmed the diagnosis of lung SCC, with morphology and immunohistochemical staining identical to the tumor obtained by bronchoscopy. Next-generation sequencing showed the presence of TP53 R158L, CDK6, and KRAS amplifications. The current case report shows that next-generation sequencing can explain why osimertinib is ineffective in EGFR-mutated SCC.

Patients' view of the differences in topical creams for radiation dermatitis prevention. A pilot study of cosmetic properties.

AIM: To investigate the feasibility of including patients' reports on the cosmetic properties of topical formulations for acute radiation dermatitis (ARD). BACKGROUND: No topical agent tested for acute radiation dermatitis (ARD) has proven to be better than any other, all achieving similar objective outcomes. No clear guidelines have therefore been established in clinics. Because the vehicle for such creams has shown to be an important factor in patient adherence to treatments in other dermatological diseases, patients' opinions are evaluated. MATERIAL AND METHODS: Seventy breast cancer patients referred for postoperative radiotherapy after conservative surgery were enrolled. Patients were assigned to use one of the 7 topical agents that are most-commonly used in the prevention of ARD. Patients' reports were assessed using continuous visual analogue scales (VAS), objective signs and symptoms produced by ARD, and were rated using the RTOG and RISRAS scales. RESULTS: The creams tested differed in their cosmetic properties significantly (p = 0.044). The performance of the agent, their absorption and any residue left over were also significantly different (p = 0.022, 0.014 and 0.02, respectively). CONCLUSIONS: Topical agents for preventive ARD are reported by patients to show different cosmetic properties. Cosmetic properties are important when choosing topical agents for ARD prevention. Recommending those with better cosmetic profiles would improve patient adherence to treatments.

Effects of sugar-sweetened beverage intake on the development of type 2 diabetes mellitus in subjects with impaired glucose tolerance: the Mihama diabetes prevention study.

In Japan, the incidence of type 2 diabetes mellitus (T2DM) is increasing for several reasons, including increased consumption of sugar-sweetened beverages (SSBs). However, whether SSBs cause T2DM by excess of energy production resulting in obesity remains unclear. Therefore, the present study was designed to evaluate the effects of SSB intake on the development of T2DM in subjects with impaired glucose tolerance (IGT). Ninety-three subjects (30 males and 63 females) with IGT aged 40-69 y and residing in the Mihama district (southern Mie Prefecture, Japan) were included in the study. The mean observational period was 3.6 y. All subjects underwent the 75-g oral glucose tolerance test (OGTT) and completed a lifestyle questionnaire survey related to SSB intake. OGTT results and SSB intake were evaluated before and after the observational period. In addition, the correlation between SSB intake and development of T2DM was investigated. Of the 93 subjects, 20 (21.5%) developed T2DM (T2DM group) and demonstrated a significantly high SSB intake compared with the group that did not develop the disease (non-T2DM group). The odds ratio for the incidence of T2DM based on SSB intake was 3.26 (95% confidence interval, 1.17-9.06). The body mass index (BMI; kg/m(2)) and the homeostasis model assessment for insulin resistance (HOMA-R) values was significantly higher in the T2DM group than in the non-T2DM group, while the insulinogenic indices were significantly lower in the former than in the latter group. The sum of insulin secretion levels during OGTT was not significantly different between groups. SSB intake correlated with the predisposition for developing T2DM, possibly by influencing body weight, insulin resistance, and the ability of the pancreatic beta cells to effectively compensate for the insulin resistance.

Evaluation of basophil CD203c as a predictor of carboplatin-related hypersensitivity reaction in patients with gynecologic cancer.

The incidence of hypersensitivity reaction (HR) to carboplatin has been reported to increase after repeated use of the drug. However, a reliable ex vivo test to predict HR to carboplatin is not currently available. We evaluated the clinical usefulness of measuring basophil CD203c to predict carboplatin-related HR in this prospective case-control study conducted at Mie University Hospital between October 2009 and September 2010. Eleven patients had history of carboplatin-related HR within the past 3 years, and 19 had no history of HR after receiving more than 5 courses of carboplatin therapy. Six of these 19 patients developed carboplatin-related HR during the study period. The CD203c+ basophils (%) and the mean fluorescence intensity (MFI) were analyzed on a flow cytometer and compared between patients with and without HR. Changes in the CD203c expression on basophils before and after HR were also assessed in patients who developed HR during the study period. The median CD203c+ basophils (%) and ΔMFI after 30-min exposure to 50 µg/mL carboplatin were significantly higher in patients with HR (3.5% and ΔMFI 9.0) compared with those without (2.2% and ΔMFI 0.4) (p<0.05). In particular, these values were significantly higher in patients with grade 4 anaphylaxis (10.6% and ΔMFI 22.0). All five patients who developed grade 2-4 anaphylaxis during the study period had high CD203c+ basophils (%) and/or increased ΔMFI on the day before HR. The results suggest that basophil CD203c may be a promising biomarker for the prediction of severe carboplatin-related anaphylaxis.

Effect of suppressor of cytokine signaling on hepcidin production in hepatitis C virus replicon cells.

AIM: Hepcidin is a key regulator of systemic iron metabolism and its expression is modulated by hepatitis C virus (HCV) infection. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 act as negative regulators of the Jak/signal transducers and activators of transcription signaling pathway. In this study, we investigated how HCV infection modulates SOCS-1 and SOCS-3 production and how these SOCS proteins affect hepcidin production. METHODS: The effects of SOCS-1 and SOCS-3 on hepcidin production were investigated using a complete genome, HCV replicon system. RESULTS: Unexpectedly, basal expression levels of hepcidin (HAMP) mRNA and the bioactive form of hepcidin protein, hepcidin-25, were significantly higher in replicon cells. Regardless of HCV infection, STAT3 was activated in response to interleukin-6 (IL-6), but this activation was greater in replicon cells than in cured cells. Basal expression of the SOCS-3 protein was enhanced, but basal expression of SOCS-1 protein was reduced, in replicon cells. Expression of SOCS-3 increased dramatically in response to IL-6 stimulation but expression of SOCS-1 was not induced by IL-6. Interestingly, silencing of SOCS-1 and SOCS-3 gene expression enhanced STAT3 activation and HAMP gene expression. In addition, overexpression of SOCS-1 protein strongly suppressed STAT3 activation and HAMP gene expression. CONCLUSIONS: This in vitro study shows that SOCS-3 expression was enhanced but SOCS-1 expression was reduced by HCV infection. The upregulation of hepcidin induced by IL-6 was found to be negatively regulated by SOCS-1 and SOCS-3. The modulation of SOCS1 and SOCS3 in HCV-infected hepatocytes may explain, at least in part, the relative shortage of hepcidin production in CH-C.

Prevalencia de infección por VIH/SIDA en hombres que tienen sexo con hombres en Bucaramanga, Colombia / Prevalence of infection by HIV/AIDS in men who have sex with men in Bucaramanga, Colombia

Introducción: La infección por VIH/SIDA continúa siendo un reto para la salud pública en términos de su prevención y control. El objetivo del estudio fue determinar la prevalencia de VIH/SIDA en el grupo de hombres que tienen sexo con hombres y los factores comportamentales que favorecen su transmisión. Materiales y métodos: Estudio descriptivo trasversal con muestreo no probabilístico en sitios de encuentro frecuentados por esta población y en la cárcel. Se aplicó una encuesta estructurada y se realizó toma de muestra sanguínea anónima ligada por códigos para el diagnóstico de infección por VIH. Resultados: Se encuestaron 336 hombres en 9 sitios con un promedio de 27,6 +/- 8,4 años. El 92,4% tenía estudios de secundaria o superiores, el 6% declaró vivir con pareja femenina y el 19,9% con pareja masculina estable. El 54,6% refirió que nunca o solo de forma ocasional utiliza preservativo con sus parejas sexuales. El 43% de los encuestados se había realizado prueba para VIH/SIDA y de éstos el 20,1% (29 hombres) ya tenían diagnóstico confirmatorio. Entre los 150 hombres tamizados se diagnosticaron 8 nuevos casos obteniendo una prevalencia general de 11,01%. Conclusiones: Los hallazgos indican que la epidemia en el municipio corresponde a una de tipo concentrada. Aunque actualmente se recomiendan estrategias de prevención dirigidas a población general, en el municipio se recomienda continuar actividades específicas en este grupo de población que aún presenta conductas de riesgo para la trasmisión del VIH.

Introduction: Prevention and control of infection by HIV/AIDS is a challenge to public health. The aim of the study was to determine the prevalence of HIV/AIDS in men who have sex with men and the behavioral factors related with transmission in Bucaramanga, Colombia. Materials and Methods: Transversal descriptive serological survey with non probabilistic sampling in meeting and reclusion places. A structured interview and serum sample linked by codes was applied. Results: 336 men with 27.6 +/- 8.4 age mean were studied in nine places. A 92.4% had secondary or upper education level. 6% were living with a female partner and 19.9% with a male partner. The 54.6% reported that never or occasionally used condom with their partners. The 43% of men had been tested for HIV and 20.1% of them (29 men) were already diagnosed as serum positive. Amongst 150 men screened, 8 new cases were diagnosed reaching 11.01% prevalence in general. Conclusions: Results show there is a concentrated epidemic HIV in Bucaramanga. In spite prevention strategies for general population currently carried out, it is recommended to continue specific strategies for this population group to control risk behavior in the HIV transmission.

Unidentified virus-like particles are detected in plasmas with elevated ALT levels: are they significant of etiological agent(s) of non-B, non-C hepatitis?

GB virus C (GBV-C) and hepatitis G virus (HGV) have been proposed as new viruses etiologically implicated in non-B, non-C hepatitis, but the morphology of these particular virus particles is still unknown, and most cases of non-A to E hepatitis do not relate to their infections. We tried to visualize virus-like particles (VLPs) in plasma samples from hepatitis B surface antigen- and antibody to hepatitis C virus (HCV)-negative blood donors with elevated alanine aminotransferase (ALT), and examined the association of the virus-like particles and the genomes of parenterally transmissible GBV-C/HGV. Twenty-three plasma samples, 13 with elevated ALT levels and 10 with normal ALT values, from blood donors without infections of hepatitis B virus (HBV) and HCV, were subjected to a 20%-60% sucrose density gradient centrifugation, and virus-like particles were observed by electron microscopy. GBV-C/HGV RNAs in the plasmas were tested. Virus-like particles were found in the fractions with densities of 1.15-1.16 g/ml from 12 of 13 (92.3%) plasmas with elevated ALT levels and 1 of 10 (10%) normal controls. The ultrastructural morphology of visualized VLPs was pleomorphic in size and appearance; the majority of the VLPs were 50- to 80-nm spherical particles with a 35- to 45-nm inner core and 9- to 12-nm-long surface spike-like projections. Rodlike VLPs 50-70 nm in diameter with a length of 110-160 nm were also observed in the same samples. The incidence of detection of the circulating VLPs was significantly (P < 0.001) related to elevated ALT levels, but GBV-C/HGV RNAs were detected in none of the plasmas containing the virus-like particles. Spherical VLPs are detected in HBV- and HCV-negative plasmas significantly correlated with the elevation of ALT, suggesting that they are implicated in non-B, non-C hepatitis.

Morphological identification of hepatitis C virus E1 and E2 envelope glycoproteins on the virion surface using immunogold electron microscopy.

It is known that hepatitis C virus (HCV) particles are spherical, 55-65 nm particles with fine surface projections of about 6 nm in length and with a 30-35 nm inner core. We have reported that free HCV particles labeled with gold particles specific to the HCV E1 glycoprotein are located in 1.14-1.16 g/ml fractions from plasma samples with high HCV RNA titers after sucrose density gradient centrifugation. However, the morphology of the HCV E2 glycoprotein on the virion has not yet been elucidated. To visualize HCV E2 localization on the virion, we used the same plasma samples where HCV particles were clearly shown. An indirect immunogold electron microscopic study was carried out using monoclonal and polyclonal anti-HCV E2 antibodies. HCV-like particles specifically reacted with the anti-HCV E2 antibodies. Moreover, to evaluate the localization of the HCV E1 and E2 glycoproteins on the virion surface, an immunogold electron microscopic study using double labeling with anti-HCV E1 antibodies and anti-HCV E2 antibodies was also performed. These particles also specifically reacted with both anti-E1 and E2 antibodies. This is the first report showing the presence of both HCV E1 and E2 glycoproteins on HCV virion surface in human plasma samples.

The ultrastructural morphology of native hepatitis B virus.

Cell lines (2.2.15 cells) capable of supporting the replication of hepatitis B virus (HBV) DNA and intact viral particles have been established by HBV DNA transfection into HepG2 cells. The purpose of this study was to determine the ultrastructural morphology of native HBV particles without purification in the culture supernatants and in sera from patients. Electron microscopy (EM) and immunogold EM of the samples were carried out using polyclonal and monoclonal anti-hepatitis B surface antigen antibodies. HBV particles in the purified samples from the culture supernatants by density-gradient centrifugation were examined to compare the morphology with that of unpurified samples. EM and immunogold EM studies demonstrated the presence of Dane particles (41.8 nm in diameter), cobra-shaped (head diameter, 42.4 nm), and horn-shaped (head diameter, 43.5 nm) particles in the culture supernatants and in the sera from two patients. The tail of the cobra-like particles had a diameter of 21.0 nm and a length of 214 nm. The hornlike particles had a long branch 20.1 nm in diameter with a length of 189 nm, and a short branch 21.4 nm in diameter with a length of 112 nm. The ratio of Dane particles and cobra- and horn-shaped particles in the supernatants was 5 : 4 : 1. After ultracentrifugation, the cobra- and horn-shaped particles completely disappeared; there were only Dane particles together with spheres of 22 nm and filaments. In conclusion, this study showed for the first time that the native replicative form of HBV is cobra- and horn-shaped.

Vacuolating cytotoxin A is associated with increased thrombin generation in gastric mucosa.

BACKGROUND: Activation of the coagulation system is a critical response for both the repair of tissue injury and the host defense against microbial pathogens. Activation of the coagulation cascade culminates with the generation of thrombin. In vitro studies have shown that thrombin protects gastric epithelial cells from injury. The present study was undertaken to assess in vivo the relationship between gastric intramucosal generation of thrombin and Helicobacter pylori infection. MATERIALS AND METHODS: This study comprised 59 patients with gastroduodenal disorders. There were 27 patients with H. pylori infection (Hp+), 14 without it (Hp-), and 18 patients with cured H. pylori infection (Hp c). The gastric intramucosal concentrations of thrombin-antithrombin complex (TAT), epidermal growth factor (EGF), prostaglandin E2 (PGE2), and vacuolating cytotoxin A (VacA) were measured by specific immunoassays. RESULTS: The level of TAT was significantly increased in patients with Hp+ compared to Hp- and Hp c. The levels of TAT, EGF and PGE2 were higher in VacA (+) patients than in those with VacA (-). VacA induced significant expression of tissue factor in gastric epithelial cells in vitro. The gastric intramucosal level of VacA antigen was proportionally and significantly correlated with TAT, EGF and PGE2 in Hp+ patients. The level of TAT was proportionally and significantly correlated with EGF in Hp+ patients but not in Hp- and HP c patients. CONCLUSIONS: These results showed that VacA produced by H. pylori is associated with increased thrombin generation, and that thrombin may play a protective role in H. pylori-associated gastroduodenal disorders.

Increased circulating levels of thrombin-activatable fibrinolysis inhibitor in lung cancer patients.

Impairment of fibrinolytic function plays an important role in the mechanism of thrombotic disorders in cancer patients. This study assessed the circulating level of thrombin-activatable fibrinolysis inhibitor in patients with lung cancer and its expression by several lung cancer cell lines. The plasma concentrations of thrombin-activatable fibrinolysis inhibitor were significantly increased in lung cancer patients compared to healthy subjects. The concentration of thrombin-activatable fibrinolysis inhibitor was particularly higher in patients with small cell carcinoma compared to those with adenocarcinoma or squamous cell carcinoma, and in cancer patients that responded to chemotherapy compared to non-responders. In vitro studies showed more expression of thrombin-activatable fibrinolysis inhibitor in small cell carcinoma than in adenocarcinoma cell lines and more expression in lung cancer cell lines sensitive to anti-cancer agents than in resistant cell lines. This study suggests that thrombin-activatable fibrinolysis inhibitor, in part secreted from lung cancer cells, may play a role in the pathogenesis of thrombotic disorders in lung cancer patients.

Protective role of activated protein C in lung and airway remodeling.

Recent studies have implicated the protein C pathway in the mechanism of lung and airway remodeling. The effector enzyme of this pathway is activated protein C (APC). Clinical studies have shown that APC generation is decreased in patients with lung injury and airway inflammation and that this decrease is associated with increased collagen deposition in the lung. In line with these findings, low APC activity has been observed in the bronchoalveolar lavage fluid in animal models of lung injury and airway inflammation. Treatment with APC significantly inhibits the development of lung fibrosis in bleomycin-induced lung injury and the development of airway hyperresponsiveness and allergic inflammation in ovalbumin-induced bronchial asthma. APC may protect the lung from fibrosis and airway remodeling by suppressing activation of coagulation, decreasing the secretion of inflammatory cytokines and platelet-derived growth factor, and promoting fibrinolysis. APC inhibits the expression of cytokines by decreasing the nuclear translocation of signal transducer and activator of transcription 6 and the nuclear factor-kappaB family of transcription factors. In view of its multiple functions, APC constitutes a potential therapeutic agent for inflammatory disorders of the lung and airways.

Thrombin-activatable fibrinolysis inhibitor and protein C inhibitor in interstitial lung disease.

Intraalveolar activation of the coagulation system due to reduced fibrinolytic function plays a critical role in the pathogenesis of interstitial lung disease. Recently, a new potent inhibitor of fibrinolysis, thrombin-activatable fibrinolysis inhibitor, has been isolated and characterized from human plasma. This study evaluated the levels of thrombin-activatable fibrinolysis inhibitor and protein C inhibitor, another suppressor of fibrinolysis, in the bronchoalveolar lavage fluid from patients with interstitial lung disease. There were 82 patients with interstitial lung disease and 8 normal subjects. The bronchoalveolar lavage fluid levels of thrombin-activatable fibrinolysis inhibitor and protein C inhibitor were significantly higher in all patients with interstitial lung disease than in normal subjects. Both inhibitors of fibrinolysis were significantly and inversely correlated with fibrinolytic activity in all patients. The levels of thrombin-activatable fibrinolysis inhibitor were significantly correlated with those of protein C inhibitor, thrombin-antithrombin complex, and monocyte chemoattractant protein-1. Reverse transcriptase-polymerase chain reaction showed that alveolar macrophages isolated from patients with interstitial lung disease as well as immortalized lung epithelial cell lines express thrombin-activatable fibrinolysis inhibitor antigen. Overall, these findings suggest that thrombin-activatable fibrinolysis inhibitor and protein C inhibitor may play important roles in the mechanism of intraalveolar hypofibrinolysis associated with interstitial lung diseases.