The burden and epidemiology of hepatitis B and hepatitis D in Georgia: findings from the national seroprevalence survey.

OBJECTIVES: The burden of hepatitis B virus (HBV) and hepatitis D virus (HDV) infections is unknown in Georgia. This analysis describes the prevalence of hepatitis B and coinfection with HDV and the demographic characteristics and risk factors for persons with HBV infection in Georgia. STUDY DESIGN: This is a cross-sectional seroprevalence study. METHODS: A cross-sectional, nationwide survey to assess hepatitis B prevalence among the general adult Georgian population (age ≥18 years) was conducted in 2015. Demographic and risk behavior data were collected. Blood specimens were screened for anti-hepatitis B core total antibody (anti-HBc). Anti-HBc-positive specimens were tested for hepatitis B surface antigen (HBsAg). HBsAg-positive specimens were tested for HBV and HDV nucleic acid. Nationally weighted prevalence estimates and adjusted odds ratios (aORs) for potential risk factors were determined for anti-HBc and HBsAg positivity. RESULTS: The national prevalence of anti-HBc and HBsAg positivity among adults were 25.9% and 2.9%, respectively. Persons aged ≥70 years had the highest anti-HBc positivity (32.7%), but the lowest HBsAg positivity prevalence (1.3%). Anti-HBc positivity was associated with injection drug use (aOR = 2.34; 95% confidence interval [CI] = 1.46-3.74), receipt of a blood transfusion (aOR = 1.68; 95% CI = 1.32-2.15), and sex with a commercial sex worker (aOR = 1.46; 95% CI = 1.06-2.01). HBsAg positivity was associated with receipt of a blood transfusion (aOR = 2.72; 95% CI = 1.54-4.80) and past incarceration (aOR = 2.72; 95% CI = 1.25-5.93). Among HBsAg-positive persons, 0.9% (95% CI = 0.0-2.0) were HDV coinfected. CONCLUSIONS: Georgia has an intermediate to high burden of hepatitis B, and the prevalence of HDV coinfection among HBV-infected persons is low. Existing infrastructure for hepatitis C elimination could be leveraged to promote hepatitis B elimination.

Successful closure of intractable tracheoesophageal fistula using a combination of a modified silicon stent and metallic stents.

Although surgery is the usual management strategy for acquired benign tracheoesophageal fistula, sometimes this approach is contraindicated or the patient declines surgical management. In this report, we describe a case of a patient with tracheoesophageal fistula at the level of the carina due to bronchial arterial infusion chemotherapy. Closure could not be achieved in response to multiple treatment strategies, including airway stenting, esophageal stenting, occlusion with microcoils, or cyanoacrylate glue. We subsequently achieved closure of this fistula through the combination of a modified silicon stent and metallic stents.

Molecular characterisation of formalin-fixed paraffin-embedded (FFPE) breast tumour specimens using a custom 512-gene breast cancer bead array-based platform.

BACKGROUND: Formalin-fixed, paraffin-embedded (FFPE) tumour tissue represents an immense but mainly untapped resource with respect to molecular profiling. The DASL (cDNA-mediated Annealing, Selection, extension, and Ligation) assay is a recently described, RT-PCR-based, highly multiplexed high-throughput gene expression platform developed by Illumina specifically for fragmented RNA typically obtained from FFPE specimens, which enables expression profiling. In order to extend the utility of the DASL assay for breast cancer, we have custom designed and validated a 512-gene human breast cancer panel. METHODS: The RNA from FFPE breast tumour specimens were analysed using the DASL assay. Breast cancer subtype was defined from pathology immunohistochemical (IHC) staining. Differentially expressed genes between the IHC-defined subtypes were assessed by prediction analysis of microarrays (PAM) and then used in the analysis of two published data sets with clinical outcome data. RESULTS: Gene expression signatures on our custom breast cancer panel were very reproducible between replicates (average Pearson's R²=0.962) and the 152 genes common to both the standard cancer DASL panel (Illumina) and our breast cancer DASL panel were similarly expressed for samples run on both panels (average R²=0.877). Moreover, expression of ESR1, PGR and ERBB2 corresponded well with their respective pathology-defined IHC status. A 30-gene set indicative of IHC-defined breast cancer subtypes was found to segregate samples based on their subtype in our data sets and published data sets. Furthermore, several of these genes were significantly associated with overall survival (OS) and relapse-free survival (RFS) in these previously published data sets, indicating that they are biomarkers of the different breast cancer subtypes and the prognostic outcomes associated with these subtypes. CONCLUSION: We have demonstrated the ability to expression profile degraded RNA transcripts derived from FFPE tissues on the DASL platform. Importantly, we have identified a 30-biomarker gene set that can classify breast cancer into subtypes and have shown that a subset of these markers is prognostic of OS and RFS.

Prostate cancer genes associated with TMPRSS2-ERG gene fusion and prognostic of biochemical recurrence in multiple cohorts.

BACKGROUND: Recent studies have indicated that prostate cancer patients with the TMPRSS2-ERG gene fusion have a higher risk of recurrence. To identify markers associated with TMPRSS2-ERG fusion and prognostic of biochemical recurrence, we analysed a cohort of 139 men with prostate cancer for 502 molecular markers. METHODS: RNA from radical prostatectomy tumour specimens was analysed using cDNA-mediated, annealing, selection, extension and ligation (DASL) to determine mRNAs associated with TMPRSS2-ERG T1/E4 fusion and prognostic of biochemical recurrence. Differentially expressed mRNAs in T1/E4-positive tumours were determined using significance analysis of microarrays (false discovery rate (FDR) <5%). Univariate and multivariate Cox regression determined genes, gene signatures and clinical factors prognostic of recurrence (P-value <0.05, log-rank test). Analysis of two prostate microarray studies (GSE1065 and GSE8402) validated the findings. RESULTS: In the 139 patients from this study and from a 455-patient Swedish cohort, 15 genes in common were differentially regulated in T1/E4 fusion-positive tumours (FDR <0.05). The most significant mRNAs in both cohorts coded ERG. Nine genes were found prognostic of recurrence in this study and in a 596-patient Minnesota cohort. A molecular recurrence score was significant in prognosticating recurrence (P-value 0.000167) and remained significant in multivariate analysis of a mixed clinical model considering Gleason score and TMPRSS2-ERG fusion status. CONCLUSIONS: TMPRSS2-ERG T1/E4 fusion-positive tumours had differentially regulated mRNAs observed in multiple studies, the most significant one coded for ERG. Several mRNAs were consistently associated with biochemical recurrence and have potential clinical utility but will require further validation for successful translation.

Intratracheal administration of anaphylatoxin C5a potentiates antigen-induced pulmonary reactions through the prolonged production of cysteinyl-leukotrienes.

The effects of intratracheal administration of anaphylatoxin C5a on airway inflammation have been studied using two sources of material, zymosan activated serum (ZAS) and purified rat C5a des Arg, in order to determine the influence of complement activation on allergic airway disorders.The intratracheal administration of ovalbumin (OA) to OA-sensitized rats generated two phases of airway response, an immediate airway response (IAR) occurring within 15 min and a late airway response (LAR) beginning 4-6 h after the allergen challenge. The simultaneous administration of ZAS and OA into the trachea generated a sustained elevation of airway resistance (Raw) following IAR, while that of OA or ZAS alone resulted in Raw returning nearly to the baseline just after the IAR. The elevation of Raw after the combined challenge of OA and ZAS was significantly inhibited by pretreatment with a CysLT(1) receptor antagonist, pranlukast 30 mg/kg, but after that OA or ZAS alone was not significantly inhibited by pranlukast. The intratracheal administration of purified C5a produced an airway response that was similar to, but higher than, that evoked by ZAS. Namely, the challenge with OA plus C5a resulted in a higher IAR than OA plus ZAS, and also caused an early animal death up to 6 h, which was prevented by a combined pretreatment with pranlukast and the H(1) receptor antagonist, diphenhydramine.A histological examination at 6 h after the OA challenge identified an infiltration of inflammatory cells into the bronchial submucosal tissue, with a predominance of neutrophils and fewer eosinophils. On the other hand, a histological examination after the OA and ZAS challenge showed more severe infiltration of granulocytes into the bronchial submucosal tissue than that with OA or ZAS alone. The challenge with OA plus C5a was associated with severe perivascular leakage in the lungs and the combined pretreatment with both the antagonists led to a marked reduction in perivascular leakage. The quantitation of N-acetyl-leukotriene E(4) (N-Ac-LTE(4)), a major metabolite of cysteinyl-leukotrienes (cysLTs), in the bile indicated a significantly greater and longer excretion of cysLTs, from 1 to 6 h after the combined challenge, than that after either OA or ZAS alone. This suggested a prolonged generation of cysLTs in the lung by the combined challenge.In conclusion, our findings suggest that anaphylatoxin C5a may mediate the airway inflammatory response induced by a specific antigen challenge partly through a prolonged production of cysLTs and the release of histamine.

Synergistic effects of pranlukast and leukotriene B4 receptor antagonist on antigen-induced pulmonary reaction.

We now attempted to differentiate effects of cysteinyl-leukotrienes and leukotriene B4 on antigen-induced pulmonary reaction by using a selective leukotriene D4/E4 (CysLT1) receptor antagonist and a selective LTB4 (BLT) receptor antagonist in rats. An intratracheal challenge with ovalbumin to Brown-Norway rats actively sensitized with ovalbumin produced two phases of airway responses which were estimated based on airway resistance, the immediate-type airway response within 30 min, and the delayed-type airway response beginning from 4 to 6 h after the challenge. Pretreatment of the rats with a CysLT1 receptor antagonist (pranlukast) failed to reduce the elevation of airway resistance, and pretreatment with a BLT receptor antagonist (ONO-4057; 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]- oxyphenoxy] valeric acid) also produced no decrease. In contrast, combined pretreatment of the rats with pranlukast and ONO-4057 did not reduce the amplitude of the immediate-type airway response, but did allow the elevated airway resistance to return to its baseline level and also significantly inhibited the delayed-type airway response. Histological examination at 6 h after ovalbumin challenge showed infiltration of inflammatory cells with a predominance of neutrophils and scattered eosinophils in the bronchial submucosa. While pretreatment with neither pranlukast nor with ONO-4057 inhibited the infiltration of inflammatory cells in the bronchial submucosa, pretreatment with the two antagonists combined significantly inhibited the infiltration of granulocytes into the bronchial submucosa. On the contrary, intratracheal administration of either leukotriene D4 or leukotriene B4 up to 10 microg resulted in the infiltration of granulocytes into the bronchial submucosa, but no synergism for the infiltration of granulocytes was observed after combined administration. These results suggest that leukotriene B4 appears to play a significant role in the antigen-induced pulmonary reaction in association with cysteinyl-leukotrienes. Accordingly, the combined antagonism at the CysLT1 receptor and BLT receptor may be a useful intervention for the treatment of bronchial asthma.