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BACKGROUND AND STUDY AIMS: Endoscopic biopsies have a low sensitivity for diagnosing malignant bile duct strictures. Tumor markers detected by mucin staining and immunohistochemistry may help to determine the malignancy of a biopsy specimen where histologic evaluation alone is nondiagnostic. PATIENTS AND METHODS: 61 patients who underwent forceps biopsies were retrospectively identified, yielding 49 and 40 biopsy specimens for strictures finally diagnosed as benign and malignant, respectively. Biopsy specimens were histologically evaluated and stained for p53, Ki-67, carcinoembryonic antigen (CEA), CA19-9, CAM5.2, and presence of intracytoplasmic lumina (ICL). Sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratios (PLR and NLR) were calculated to evaluate the performance of each test. RESULTS: Histology alone provided sensitivity and specificity of 53 % and 100 %. Addition of ICL or CAM5.2 increased sensitivity to 73 % or 60 %, respectively, and provided excellent specificity, PPV, and PLR (ICL, 98 %, 97 %, and 36; CAM5.2, 100 %, 100 %, and infinite). Both stains in combination increased the sensitivity to 75 %. Staining for Ki-67, p53, CEA, and CA19-9 increased the sensitivity to detect malignancy (range 60 % to 83 %), but significantly reduced the specificity, PPV and PLR (ranges 73 % to 90 %, 72 % to 86 %, and 3 to 7, respectively). Markers in all combinations performed poorly as a negative test (NPV 69 % to 87 %, and NLR 0.19 to 0.55). CONCLUSIONS: Staining for tumor markers ICL and CAM5.2 can improve the diagnostic value of endoscopic biopsies, and may change the course of management for patients with indeterminate histological findings.

Background Treatment of latent tuberculosis infection with isoniazid (INH) or rifampin (RIF) is controversial in liver transplant candidates due to potential hepatotoxicity. In this study, treatment of latent tuberculosis during transplant candidacy period is explored, and relevant literature is reviewed. Methods Liver transplant candidates with latent tuberculosis infection by positive tuberculin skin test (>5 mm) were prospectively enrolled and treated with 9 months of INH or 4 months of RIF, and were monitored monthly for their liver enzyme profiles, adverse effects, compliance, and completion rate. Results Four of nine patients with INH had asymptomatic, mild elevations of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) versus none of five patients in the RIF group. Two cases of elevations were attributed to INH. Two other cases were attributed to alcoholism or active chronic hepatitis B virus infection. Only one patient in the INH group experienced symptoms possibly attributed to INH hepatotoxicity. Compliance was 100% per patient reporting. Completion rates were 79% for INH and 100% for RIF. No fulminant hepatic failure or death was observed. Conclusion Treatment of latent tuberculosis in liver transplant patients during their candidacy with INH or RIF appears to be a safe, viable option, if carefully monitored for adverse effects and liver enzymes.

To characterize tissue destruction after CO(2) laser-ablation of the vocal cords with the use of optical coherence tomography (OCT).OCT was used to image fresh porcine vocal cords after laser ablation. OCT and histology estimates of the ablation crater dimensions and the depth of thermal injury were obtained.The vocal cord substructures up to 2.29 mm in depth at 10 microm resolution, and the thermal disruption after laser ablation were identified by OCT. OCT and histology estimates of the lesion dimensions showed no significant differences. Crater depth is directly proportional to laser power, whereas crater width and the zone of thermal injury appear to be unrelated to laser power.OCT may be used to accurately characterize the native states and the laser-induced thermal injury of laryngeal mucosa, within the inherent limitation in its depth of penetration. OCT may be a useful diagnostic and monitoring tool in an otolaryngology practice.

Adenovirus vectors are increasingly being used for genetic vaccination and may prove highly suitable for intervention in different pathological conditions due to their capacity to generate high level, transient gene expression. In this study, we report the use of a recombinant adenovirus vector to induce regulatory responses for the prevention of autoimmune diseases through transient expression of a TCR β-chain. Immunization of B10.PL mice with a recombinant adenovirus expressing the TCR Vβ8.2 chain (Ad5E1 mVβ8.2), resulted in induction of regulatory type 1 CD4 T cells, directed against the framework region 3 determinant within the B5 peptide (aa 76–101) of the Vβ8.2 chain. This determinant is readily processed and displayed in an I-Au context, on ambient APC. Transient genetic delivery of the TCR Vβ8.2 chain protected mice from Ag-induced experimental autoimmune encephalomyelitis. However, when the Ad5E1 mVβ8.2 vector was coadministered with either an IL-4- or IL-10-expressing vector, regulation was disrupted and disease was exacerbated. These results highlight the importance of the Th1-like cytokine requirement necessary for the generation and activity of effective regulatory T cells in this model of experimental autoimmune encephalomyelitis.

Natural killer (NK) T cells recognize lipid antigens in the context of the major histocompatibility complex (MHC) class 1-like molecule CD1 and rapidly secrete large amounts of the cytokines interferon (IFN)-gamma and interleukin (IL)-4 upon T cell receptor (TCR) engagement. We have asked whether NK T cell activation influences adaptive T cell responses to myelin antigens and their ability to cause experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. While simultaneous activation of NK T cells with the glycolipid alpha-galactosylceramide (alpha-GalCer) and myelin-reactive T cells potentiates EAE in B10.PL mice, prior activation of NK T cells protects against disease. Exacerbation of EAE is mediated by an enhanced T helper type 1 (Th1) response to myelin basic protein and is lost in mice deficient in IFN-gamma. Protection is mediated by immune deviation of the anti-myelin basic protein (MBP) response and is dependent upon the secretion of IL-4. The modulatory effect of alpha-GalCer requires the CD1d antigen presentation pathway and is dependent upon the nature of the NK T cell response in B10.PL or C57BL/6 mice. Because CD1 molecules are nonpolymorphic and remarkably conserved among different species, modulation of NK T cell activation represents a target for intervention in T cell-mediated autoimmune diseases.

The T1 domain, a highly conserved cytoplasmic portion at the N-terminus of the voltage-dependent K+ channel (Kv) alpha-subunit, is responsible for driving and regulating the tetramerization of the alpha-subunits. Here we report the identification of a set of mutations in the T1 domain that alter the gating properties of the Kv channel. Two mutants produce a leftward shift in the activation curve and slow the channel closing rate while a third mutation produces a rightward shift in the activation curve and speeds the channel closing rate. We have determined the crystal structures of T1 domains containing these mutations. Both of the leftward shifting mutants produce similar conformational changes in the putative membrane facing surface of the T1 domain. These results suggest that the structure of the T1 domain in this region is tightly coupled to the channel's gating states.

AIM: To investigate whether tumor marker staining can improve the sensitivity of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) to diagnose pancreatic malignancy. METHODS: Patients who underwent EUS-FNA were retrospectively identified. Each EUS-FNA specimen was evaluated by routine cytology and stained for tumor markers p53, Ki-67, carcinoembryonic antigen (CEA) and CA19-9. Sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratios (PLR and NLR) were calculated in order to evaluate the performance of each test to detect malignancy. RESULTS: Sixty-one specimens had complete sets of stains, yielding 49 and 12 specimens from pancreatic adenocarcinomas and benign pancreatic lesions due to pancreatitis, respectively. Cytology alone had sensitivity and specificity of 41% and 100% to detect malignancy, respectively. In 46% of the specimens, routine cytology alone was deemed indeterminate. The addition of either p53 or Ki-67 increased the sensitivity to 51% and 53%, respectively, with perfect specificity, PPV and PLR (100%, 100% and infinite). Both stains in combination increased the sensitivity to 57%. While additional staining with CEA and CA19-9 further increased the sensitivity to 86%, the specificity, PPV and PLR were significantly reduced (at minimum 42%, 84% and 1, respectively). Markers in all combinations performed poorly as a negative test (NPV 26% to 47%, and NLR 0.27 and 0.70). CONCLUSION: Immunohistochemical staining for p53 and Ki-67 can improve the sensitivity of EUS-FNA to diagnose pancreatic adenocarcinoma.

Here we briefly review our understanding of the immune response to myelin-derived glycolipids during an inflammatory autoimmune response in the central nervous system (CNS). We focus primarily on the recognition of the self-glycolipid sulfatide by a distinct population of non-invariant NK T cells. The results of studies we have obtained so far in investigating the presentation of sulfatide by CNS-resident cells including microglia and their interactions with T cells indicate that this pathway might be successfully targeted for the treatment of autoimmune demyelination in multiple sclerosis.

We present a unique case of a neuroendocrine syndrome in a patient with Stage IV vaginal melanoma metastatic to the liver that was successfully palliated with octreotide. Similar to the carcinoid syndrome, the patient exhibited chronic diaphoresis, intermittent low-grade fevers, dizziness, nausea with vomiting, and hot flashes. The symptoms on admission of acute hypotension, acute exacerbation of abdominal pains, and intractable nausea with vomiting suggested a neuroendocrine crisis secondary to massive degranulation and hormone release. Consistent with our hypothesis, her plasma chromogranin A was found to be elevated. Octreotide was used successfully to palliate her symptoms. When the octreotide was stopped, all her symptoms returned. As the use of octreotide is gaining application in palliative care, this case highlights the effectiveness of its use in a select group of patients whose symptoms would be otherwise difficult to manage.

Class I and class II MHC-restricted T cells specific for proteins present in myelin have been shown to be involved in autoimmunity in the central nervous system (CNS). It is not yet known whether CD1d-restricted T cells reactive to myelin-derived lipids are present in the CNS and might be targeted to influence the course of autoimmune demyelination. Using specific glycolipid-CD1d tetramers and cloned T cells we have characterized a T cell population reactive to a myelin-derived glycolipid, sulfatide, presented by CD1d. This population is distinct from the invariant Vα14+ NK T cells, and a panel of Vα3/Vα8+ CD1d-restricted NK T cell hybridomas is unable to recognize sulfatide in the presence of CD1d+ antigen-presenting cells. Interestingly, during experimental autoimmune encephalomyelitis a model for human multiple sclerosis, sulfatide-reactive T cells but not invariant NK T cells are increased severalfold in CNS tissue. Moreover, treatment of mice with sulfatide prevents antigen-induced experimental autoimmune encephalomyelitis in wild-type but not in CD1d-deficient mice. Disease prevention correlates with the ability of sulfatide to suppress both interferon-γ and interleukin-4 production by pathogenic myelin oligodendrocyte glycoprotein-reactive T cells. Since recognition of sulfatide by CD1d-restricted T cells has now been shown both in mice and humans, study of murine myelin lipid-reactive T cells may form a basis for the development of intervention strategies in human autoimmune demyelinating diseases.

We report the first case of Dermatophilus congolensis infection of the human esophagus. We demonstrate initial endoscopic diagnosis, progression and then spontaneous resolution of D. congolensis infection, once the patient's occupational exposure had ceased.

Background/Aims: Proton Pump Inhibitors (PPIs) have been proposed to be the missing link in the controversy surrounding Small Intestinal Bacterial Overgrowth (SIBO) and Irritable Bowel Syndrome (IBS). Recent studies examining the relationship between PPIs and SIBO have been limited by retrospective analysis and failure to control for confounding factors such as somatization which may be common to both PPI use and SIBO. Consequently, the aims of this prospective cross sectional study were: 1) To calculate adjusted Odds Ratios (ORs) for hydrogen (H2) and methane (CH4) SIBO based upon PPI use 2) To determine the impact of PPI use on Lactulose Breath Testing (LBT) parameters. Methods: 149 nondiabetic veterans (67 PPI users, 82 non-users, 82% male, mean age 45) meeting Rome III IBS criteria undergoing LBT were recruited. Data on IBS subtype and severity (IBS Severity Scoring System), bloating, depression/anxiety (Hospital Anxiety Depression Score) and somatization (Psychosomatic Symptom Checklist) were obtained by questionnaire. Use of PPIs, fiber, laxatives, probiotics, H2-Blockers, anti-cholinergics, diagnoses of GERD and BMI were obtained from the medical record. LBT's were defined as positive using different criteria: 1) Two H2 Peaks (Increase .20 ppm over the baseline by 90 min with a single peak occurring at least 15 min prior to the second peak with a trough after the first peak of . 5ppm) 2) Increase in H2 by . 20 ppm by 90 min. 3) Any CH4 . 5 ppm 4) Rise in CH4 by. 20 ppm by 90 min. Adjusting for confounding factors using logistic regression, adjusted ORs for PPI use and SIBO were calculated. LBT parameters including baseline H2 and CH4, amplitude of rise to first H2 peak (P1), and time to P1 were compared between PPI and non-PPI groups using Wilcoxon rank sum and t-tests. Results: The prevalence of H2-SIBO using Two H2 Peak criteria was 36.9% in PPI vs. 17.9% in Non-PPI groups (p=0.01). Adjusted OR for PPI Use and Two Peak H2-SIBO was 4.3 (95% CI 1.4-12.9, p=0.01). PPI use of . 180 days was found to be associated with Two Peak H2-SIBO with OR 3.2 (95% CI 1.2-8.9, p=0.02). ORs for PPI use and SIBO were not statistically significant using the other H2 or CH4 criteria (Table). Among LBT parameters, there was a trend towards a shorter time to P1 in the PPI group (Fig 1). However, a statistically significant difference was found in time to P1 when comparing PPI use of .180 days vs. , 180 days (58.7 vs. 75.7 min, p=0.02) (Fig 1). Comparisons between PPI vs. Non-PPI groups did not find differences in baseline H2 (0 vs. 0 ppm, p=0.45), CH4 (1 vs.1.2 ppm, p=0.70) or amplitude to P1 (50 vs. 45 ppm, p=0.55). Conclusions: PPI use is associated with an increased prevalence of H2-SIBO on LBT but only when using the Two H2 Peak criteria. This may be caused by an earlier rise in H2 in the proximal small bowel seen with prolonged PPI use. (Table) Adjusted Odds Ratios for PPI Use and SIBO Using Different H2 and CH4 Criteria