Adenosine A2A receptors in diffuse dermal fibrosis: pathogenic role in human dermal fibroblasts and in a murine model of scleroderma.

OBJECTIVE: Adenosine regulates inflammation and tissue repair, and adenosine A2A receptors promote wound healing by stimulating collagen matrix production. We therefore examined whether adenosine A2A receptors contribute to the pathogenesis of dermal fibrosis. METHODS: Collagen production by primary human dermal fibroblasts was analyzed by real-time polymerase chain reaction, 14C-proline incorporation, and Sircol assay. Intracellular signaling for dermal collagen production was investigated using inhibitors of MEK-1 and by demonstration of ERK phosphorylation. In vivo effects were studied in a bleomycin-induced dermal fibrosis model using adenosine A2A receptor-deficient wild-type littermate mice, C57BL/6 mice, and mice treated with adenosine A2A receptor antagonist. Morphometric features and levels of hydroxyproline were determined as measures of dermal fibrosis. RESULTS: Adenosine A2A receptor occupancy promoted collagen production by primary human dermal fibroblasts, which was blocked by adenosine A2A, but not A1 or A2B, receptor antagonism. Adenosine A2A receptor ligation stimulated ERK phosphorylation, and A2A receptor-mediated collagen production by dermal fibroblasts was blocked by MEK-1 inhibitors. Adenosine A2A receptor-deficient and A2A receptor antagonist-treated mice were protected from developing bleomycin-induced dermal fibrosis. CONCLUSION: These results demonstrate that adenosine A2A receptors play an active role in the pathogenesis of dermal fibrosis and suggest a novel therapeutic target in the treatment and prevention of dermal fibrosis in diseases such as scleroderma.

Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome with acute cortical blindness.

The coincidence of hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome and cortical blindness is an uncommon but very dramatic event. We describe a case of HELLP syndrome complicating with acute cortical blindness before delivery. A 27 year-old woman, gravida 1, para 0, with normal medical history, was referred to our emergency department at the 33th week of gestation due to headache, vomiting, and blurred vision. The ophthalmologic examination showed intact pupillary light reflexes and normal ophthalmoscopic findings, but no light perception in either eye. Brain computed tomography showed normal findings. HELLP syndrome and preeclampsia was diagnosed based on the findings of hypertension and proteinuria as well as laboratory data. Prompt delivery was performed in order to achieve good maternal and neonatal outcomes.

Expression and clinical significance of antinuclear antibody in hepatitis C virus infection.

BACKGROUND: The prevalence of antinuclear antibody (ANA) has been documented in patients with hepatitis C virus (HCV) infection. We attempted to determine the titer and to characterize the patterns and clinical significance of ANA in HCV infection. STUDY: Forty-eight consecutive patients with positive anti-HCV antibody and positive HCV RNA were included in this study. Sera from patients were tested for ANA and anti-smooth muscle antibody by indirect immunofluorescence. Serum aminotransferase, alkaline phosphatase, alpha-fetoprotein, and cryoglobulin levels also were determined. RESULTS: Eleven (23%) of 48 HCV-infected patients were positive for ANA. Antinuclear antibody revealed speckled pattern in 10 (91%) of the 11 ANA-positive HCV-infected patients. Twenty (54%) of 37 ANA-negative HCV-infected patients had detectable pattern with equivocal titer (titer <1.5). The ANA pattern was speckled in all 20 patients. Hepatitis C virus-infected patients with positive ANA were older than the HCV-infected patients with negative ANA (62.90 +/- 11.05 years vs. 56.46 +/- 14.94 years, respectively; p < 0.1). Serum levels of aspartate aminotransferase (39.36 +/- 14.98 IU/L vs. 30.70 +/- 23.15 IU/L, p < 0.05), alkaline phosphatase (189.00 +/- 75.63 IU/L vs. 122.41 +/- 40.88 IU/L, p < 0.01), and alpha-fetoprotein (47.72 +/- 80.47 pg/dL vs. 7.00 +/- 8.28 pg/dL, p < 0.01) were higher in ANA-positive HCV-infected patients than in ANA-negative HCV-infected patients, respectively. There were no significant differences in gender, alanine aminotransferase, anti-smooth muscle antibody, or cryoglobulin between the two groups. CONCLUSIONS: Antinuclear antibody was present in 11 (23%) of 48 patients with HCV infection in our study. Speckled pattern is the major expression pattern of ANA in HCV infection. Antinuclear antibody-positive HCV-infected patients have significantly higher serum aspartate aminotransferase, alkaline phosphatase, and alpha-fetoprotein levels than ANA-negative HCV-infected patients.

Role of Helicobacter pylori in cirrhotic patients with dyspepsia: a 13C-urea breath test study.

The role of Helicobacter pylori in dyspeptic, cirrhotic patients remains unclear. This prospective outpatient study, conducted to assess the relationship of gastroduodenal disease and H. pylori as determined by the (13C) urea breath test, enrolled 109 consecutive cirrhotic patients with dyspepsia. All patients underwent upper-gastrointestinal endoscopy, which revealed respective prevalences of peptic ulcer, gastric ulcer, and duodenal ulcer of 41.3%, 23.9%, and 22.9%; H. pylori infection was found in 52.3%. The rate of peptic ulcer disease in the H. pylori-positive (45.6%) and -negative (36.5%) groups was not significantly different; neither was the prevalence of H. pylori in patients with or without portal hypertensive gastropathy and with or without esophageal varices. The relationship between peptic ulcer disease and H. pylori in dyspeptic patients with cirrhosis appears to be weak. Likewise, no significant relationship was evident between H. pylori and portal hypertensive gastropathy or esophageal varices. This organism may not be a major pathogenetic factor in gastroduodenal diseases in dyspeptic patients with cirrhosis.

In situ activation of helper T cells in the lung.

To better understand the lung and systemic responses of helper T cells mediating memory immunity to Mycobacterium tuberculosis, we used three- and four-color flow cytometry to study the surface phenotype of CD4(+) lymphocytes. Bronchoalveolar lavage (BAL) fluid and peripheral blood (PB) samples were obtained from a total of 25 subjects, including 10 tuberculosis (TB)-infected subjects, 8 purified-protein-derivative-negative subjects, and 7 purified-protein-derivative-positive subjects. In marked contrast to CD4(+) lymphocytes from PB (9% +/- 5% expressing CD45RA and CD29), the majority (55% +/- 16%) of CD4(+) lymphocytes in BAL (ALs) simultaneously expressed CD45RA, a naïve T-cell marker, and CD29, members of the very late activation family. Further evaluation revealed that CD4(+) ALs expressed both CD45RA and CD45RO, a memory T-cell marker. In addition, the proportion of CD4(+) lymphocytes expressing CD69, an early activation marker, was drastically increased in BAL fluid (83% +/- 9%) compared to PB (1% +/- 1%), whereas no significant difference was seen in the expression of CD25, the low-affinity interleukin 2 receptor (34% +/- 15% versus 40% +/- 16%). More importantly, we identified a minor population of CD69(bright) CD25(bright) CD4(+) lymphocytes in BAL (10% +/- 6%) that were consistently absent from PB (1% +/- 1%). Thus, CD4(+) lymphocytes in the lung paradoxically coexpress surface molecules characteristic of naïve and memory helper T cells as well as surface molecules commonly associated with early and late stages of activation. No difference was observed for ALs obtained from TB-infected and uninfected lung segments in this regard. It remains to be determined if these surface molecules are induced by the alveolar environment or if CD4(+) lymphocytes coexpressing this unusual combination of surface molecules are selectively recruited from the circulation. Our data suggest that ex vivo experiments on helper T-cell subsets that display distinctive phenotypes may be pivotal to studies on the human immune response to potential TB vaccines.

Efficacy of endoscopic isotonic saline-epinephrine injection for the management of active Mallory-Weiss tears.

Therapeutic endoscopy with isotonic saline-epinephrine (ISE) injection is a convenient and widely used procedure for hemostasis in upper gastrointestinal bleeding. We retrospectively evaluated 36 patients (from January 1996 to April 1999) who had been diagnosed with recent or active bleeding due to Mallory-Weiss tears in emergency endoscopic examination. The endoscopic hemostatic method with ISE injection was performed in 15 of 36 patients. The other 21 patients received conservative treatment with hemodynamic support. Patient's clinical data, laboratory data, transfusion requirements, endoscopic findings, and length of hospital stays were evaluated. Initial hemoglobin was significantly lower in the ISE group than the conservative treatment group (9.74 +/- 2.86 g/dL vs. 12.57 +/- 2.80 g/dL, respectively; p < 0.01). Mean transfusion requirements were significantly higher in the ISE group than the conservative treatment group (7.26 +/- 8.78 units vs. 2.85 +/- 6.21 units, respectively; p < 0.1). Patients in the ISE group were supposed to be having a more severe bleeding episode. Most patients achieved initial hemostasis in the ISE group and the conservative treatment group (93% and 95%, respectively). The rebleeding rate was also similar in both groups (1 in 15 in the ISE group and I in 21 in the conservative treatment group). There was no significant difference in length of hospital stay and rebleeding between these two groups (3.47 +/- 1.92 days vs. 2.47 +/- 1.47 days, respectively: p = 0.89). The endoscopic ISE injection is an inexpensive, simple, convenient therapeutic method and it can achieve initial hemostasis for active Mallory-Weiss tears.

Effect of cisapride on gastric dysrhythmia and emptying of indigestible solids in type-II diabetic patients.

BACKGROUND: Abnormal gastric slow-wave frequencies have been observed in diabetic gastroparesis. To evaluate the effect of cisapride on gastric dysrhythmia and emptying of indigestible solids, 20 type-II diabetic patients with symptoms suggestive of gastroparesis were enrolled in this study. METHODS: Cutaneous electrogastrography, gastric emptying of radiopaque markers, and evaluation of upper gastrointestinal symptoms were performed before and after administration of an 8-week course of cisapride. RESULTS: The fasting-state percentages of dominant frequency in normal and tachygastric ranges improved significantly after an 8-week course of cisapride treatment (P < 0.01 and P < 0.05, respectively). The post-meal percentages of dominant frequency in the tachygastric range also improved significantly after cisapride treatment (P < 0.05). The upper gastrointestinal symptoms score decreased significantly, and gastric emptying of radiopaque markers also increased significantly after 8 weeks of cisapride treatment (P < 0.01). CONCLUSIONS: In conclusion, this study showed that cisapride can improve gastric dysrhythmia during both fasting and post-meal phases in patients with diabetic gastroparesis. In addition, upper GI symptoms and gastric emptying of indigestible solids may also show significant improvement after 8 weeks of cisapride treatment.

Comprehensive gastric emptying study for type-II diabetes mellitus dyspeptic patients.

BACKGROUND: Gastrointestinal symptoms without demonstrable lesions in the upper gastrointestinal tract are common in diabetic patients. Scintigraphic liquid- and solid-phase gastric emptying studies and gastric emptying of indigestible particles were performed to determine the gastric emptying function in type-II diabetes mellitus patients with dyspepsia. METHODS: Twenty type-II diabetic patients with symptoms suggestive of delayed gastric emptying were included. A gelatin capsule containing 10 rod-shaped radiopaque markers was ingested, along with the solid-phase test meal, to assess the emptying of indigestible particles. Scintigraphic liquid-phase gastric emptying studies were performed on a separate day. RESULTS: There were 7 patients (35%) with delayed liquid-phase gastric emptying, 14 patients (70%) with delayed solid-phase gastric emptying, and 14 patients (70%) with abnormal gastric emptying of indigestible particles. There were only three patients (15%) with normal gastric emptying of both the liquid and solid phase. Furthermore, only one patient showed normal result in all three gastric emptying studies. CONCLUSIONS: For determining abnormalities in gastric emptying function for type-II diabetic dyspepsia patients, comprehensive gastric emptying studies, including scintigraphic liquid- and solid-phase gastric emptying studies and gastric emptying of indigestible particles, are most helpful.