Epstein-Barr Virus-Positive Blastoid Variant of Mantle Cell Lymphoma in an Adult with Recurrent Infectious Mononucleosis-Like Symptoms: A Case Report

Epstein-Barr virus (EBV) is closely associated with several lymphomas, such as Burkitt lymphoma, natural killer/T-cell lymphoma, peripheral T-cell lymphoma, and Hodgkin's lymphoma; however, whether EBV is implicated in mantle cell lymphoma (MCL) has not been established. We report the case of an adult with recurrent infectious mononucleosis (IM)-like symptoms who developed an EBV-positive blastoid variant of MCL. A 54-year-old Japanese man presented with fever, swelling of the oral mucosa and tongue, dispersed pulmonary infiltrations, systemic lymphadenopathy, and splenomegaly. He had a history of recurrent IM-like symptoms (prolonged fever and cervical lymphadenopathy) for at least 1 year. MCL was diagnosed by biopsy of the cervical lymph node. The anti-EBV antibody titer indicated a reactivation of chronic infection with this virus. EBV was detected in most of the lymphoma cells and in the peripheral blood. EBV might have played some role in the tumorigenesis of blastoid MCL.     

Anti-Inflammatory Effects of Pravastatin on Helicobacter Pylori-Induced Gastritis in Mice

Pravastatin, an HMG-CoA reductase inhibitor, exerts anti-inflammatory effects via several mechanisms including induction of endothelial nitric oxide synthase (eNOS). We investigated the effect of pravastatin on Helicobacter pylori-induced gastritis in mice. Mice with or without H. pylori infection received intraperitoneal pravastatin daily for 1 week. Expression of eNOS mRNA and tumor necrosis factor-α mRNA and myeloperoxidase activity in gastric tissue was determined. Myeloperoxidase activity was reduced in a dose-dependent manner by pravastatin, with activity inhibited by 53.5 and 73.7% at doses of 0.3 and 1 mg/kg, respectively. At a dose of 1 mg/kg, pravastatin reduced the level of tumor necrosis factor-α mRNA by 52.7%, while it did not affect eNOS expression. Pravastatin had no effects on these inflammatory parameters in uninfected mice. Pravastatin did not affect the viability of H. pylori. In conclusion, pravastatin exerts an anti-inflammatory effect on H. pylori-induced gastritis in mice without affecting eNOS expression.     

Identification of key phosphorylation sites in the circadian clock protein KaiC by crystallographic and mutagenetic analyses

In cyanobacteria, KaiC is an essential hexameric clock protein that forms the core of a circadian protein complex. KaiC can be phosphorylated, and the ratio of phospho-KaiC to non-phospho-KaiC is correlated with circadian period. Structural analyses of KaiC crystals identify three potential phosphorylation sites within a 10-A radius of the ATP binding regions that are at the T432, S431, and T426 residues in the KaiCII domains. When these residues are mutated by alanine substitution singly or in combination, KaiC phosphorylation is altered, and circadian rhythmicity is abolished. These alanine substitutions do not prevent KaiC from hexamerizing. Intriguingly, the ability of KaiC overexpression to repress its own promoter is also not prevented by alanine substitutions at these sites, implying that the capability of KaiC to repress its promoter is not sufficient to allow the clockwork to oscillate. The KaiC structure and the mutational analysis suggest that S431 and T426 may share a phosphate that can shuttle between these two residues. Because the phosphorylation status of KaiC oscillates over the daily cycle, and KaiC phosphorylation is essential for clock function as shown here, daily modulations of KaiC activity by phosphorylation at T432 and S431/T426 seem to be key components of the circadian clockwork in cyanobacteria.     

Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts

The mechanism responsible for cardiac depression in septic shock remains unknown. The present study examined whether nitric oxide (NO) overproduced by inducible NO synthase (iNOS) can inhibit aerobic energy metabolism and impair the myocardial function in endotoxin-treated rat hearts. Lipopolysaccharide (LPS) significantly decreased systolic blood pressure (BP) to 44% of control during the 48 h treatment. Hearts from control and LPS-treated rats were perfused in a Langendorff apparatus. After LPS injection, left ventricular (LV) developed pressure (LVDP) was significantly depressed, plasma NO2-/NO3- (NO(x)) concentration was markedly increased, and myocardial adenosine 5'-triphosphate (ATP), creatine phosphate (CrP), and the ratio of ATP/adenosine 5'-diphosphate were progressively decreased with time. Immunological examination showed a significant expression of iNOS protein in the LPS-treated myocytes. Aminoguanidine, an inhibitor of iNOS, significantly attenuated these LPS-induced functional and metabolic changes. Myocardial cyclic guanosine 3',5'-monophosphate (cGMP) content was significantly increased after LPS injection. Methylene blue, an inhibitor of soluble guanylate cyclase, blunted this increase in cGMP and significantly restored the LPS-induced contractile dysfunction 6 h after LPS injection. In addition, there was a significant negative correlation between LVDP and myocardial cGMP levels as well as a significant negative correlation between LVDP and plasma NO(x) levels. In contrast, 48 h after LPS injection, methylene blue no longer affected cardiac performance, and there was a significant positive correlation between LVDP and myocardial ATP content. Furthermore, the normalized activities (as a ratio of the citrate synthase activity) of mitochondrial NADH-CoQ reductase, succinate-CoQ reductase, and ATPase, were significantly inhibited, and the swelling or disruption of mitochondria cristae was seen in the 48 h LPS treatment. These LPS-induced functional and morphological disorders in the mitochondria were significantly improved by aminoguanidine. The findings suggest that sustained production of NO by iNOS leads to contractile dysfunction via cGMP in the early stage, but that it can directly impair the mitochondrial function, lower myocardial energy production, and contribute significantly to the myocardial dysfunction in the later stage of septic shock.     

Assessment of coronary artery calcification in hemodialysis patients using multi-detector spiral CT scan.

Cardiovascular disease in association with coronary artery calcification (CAC) is the leading cause of death in patients with end-stage renal disease (ESRD). The evaluation of CAC has been performed by electron beam CT scan. The purpose of the present study was to assess CAC using multi-detector spiral CT (MDCT) and to evaluate contributors to CAC in these patients. Fifty-three patients on chronic hemodialysis participated in this study. Their mean age was 61.0+/-9.6 years, and the mean duration of dialysis therapy was 6.7+/-5.4 years. We used an automatic device to measure arterial pulse wave velocity (PWV) as an index of arterial wall stiffness. The aortic calcification index (ACI) was quantified morphometrically by CT scan. The CAC score correlated positively with ACI score (r =0.863, p <0.0001). Linear regression analysis indicated that the CAC scores correlated positively with age (r =0.406, p =0.0023), C-reactive protein (r =0.38, p =0.0047) and PWV (r =0.303, p =0.0271). Stepwise regression analysis indicated that ACI (beta-coefficient=0.862, p <0.0001) and arterial PWV (beta-coefficient=0.303, p <0.0001) were independently associated with CAC score. The mean CAC score of patients with cardiac events (2,568.5+/-2,575.1 mm3) was significantly higher than that (258.0+/-409.2 mm3) of patients without cardiac events. In conclusion, our results showed clearly that assessment of CAC score using MDCT may be predictive for detecting the presence of coronary artery disease. CAC is indirectly associated with increased arterial stiffness and the extent of aortic calcification in hemodialysis patients. We did not find a significant correlation between CAC score and parameters of mineral metabolism, including serum levels of calcium, phosphorus and parathyroid hormone. A longitudinal prospective study is required to assess the predictive value of this technique in determining cardiac events in large numbers of hemodialysis patients.     

Reduced expression of heme oxygenase-1 in patients with coronary atherosclerosis.

Heme oxigenase-1 (HO-1) is known to be an inducible cytoprotective enzyme that copes with oxidative stress. However, changes in HO-1 expression and their association with human diseases have not been studied. To test the hypothesis that the capacity to upregulate HO-1 in response to oxidative stress is an intrinsic marker for susceptibility to coronary atherosclerosis, we assessed stimulation-induced change in HO-1 expression in blood cells in 110 patients who underwent coronary angiography, comparing the results with the extent of coronary atherosclerosis and (GT)(n) repeat polymorphism in the HO-1 gene promoter region, which is believed to affect the gene expression level. The extent of coronary atherosclerosis was assessed by coronary score. Mononuclear cells were incubated with 10 micromol/l hemin or vehicle for 4 h to maximally stimulate HO-1 expression, then the HO-1 expression level was determined by real-time polymerase chain reaction (PCR). The difference between the HO-1 mRNA levels of hemin- and vehicle-treated cells (DeltaHO-1 mRNA) was taken as an index of the capacity to upregulate HO-1 mRNA. The coefficient of variance of DeltaHO-1 mRNA was 7.2%. Consistent with previous studies, DeltaHO-1 mRNA was significantly lower in patients carrying a long (GT)(n) repeat. DeltaHO-1 mRNA negatively and significantly correlated with the coronary score (r(2)=0.50, p<0.01). In conclusion, the capacity to upregulate HO-1 expression may be determined, at least in part, by genetics, and reduced ability to induce HO-1 may be involved in the mechanism of coronary atherosclerosis.     

Stress and thyroid autoimmunity.

While many studies have shown a connection between stress and autoimmune disease, most of the evidence for stress contributing to the onset and course of autoimmune disease is circumstantial and the mechanisms by which stress affects autoimmune disease are not fully understood. The best circumstantial evidence for an effect of stress on autoimmune thyroid disease is the well-known relationship between the onset of Graves' hyperthyroidism and major stress but even this is debated. However, most of the recent case-control studies have supported stress as a factor that affects the onset and clinical course of Graves' disease. On the other hand, there have been few reports concerning the possible relationship between stress and Hashimoto's thyroiditis. Because the onset and course of Hashimoto's thyroiditis is generally insidious, the effect of stress on Hashimoto's thyroiditis might be overlooked. Numerous human and animal studies have demonstrated that psychological and physiologic stressors induce various immunologic changes. Stress affects the immune system either directly or indirectly through the nervous and endocrine systems. These immune modulations may contribute to the development of autoimmunity as well as the susceptibility to autoimmune disease in genetically predisposed individuals. Stress can be one of the environmental factors for thyroid autoimmunity.     

A case of tuberculous aneurysm of subclavian artery occurred in the course of treatment for miliary tuberculosis

This case is a 56-year old woman. Steroids were being administered perorally after a thymectomy for myasthenia gravis. A fever of 38-39 degrees Celsius appeared during night, an abnormal shadow showed up on a chest X-ray and the patient was hospitalized. Gaffky No. 2 acid-fast bacilli were detected in the patient's sputum and the chest CT showed diffuse granular-like shadow, the patient was diagnosed as miliary tuberculosis and treatment with combined use of INH, RFP, EB, and PZA was started. Subsequently, fever started to subside and the miliary shadow on chest X-ray improved, however, six weeks after the start of treatment, hoarseness and dysphagia appeared. From the cervical CT and cervical angiography findings, the diagnosis of right subclavian artery impending ruptured aneurysm was made. Because the patient's sputum was acid-fast bacilli positive and because the patient had undergone thymectomy, it was decided that it would be difficult to treat her by a thoracotomy again. Therefore, a right subclavian artery stent insertion, right subclavian artery-right common carotid artery bypass creation operation was carried out with the objective of blocking the flow of blood to the aneurysm. The hoarseness and dysphagia improved post-operatively and the patient's progress is being monitored. Tuberculous aneurysms are a rare affection and they are mostly discovered when the autopsy is done, however, this case was diagnosed due to the manifestation of subjective symptoms. While this case was not diagnosed histopathologically, it is envisaged from the clinical progress that this was a tuberculous subclavian aneurysm complicated during the treatment for miliary tuberculosis.     

Does long-term medication with a proton pump inhibitor induce a tolerance to H<Subscript>2</Subscript> receptor antagonist?

Background Previous reports suggest that complete tolerance to H₂ receptor antagonists (H₂RAs) in patients with regular H₂RA medication may be due to hypergastrinemia-increased histamine synthesis or upregulation of H₂ receptors. As proton pump inhibitors (PPIs) have been reported to induce hypergastrinemia (similar to H₂RAs), patients receiving long-term medication with PPIs may show tolerance to preanesthetic H₂RA. Therefore, we studied the efficacy of an H₂RA, roxatidine, in patients receiving long-term PPI medication. Methods Effects of H₂RA in 15 surgical patients receiving a regular PPI for more than 4 weeks (PPI+H₂RA group) were compared with those in 30 patients not receiving regular PPIs or H₂RAs (None+H₂RA group and None+None group, n = 15 each). Oral roxatidine was given to both PPI+H₂RA and None+H₂RA group patients as an anesthetic premedication, while it was not given to None+None group patients. Gastric volume and pH were measured after induction of anesthesia. Results Gastric pH and volume (ml) in the PPI+H₂RA group (5.79 ± 1.61 and 9.1 ± 16.7, respectively) were both similar to those in the None+H₂RA group (5.54 ± 2.20 and 9.7 ± 10.8, respectively) but were significantly higher (gastric pH) and lower (volume) than in the None+None group (2.29 ± 1.84 and 29.3 ± 22.8, respectively, P < 0.01). Conclusions These data suggest that long-term PPI medication may not induce a tolerance to H₂RAs.     

A case of metachronous cholangiocellular and hepatocellular carcinoma with good prognosis

A 63-year-old man was treated for 6 months with interferon (IFN) for chronic hepatitis C but the treatment failed to eradicate hepatitis C virus. Six months after completion of IFN therapy, cholangiocellular carcinoma (CCC) was detected in the posterior inferior segment and was resected surgically. He had been in good condition except for diabetic nephropathy progressing to renal failure at 3 years after the resection of CCC. Seven years after the resection of CCC, hepatocellular carcinoma (HCC) was detected in the posterior superior segment of the liver. The tumor was pathologically confirmed by fine needle aspiration biopsy. The patient was successfully treated with two courses of percutaneous ethanol injection and has been well 1 year after the treatment. HCV status did not change as genotype 1b with moderate viral load (300 to 500 kilo copies/mL by amplicore monitoring) during the follow-up. Thus, even though the patient was treated with IFN, hepatitis C could progress to not only HCC but also CCC in the same patient. Our patient is still alive, 9.5 years after detection of the first tumor.