Genetic variations of regulator of G-protein signaling 2 in hypertensive patients and in the general population

OBJECTIVES: Mice deficient in the regulator of G-protein signaling 2 (RGS2) exhibit a strong hypertensive phenotype. We studied whether genetic variations in RGS2 are implicated in hypertension or other phenotypes in Japanese hypertensive individuals and the general population. METHODS: We sequenced all exons of RGS2 and the promoter region in 953 and 48 hypertensive individuals, respectively. Genotyping by the TaqMan polymerase chain reaction method was performed for six missense or frameshift mutations and common single nucleotide polymorphisms in the general population, with a sample size of 1872 individuals (862 men and 1011 women). RESULTS: We identified five novel missense mutations (Q2L; n = 2, Q2R; n = 1, M5V; n = 1, R44H; n = 2, Q78H; n = 1) and one novel frameshift mutation (1925-1926insT; n = 2) in a heterozygous state, in addition to 33 variations including five common single nucleotide polymorphisms. Six missense/frameshift mutations and three common single nucleotide polymorphisms (-638A > G, 1026T > A, 1891-1892delTC) were successfully genotyped in the general population. Mutations Q2L (n = 2), M5V (n = 1), and 1925-1926insT (n = 2) were only identified in hypertensive subjects. Six out of seven individuals with the R44H mutation, which occurs in the amphipathic alpha-helical domain of RGS2, had hypertension. The results showed a significant association of two common single nucleotide polymorphisms, 1026T > A [TT versus TA + AA: odds ratio (OR) 1.33; 95% confidence interval (CI) 1.02-1.74; P = 0.035] and 1891-1892delTC (I: insertion allele, D: deletion allele, II versus ID + DD: OR 1.47; 95% CI 1.09-1.97; P = 0.012), with hypertension in women by multivariate logistic regression analysis. CONCLUSION: Our results suggest that genetic variations in RGS2 contribute partly to the hypertensive phenotype.     

Human Herpes Virus 8-Negative Primary Effusion Lymphoma in a Patient With a Ventriculoperitoneal Shunt Tube

A 60-year-old woman was referred to our hospital in 1996 due to an abdominal distension in the right lower quadrant. She had undergone a partial resection of a cholesteatoma at the right temporal lobe of the cerebrum 30 years previously, and a ventriculoperitoneal shunt (VPS) tube had been placed with drainage into the right lower peritoneal cavity. The patient developed paralytic ileus in December 1966, and ultrasound and computed tomography of the abdomen revealed a cystic mass in the right lower quadrant without lymphadenopathies or masses. Cytologic examinations of the fluid in the cystic mass revealed signs of malignant lymphoma. After the resection of the cystic mass, lymphoma cells were detected in the fluid, but the wall of the cyst consisted of only fibrous tissues. Results of immunophenotypic analysis of the lymphoma cells by immunocytochemistry or flow cytometry were positive for CD19, CD20, CD22, CD45, and HLA-DR but negative for CD45RO, CD3, CD4, and CD8. The genome of human herpes virus (HHV)-8 was not detected in the lymphoma cells, but Epstein-Barr (EB) nuclear antigen 1 and EB virus (EBV)-encoded small nuclear RNAs were detected. Chromosome analysis by the G-banding method showed complicated abnormalities including der(8)t(2;8)(q31;q24), but Southern blotting analysis suggested that the c-myc oncogene did not participate in the lymphomagenesis. The patient's disease was diagnosed as HHV-8-negative primary effusion lymphoma (PEL). The long-standing inflammatory stimulation by a VPS tube might have contributed to the clonal evolution of EBV-infected lymphocytes. resulting in the development of PEL.     

Effectiveness of oseltamivir on influenza and influencing factors: age of patients,type of influenza virus and timing of initial administration

A multi-center open study using the internet was performed during the influenza season of 2001-2002 to evaluate the effectiveness of the anti-influenza agent, oseltamivir, on influenza in relation to: (1) age of patients; (2) type of influenza virus; and (3) timing of initial administration after the onset of the first symptoms of influenza. The study comprised of 779 cases of influenza confirmed by rapid detection tests from 44 clinics in Japan. Patients consisted of 4 age groups, 0-6, 7-15, 16-64 and 65-85 years. All patients were administered oseltamivir within 24 hours, at 25-48 or after 48 hours from the onset of the first symptoms of influenza. Data collected from each age group were the highest body temperature and duration of fever (> or = 37.5 degrees C). The percentage of afebrile patients was calculated at 24, 48 and 72 hours after the initial administration; data were also evaluated by the type of influenza virus A and B. The highest body temperature was higher with statistical significance as patients' age decreased. The duration of febrile period (days) was significantly longer in 0-6 years (2.57 +/- 0.95) than in 65-85 years (2.18 +/- 0.93). Evaluation of the percentage of afebrile patients revealed: the percentage at 24 hours was significantly lower in 0-6 years (28.4%) than in 16-64 years (44.0%); the percentage at 48 and 72 hours showed similar results in each age group; the percentage at 48 and 72 hours was significantly higher when administered initially within 24 hours than over 48 hours after the onset of the first symptoms of influenza; the percentage at 24 and 48 hours was significantly higher when administered within 24 hours than at 25-48 hours; and the type of influenza virus did not affect the percentage. In conclusion, effectiveness of oseltamivir seemed to be affected to an extent by the patients' age and little by the type of influenza virus. Oseltamivir was more effective when administered as early as possible after the onset of the symptoms of influenza.     

Two elderly patients with mineralocorticoid excess due to 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) impairment

A 75-year-old woman had a low circulating level of aldosterone, despite the mineralocorticoid excess state. These abnormalities were improved by spironolactone administration. The distinct elevation of urinary cortisol/cortisone ratio revealed 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) impairment. Moreover, slight but distinct elevation of the ratio was found in a 95-year-old woman with normotension and normopotassemia. The mineralocorticoid excess state with reduced aldosterone level appeared following with vomiting and diarrhea, exaggerating asymptomatic impairment of 11beta-HSD2 to induce apparent mineralocorticoid excess (AME)-like condition.     

Allogenic mesenchymal stem cell transplantation has a therapeutic effect in acute myocardial infarction in rats

The goal of the study was to examine if allogenic mesenchymal stem cell (MSC) transplantation is a useful therapy for acute myocardial infarction (AMI). Buffer (control; group C, n = 41), MSCs of male ACI rats (allogenic; group A, n = 38, 5 × 10⁶), or MSCs of male LEW rats (syngenic; group S, n = 40, 5 × 10⁶) were injected into the scar 15 min after myocardial infarction in female LEW rats. After 28 days, fractional left ventricular shortening significantly increased in groups A (21.3 ± 1.7%, P = 0.0467) and S (23.2 ± 1.9%, P = 0.0140), compared to group C (17.1 ± 0.9%). Fibrosis in groups A and S was significantly lower. Quantitative PCR of the male-specific sry gene showed disappearance of donor cells within 28 days (5195 ± 1975 cells). Secretion of vascular endothelial growth factor (VEGF) by MSCs was enhanced under hypoxic conditions in vitro. In groups A and S, the plasma VEGF concentration, VEGF level, and capillary density in recipient hearts increased after 28 days. Flow cytometry revealed the absence of B7 signal molecules on MSCs. A mixed lymphocyte reaction showed that ACI MSCs failed to stimulate proliferation of LEW lymphocytes. After 1 day after cell transplantation, transient increases in interleukin-1 beta and monocyte chemoattractant protein-1 in recipient hearts were enhanced in group A, with macrophage infiltration at the injection site. T cells remained at the level of normal tissue in all groups. We conclude that allogenic MSC transplantation therapy is useful for AMI. The donor MSCs disappear rapidly, but become a trigger of VEGF paracrine effect, without induction of immune rejection.     

Cardiovascular disorders in patients with diabetes mellitus

Diabetes mellitus is a disease with multiorgan involvement. Besides retinopathy, nephropathy and peripheral neuropathy induced by microangiopathy, both cardiovascular and cerebrovascular complications are significant. Both cardiomyopathy and coronary artery disease are observed in patients with diabetes, and the latter is clinically more important because of its high incidence and seriousness.     

Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment

BACKGROUND & AIMS: The most effective therapy currently available for treatment of chronic hepatitis C virus (HCV) is the combination of peginterferon and ribavirin. This study evaluated the effectiveness of this treatment in patients who were nonresponders to previous interferon-based therapy. METHODS: The first 604 patients enrolled in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial were evaluated. All were HCV RNA positive, previous nonresponders to interferon, with or without ribavirin, and had bridging fibrosis or cirrhosis on liver biopsy (Ishak fibrosis stage 3-6). Patients were retreated with peginterferon alfa-2a 180 microg/wk plus ribavirin 1000-1200 mg/day. Those with no detectable HCV RNA in serum at week 20 continued treatment for a total of 48 weeks and were then followed for an additional 24 weeks. RESULTS: Thirty-five percent of patients had no detectable HCV RNA in serum at treatment week 20, and 18% achieved sustained virologic response (SVR). Factors associated with an SVR included previous treatment with interferon monotherapy, infection with genotypes 2 or 3, a lower AST:ALT ratio, and absence of cirrhosis. Reducing the dose of ribavirin from > or =80% to < or =60% of the starting dose during the first 20 weeks of treatment was associated with a decline in SVR from 21% to 11% (P < or = 0.05). In contrast, reducing the dose of peginterferon or reducing ribavirin after week 20, when HCV RNA was already undetectable, did not significantly affect SVR. CONCLUSIONS: Selected nonresponders to previous interferon-based therapy can achieve SVR following retreatment with peginterferon alfa-2a and ribavirin.     

Functionally important glycosyltransferase gain and loss during catarrhine primate emergence

A glycosyltransferase, alpha1,3galactosyltransferase, catalyzes the terminal step in biosynthesis of Galalpha1,3Galbeta1-4GlcNAc-R (alphaGal), an oligosaccharide cell surface epitope. This epitope or antigenically similar epitopes are widely distributed among the different forms of life. Although abundant in most mammals, alphaGal is not normally found in catarrhine primates (Old World monkeys and apes, including humans), all of which produce anti-alphaGal antibodies from infancy onward. Natural selection favoring enhanced resistance to alphaGal-positive pathogens has been the primary reason offered to account for the loss of alphaGal in catarrhines. Here, we question the primacy of this immune defense hypothesis with results that elucidate the evolutionary history of GGTA1 gene and pseudogene loci. One such locus, GGTA1P, a processed (intronless) pseudogene (PPG), is present in platyrrhines, i.e., New World monkeys, and catarrhines but not in prosimians. PPG arose in an early ancestor of anthropoids (catarrhines and platyrrhines), and GGTA1 itself became an unprocessed pseudogene in the late catarrhine stem lineage. Strong purifying selection, denoted by low nonsynonymous substitutions per nonsynonymous site/synonymous substitutions per synonymous site values, preserved GGTA1 in noncatarrhine mammals, indicating that the functional gene product is subjected to considerable physiological constraint. Thus, we propose that a pattern of alternative and/or more beneficial glycosyltransferase activity had to first evolve in the stem catarrhines before GGTA1 inactivation could occur. Enhanced defense against alphaGal-positive pathogens could then have accelerated the replacement of alphaGal-positive catarrhines by alphaGal-negative catarrhines. However, we emphasize that positively selected regulatory changes in sugar chain metabolism might well have contributed in a major way to catarrhine origins.