Changes in the serum level of hepatitis B virus (HBV) surface antigen over the natural course of HBV infection

Background

Despite its status as a potential biomarker of hepatitis B virus (HBV) response to interferon treatment, the changes in hepatitis B surface antigen (HBsAg) levels over the natural course of HBV carriers have not been analyzed sufficiently.

Methods

A total of 101 HBV carriers were followed prospectively from 1999 to 2009. HBsAg level was measured yearly during the followed period.

Results

HBsAg levels at baseline ranged from ?1.4 to 5.32 log IU/ml, with a median value of 3.2 log IU/ml. Lower HBsAg levels were significantly associated with higher age and lower HBV replication status. The rate of change of HBsAg levels showed two peaks, with a cut-off value of ?0.4 log IU/year. Based on this, patients were tentatively classified into rapid decrease (rate of change P?=?0.028) lower in the rapid decrease group than in the non-rapid decrease group.

Conclusions

Lower baseline HBsAg levels were significantly associated with older age and lower viral activity. Both a loss of HBeAg detection as well as inactive replication of HBV are suggested to be fundamental factors contributing to a rapid decrease in HBsAg over the natural course of HBV infection.     

Lack of evidence for association between the endothelial nitric oxide synthase gene and hypertension

Significant association between a Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene and essential hypertension was recently reported in Japanese populations, with the 298Asp variant showing a higher prevalence in hypertensive patients (10.3% to 12.0%) than in normotensive subjects (5.0% to 5.8%). In contrast, another study demonstrated that the 298Glu variant was significantly associated with hypertension in a Caucasian population. We therefore undertook an extensive association study in Japanese to resolve these contradictory claims. A total of 1165 individuals were selected from clinic outpatients and hospital staff in a single institution. The relevance of the Glu298Asp polymorphism to hypertension in this population was tested in 2 ways. First, a case-control study was conducted in 549 hypertensive and 513 normotensive subjects within the study population, with the chi2 statistic used to test the significance of an association between eNOS genotype and the presence of hypertension. Second, an ANOVA was used to test the significance of an association between eNOS genotype and the level of blood pressure within the entire population except for 167 hypertensive subjects who had been under treatment for hypertension. No significant association was observed in either of the statistics tested. Allele frequencies of 298Asp were concordant across the panels: 8.4% in hypertensive subjects, 8. 2% in normotensive subjects, and 7.9% and 9.5% in 2 additional sample populations used as reference panels. Taken together, our results do not support the previous observation that the molecular variant of the eNOS gene may confer principal susceptibility for essential hypertension but rather suggest the existence of sampling variation.     

Efficacy of immunized milk for preventing viral infection

This paper investigated the efficacy of passive protection provided by milk (immunized milk) against enterovirus infection in mice experimentally infected with enterovirus. Milk with a high antibody titer against six enterovirus serotypes was prepared from hyperimmunized goat. In vivo and in vitro experiments were performed and the results showed that immunized milk has an antiviral activity against enterovirus infection. Further observation was performed using Coxsackie B 3 virus (CVB 3). When immunized milk was orally applied to mice prior to oral inoculation with CVB 3, preventive effects against viral infection such as reduction of histopathological changes in the heart and reduced detection of the virus genome in the organs were seen. The antiviral effect was also indicated by the increase of CD4+T cells proportion in the i-IEL. The proportion of virus specific CD4+T cells was increased in mice treated with immunized milk, whereas no such increase was detected in control mice. These results suggest that oral application of immunized milk is not only capable of preventing viral infection but also induces specific immunological responses. These phenomena may play an important role in host defense mechanisms.     

Prognostic impact of left ventricular noncompaction in patients with Duchenne/Becker muscular dystrophy — Prospective multicenter cohort study

Background

The reported prevalence of left ventricular noncompaction (LVNC) varies widely and its prognostic impact remains controversial. We sought to clarify the prevalence and prognostic impact of LVNC in patients with Duchenne/Becker muscular dystrophy (DMD/BMD).

Methods

We evaluated the presence of LNVC in patients with DMD/BMD aged 4–64 years old at the study entry (from July 2007 to December 2008) and prospectively followed-up their subsequent courses (n = 186). The study endpoint was all-cause death and the presence of LVNC was blinded until the end of the study (median follow-up: 46 months; interquartile range: 41–48 months).

Results

There were no significant differences in baseline characteristics between patients with LVNC (n = 35) and control patients without LVNC (n = 151), with the exception of LV function. Patients with LVNC showed, in comparison with patients without LVNC, a significant negative correlation between age and LVEF (R = − 0.7 vs. R = − 0.4) at baseline; and showed a significantly greater decrease in absolute LVEF (− 8.6 ± 4.6 vs. − 4.3 ± 4.5, p < 0.001) during the follow-up. A worse prognosis was observed in patients with LVNC (13/35 died) than in patients without LVNC (22/151 died, Log-rank p < 0.001). Multivariate Cox analysis revealed that LVNC is an independent prognostic factor (relative hazard 2.67 [95% CI: 1.19–5.96]).

Conclusion

LVNC was prevalent in patients with DMD/BMD. The presence of LVNC is significantly associated with a rapid deterioration in LV function and higher mortality. Neurologists and cardiologists should pay more careful attention to the presence of LVNC.     

Patient with adult‐onset type II citrullinemia beginning 2 years after operation for duodenal malignant somatostatinoma: Indication for liver transplantation

We report a 51‐year‐old female patient with adult‐onset type II citrullinemia (CTLN2) who had a history of pancreatoduodenectomy for duodenal somatostatinoma with metastases to regional lymph nodes at age 49 years, paying special attention to indications for liver transplantation. At age 50 years, she developed hepatic encephalopathy with elevation of plasma ammonia and citrulline levels. A diagnosis of CTLN2 was made by DNA analysis of the SLC25A13 gene and treatment with conservative therapies was begun, including a low‐carbohydrate diet and supplementation with arginine and sodium pyruvate. However, despite these treatments, frequent attacks of encephalopathy occurred with markedly elevated plasma ammonia levels. While we were apprehensive regarding the risk of recurrence of somatostatinoma due to immunosuppressive therapy after liver transplantation, the patient was in a critical condition with CTLN2 and it was decided to perform living‐donor liver transplantation using a graft obtained from her son. Her postoperative clinical course was uneventful and she has had an active life without recurrence of somatostatinoma for 2 years. This is the first case of CTLN2 with somatostatinoma. As the condition of CTLN2 patients with rapidly progressive courses is often intractable by conservative therapies alone, liver transplantation should be considered even after surgery for malignant tumors in cases with neither metastasis nor recurrence.     

Combined examination of glyceryl trinitrate‐mediated vascular dilation with flow‐mediated vascular dilation is essential for assessment of vascular function in type 2 diabetes

Aims/Introduction

In order to characterize the impaired vascular function in type 2 diabetes (DM) patients, we evaluated the flow‐mediated vascular dilation (FMD) with glyceryl trinitrate‐mediated vascular dilation (NMD) using ultrasonography.

Materials and Methods

A total of 111 DM patients and 42 healthy control participants were studied. The maximal dilatation of FMD and NMD (%FMD and %NMD, respectively), the beginning time (T) of dilatation after stimulation and the velocity (V) of the vascular dilatation were also measured.

Results

Among DM patients, 49% had impaired %NMD, which affects the results of %FMD. In DM patients with normal %NMD, the %FMD was also significantly lower than that in control participants, although the T and the V were not impaired. In contrast, both the T and the V were disturbed in the DM patients with low %NMD. Multiple linear regression analysis showed that %NMD was independently correlated with albuminuria. Our results indicate that the impaired FMD in DM is be affected by low NMD, and impaired endothelial function already exists even in DM patients whose vascular smooth muscle function is still retained, and also albuminuria is the clinical feature of DM with low %NMD.

Conclusions

Examination of NMD, not only FMD, should be carried out as it offers the possibility of clarifying vascular function in DM patients.     

Kir6.2 E23K polymorphism is related to secondary failure of sulfonylureas in non‐obese patients with type 2 diabetes

Aims/Introduction

The Kir6.2 E23K polymorphism was studied with a special reference to secondary sulfonylurea (SU) failure in non‐obese patients with type 2 diabetes.

Materials and Methods

We recruited 278 non‐obese (body mass index ≤30.0 kg/m²) Japanese patients with type 2 diabetes who had a history of SU treatment (for 11.2 ± 6.3 years) and compared the frequency of the secondary SU failure among the genotypes of the polymorphism. Genotyping of the Kir6.2 E23K was carried out by polymerase chain reaction‐restriction fragment length polymorphism.

Results

The genotype frequencies of the polymorphism were similar to those previously reported in Japanese patients with type 2 diabetes. The frequency with which patients deteriorated into secondary SU failure was significantly higher in those with the KK genotype than those with EE or EK genotypes. Among 214 patients who eventually received insulin therapy because of secondary SU failure, the period of SU treatment in those with the KK genotype was significantly shorter than those with the EE or EK genotype, although the period from diagnosis to the start of SU treatment was not significantly different.

Conclusions

These data suggest that the Kir6.2 E23K polymorphism is related to the acceleration of secondary SU failure in non‐obese Japanese patients with type 2 diabetes.     

Viral, fungal and mycobacterial infections in patients with systemic lupus erythematosus

Prevalence and outcome of infections such as herpes zoster (HZ),Mycobacterium tuberculosis (M. tuberculosis, Tbc), cytomegalovirus (CMV) and fungi were investigated in total of 132 patients with systemic lupus erythematosus (SLE) including 15 autopsied cases diagnosed and treated between 1975 and 1996. HZ was identified in 22 patients (17%) and five (23%) of 22 cases experienced multiple HZ onset. None of the HZ exhibited severe cutaneous dissemination or aggravation of SLE.Tbc infection was identified in three patients (2%) and two patients recovered, but the one died from leptomeningitis tuberculosis. Out of 15 autopsy cases, deep CMV infections were identified in three (20%), candidiasis in four (27%), and zygomycosis and aspergillosis in one (7%). One patient with CMV infection and the patient with zygomycosis and aspergillosis died as a result of the infection. These infections, however, did not aggravate SLE, except in the patient with zygomycosis and aspergillosis. In contrast to HZ,Tbc and deep CMV and fungal infections seem to disseminate and threaten the prognosis of SLE patients, and some fungi such as zygomycetes tended to aggravate the basic disease.     

Thrombopoietin Induces Association of Crkl With STAT5 But Not STAT3 in Human Platelets

Crkl, a 39-kD SH2, SH3 domain-containing adapter protein, isconstitutively tyrosine phosphorylated in hematopoietic cells fromchronic myelogenous leukemia (CML) patients. We recently reported thatthrombopoietin induces tyrosine phosphorylation of Crkl in normalplatelets. In this study, we demonstrate that thrombopoietin inducesassociation of Crkl with a tyrosine phosphorylated 95- to 100-kDprotein in platelets and in UT7/TPO cells, a thrombopoietin-dependent megakaryocytic cell line. With specific antibodies against STAT5, wedemonstrate that the 95- to 100-kD protein in Crkl immunoprecipitates is STAT5. This coimmunoprecipitation was specific in that Crkl immunoprecipitates do not contain STAT3, although STAT3 becomes tyrosine phosphorylated in thrombopoietin-stimulated platelets. Thecoimmunoprecipitaion of Crkl with STAT5 was inhibited by the immunizingpeptide for Crkl antisera or phenyl phosphate (20 mmol/L). Afterdenaturing of Crkl immunoprecipitates, Crkl was stillimmunoprecipitated by Crkl antisera. However, coimmunoprecipitation ofSTAT5 was not observed. Coincident with STAT5 tyrosine phosphorylation, thrombopoietin induces activation of STAT5 DNA-binding activity asdemonstrated by electrophoretic mobility shift assays (EMSA). Using a-casein promoter STAT5 binding site as a probe, we have alsodemonstrated that Crkl antisera supershift the STAT5-DNA complex,suggesting that Crkl is a component of the complex in the nucleus.Furthermore, interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin also induce Crkl-STAT5 complex formation in responding cells in astimulation-dependent manner. In vitro, glutathione S-transferase(GST)-Crkl bound to STAT5 inducibly through its SH2 domain. Theseresults indicate that thrombopoietin, IL-3, GM-CSF, and erythropoietincommonly induce association of STAT5 and Crkl and that the complextranslocates to the nucleus and binds to DNA. Interestingly, suchassociation between STAT5 and Crkl was not observed incytokine-stimulated murine cells, suggesting an intriguing possibilitythat components of the human STAT5-DNA complex may be different fromthose of the murine counterpart.