Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia with immunodeficiency

Somatic mosaicism has been described in several primary immunodeficiency diseases and causes modified phenotypes in affected patients. X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the NF-κB essential modulator (NEMO) gene and manifests clinically in various ways. We have previously reported a case of XL-EDA-ID with somatic mosaicism caused by a duplication mutation of the NEMO gene, but the frequency of somatic mosaicism of NEMO and its clinical impact on XL-EDA-ID is not fully understood. In this study, somatic mosaicism of NEMO was evaluated in XL-EDA-ID patients in Japan. Cells expressing wild-type NEMO, most of which were derived from the T-cell lineage, were detected in 9 of 10 XL-EDA-ID patients. These data indicate that the frequency of somatic mosaicism of NEMO is high in XL-ED-ID patients and that the presence of somatic mosaicism of NEMO could have an impact on the diagnosis and treatment of XL-ED-ID patients.     

The hematopoietic cell-specific Rho GTPase inhibitor ARHGDIB/D4GDI limits HIV type 1 replication

Rho GTPases are able to influence the replication of human immunodeficiency virus type 1 (HIV-1). However, little is known about the regulation of HIV-1 replication by guanine nucleotide dissociation inhibitors (GDIs), one of the three major regulators of the Rho GTPase activation cycle. From a T cell-based cDNA library screening, ARHGDIB/RhoGDIβ, a hematopoietic lineage-specific GDI family protein, was identified as a negative regulator of HIV-1 replication. Up-regulation of ARHGDIB attenuated the replication of HIV-1 in multiple T cell lines. The results showed that (1) a significant portion of RhoA and Rac1, but not Cdc42, exists in the GTP-bound active form under steady-state conditions, (2) ectopic ARHGDIB expression reduced the F-actin content and the active forms of both RhoA and Rac1, and (3) HIV-1 infection was attenuated by either ectopic expression of ARHGDIB or inhibition of the RhoA signal cascade at the HIV-1 Env-dependent early phase of the viral life cycle. This is in good agreement with the previous finding that RhoA and Rac1 promote HIV-1 entry by increasing the efficiency of receptor clustering and virus-cell membrane fusion. In conclusion, the ARHGDIB is a lymphoid-specific intrinsic negative regulator of HIV-1 replication that acts by simultaneously inhibiting RhoA and Rac1 functions.     

Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease

Background

Klotho is a single-pass transmembrane protein, which appears to be implicated in aging. The purpose of the present study was to characterize the relationship between the soluble Klotho level and renal function in patients with various degrees of chronic kidney disease (CKD).

Methods

The levels of soluble Klotho in the serum and urine obtained from one hundred thirty-one CKD patients were determined by a sandwich enzyme-linked immunosorbent assay system.

Results

The amount of urinary excreted Klotho during the 24 hr period ranged from 1.6 to 5178 ng/day (median 427 ng/day; interquartile range [IR] 56.8-1293.1), and the serum Klotho concentration ranged from 163.9 to 2123.7 pg/ml (median 759.7 pg/ml; IR 579.5-1069.1). The estimated glomerular filtration rate (eGFR) was significantly correlated with the log-transformed values of the amount of 24 hr urinary excreted Klotho (r?=?0.407, p?<?0.01) and the serum Klotho levels (r?=?0.232, p?<?0.01). However, a stepwise multiple regression analysis identified eGFR to be a variable independently associated only with the log-transformed value of the amount of 24-hr urinary excreted Klotho but not with the log-transformed serum Klotho concentration. Despite the strong correlation between random urine protein-to-creatinine ratio and the 24 hr urinary protein excretion (r?=?0.834, p?<?0.01), a moderate linear association was observed between the log-transformed value of the amount of 24 hr urinary excreted Klotho and that of the urinary Klotho-to-creatinine ratio (Klotho/Cr) in random urine specimens (r?=?0.726, p?<?0.01).

Conclusions

The amount of urinary Klotho, rather than the serum Klotho levels, should be linked to the magnitude of the functioning nephrons in CKD patients. The use of random urine Klotho/Cr as a surrogate for the amount of 24-hr urinary excreted Klotho needs to be evaluated more carefully.

     

Genetic variants in antioxidant pathway: risk factors for hepatotoxicity in tuberculosis patients

Tuberculosis (TB) treatment can cause serious sequelae including adverse effects such as anti-TB drug-induced hepatotoxicity (ATDH). We performed a candidate gene-based association study between single nucleotide polymorphisms (SNPs) in 10 genes in the antioxidant pathway and ATDH susceptibility. The subjects comprised 100 Japanese patients with pulmonary TB who received a treatment regimen including isoniazid and rifampicin. Out of them, 18 patients had ATDH. Thirty-four tag SNPs in 10 genes were analyzed by PCR-restriction fragment length polymorphism or PCR-direct DNA sequencing. The frequencies of alleles and genotypes between patients with and without ATDH were compared in three different genetic models. Statistical analyses revealed that a C/C genotype at rs11080344 in NOS2A, a C/C genotype at rs2070401 in BACH1, and a G/A or A/A genotype at rs4720833 in MAFK independently conferred ATDH susceptibility. Remarkably, the association of the latter two tag SNPs with ATDH susceptibility was highly statistically significant (P?=?0.0006) with an odds ratio of 9.730. This study is the first report to demonstrate that NOS2A, BACH1, and MAFK appear to be genetic determinants of ATDH in Japanese patients with TB. Furthermore, a combination of BACH1 and MAFK polymorphisms may be useful as new biomarkers to identify high-risk Japanese TB patients for ATDH.     

Renal Biopsy in Elderly Patients: A Clinicopathological Analysis

As the numbers of aging patients with manifestations of renal disease increase, the elderly must frequently undergo renal biopsies. This study examined the characteristics of clinicopathological correlations in elderly patients. Medical and clinical records from renal biopsies registered in two hospitals between January 2000 and December 2004 were reviewed. Among 406 patients (female: male 224/182; age 43.9 ± 18.8 years, mean ± SD) who underwent renal biopsies, 61 (15.1%) who were aged 65 years and older (female: male, 29/32; age 72.8 ± 5.2 years) were selected. The elderly usually underwent percutaneous renal biopsies for renal diseases such as nephrotic syndrome (43%) and acute or rapidly progressive renal failure (A/RPRF, 39%). Focal/segmental glomerulosclerosis (23%), minimal change disease (19%), and membranous nephropathy (15%) are frequently diagnosed based on biopsy specimens from patients with nephrotic syndrome. Among patients presenting with A/RPRF, 17 (71%) and 4 (17%) had pauci-immune, MPO-ANCA positive, crescentic glomerulonephritis and interstitial nephritis, respectively, and benefited from therapeutic intervention. Histopathological and pre-biopsy clinical diagnoses differed in nine (15%) patients. The complication rate after biopsy was low (3%). Primary glomerular diseases presenting with nephrotic syndrome and primary crescentic glomerulonephritis associated with rapidly progressive renal failure were the most frequently diagnosed among the elderly who underwent renal biopsy. Percutaneous renal biopsy provides clinically useful information about the elderly because clinical presentation and the predicted diagnosis sometimes vary.     

Predictive Factors of Clinical Outcome in Patients with Diffuse Proliferative Lupus Nephritis Treated Early by Intravenous Methylprednisolone Pulse Therapy

Background. Diffuse proliferative lupus nephritis (DPLN) is associated with significant morbidity and mortality unless aggressive immunosuppressive therapy is initiated early in the course of the disease. It has been observed that with steroid pulse therapy, some patients with DPLN enter clinical remission while others do not. The factors predictive of clinical remission with steroid pulse therapy in these patients has not yet been elucidated. Methods. The authors retrospectively reviewed the records of 52 consecutive patients of DPLN treated by steroid pulse therapy in order to compare the characteristics of patients in the clinical remission group and those in the non-remission group. Clinical remission was defined as a serum creatinine level of ≤1.2 mg/dL, negative or trace proteinuria, and the observation of ≤1–4 red blood cells / high-power field in a routine urine examination. The 52 patients were divided into the clinical remission group (n?=?29) and the non-remission group (n?=?23), and also into subcategories of DPLN, namely, the IV-G group (n?=?28) and the IV-S (n?=?24). The characteristics of the patients were then compared between the two respective groups to identify factors that might be significantly related to clinical remission using Mann-Whitney's U test and the Cox proportional hazards model. Results. In regard to the clinical and immunological characteristics of the patients, except for a significant difference in the serum albumin level, there were no significant differences in any of the parameters examined, including blood pressure, degree of proteinuria, and serum creatinine, between the remission group and non-remission group. Added to that, in the non-remission group, the pretreatment period was significantly longer than in the remission group. In relation to the histological characteristics, the Chronicity Index (CI) and severity of interstitial fibrosis were significantly higher (p?=?0.021) in the non-remission group than in the remission group. The result of the Cox proportional hazards analysis revealed that the serum albumin, pretreatment period, CI, and severity of interstitial fibrosis were strongly related to the clinical outcome, whereas the results of the multivariate Cox proportional hazards analysis revealed only a weak correlation between the CI and the outcome. Conclusion. It was concluded that the diagnosis should be performed early and the pretreatment period should be shortened before treatment. Also, an aggressive therapeutic intervention should be initiated early, before chronic renal injury becomes established, to increase the likelihood of remission in patients with DPLN.     

Effects of Nordic Walking Compared to Conventional Walking and Band-Based Resistance Exercise on Fitness in Older Adults

The purpose of this study was to compare the effects of Nordic walking with conventional walking and band-based resistance exercise on functional fitness, static balance and dynamic balance in older adults. Volunteers (n = 65) were divided into four groups: Nordic walking (NW), conventional walking (CW), resistance (RES), and control. Each group performed activity 50-70 min·day⁻¹ (warm-up 10-15 min, main exercise 30-40, and cool down 10-15 min), 3 days·week⁻¹ (NW and CW) or 2 day·week⁻¹ (RES) for 12 wks. Upper-body strength improved (p < 0. 05) in the RES (22.3%) and the NW (11.6%) groups compared to the CW and control groups. Cardio- respiratory fitness improved more in the NW (10.9%) and CW (10.6%) groups compared to the RES and control groups. Upper- and lower-body flexibility also improved in all exercise groups compared to the control group. There were no improvements in balance measures in any group. While all modes of exercise improved various components of fitness, Nordic walking provided the best well-rounded benefits by improving upper-body strength, cardiovascular endurance, and flexibility. Therefore, Nordic walking is recommended as an effective and efficient mode of concurrent exercise to improve overall functional fitness in older adults.

Key Points

• Nordic walking, conventional walking, and resistance training are beneficial for older adults.
• Nordic walking and conventional walking both improve cardio-respiratory fitness while resistance training does not.
• Nordic walking provides additional benefits in upper-body muscular strength compared to conventional walking.
• Nordic walking is an effective and efficient mode of exercise to improve overall fitness in older adults.

Key words: Walking, resistance exercise, concurrent exercise, aging, functional fitness