Transforming growth factor-beta1 gene polymorphism modifies the histological and clinical manifestations in Japanese patients with IgA nephropathy

Transforming growth factor (TGF)-beta1, a multifunctional cytokine, which regulates proliferation and differentiation of a variety of cell types, has the central role in the development and progression of renal injury in both animal models and human. Although it has been suggested that genetic variations in the TGF-beta1 gene are associated with the activity of the gene product, their clinical significance in glomerular disease is unknown. We investigated whether the polymorphisms of C-509T and T869C in TGF-beta1 account for interindividual variation in manifestations of IgA nephropathy (IgAN) using 626 Japanese subjects including 329 patients with histologically proven IgAN and 297 healthy controls with normal urinalysis. The frequencies of genotypes, alleles, and major haplotypes were similar between the patients and controls. The C-509T and T869C polymorphisms were in tight linkage disequilibrium, and the major haplotypes were C-C and T-T, which accounted for more than 95% of the total. In patients with -509CC and in those with the 869CC, urinary protein excretion was higher than in those with other genotypes, whereas no difference in other clinical manifestations was noted. Moreover, patients with -509CC and those with 869CC genotypes presented with a significant higher score of mesangial cell proliferation than in those with other genotypes. These results suggest that TGF-beta1 gene polymorphisms are specifically associated with heavy proteinuria and mesangial cell proliferation in Japanese patients with IgAN, although they do not confer susceptibility to this disease.     

Significance of flow cytometric DNA analysis from freshly aspirated samples

The procedure of aspiration biopsy cytology by fine needle aspiration (ABC) is as option in establishing definitive diagnoses for breast cancers. In this series, a needle size of 21G was considered most suitable for ABC as well as flow cytometric DNA analysis. Histograms from fresh samples aspirated by fine needle clearly delineated a sharp peak in G&sup0;G(1) phases and also a better CV was obtained than with paraffin-embedded preparations. In addition, fresh samples gave more reliable DI and suggested the value of measuring nuclear DNA contents. It is believed that the prognoses of breast cancers are closely associated with DNA ploidy patterns. In this sense, flow cytometric DNA analysis of fresh samples of ABC is regarded as important in clinical use.     

Interaction between ACE and ADD1 gene polymorphisms in the progression of IgA nephropathy in Japanese patients

An interaction effect between the angiotensin-converting enzyme insertion/deletion (ACE I/D) and alpha-adducin (ADD1) Gly460Trp polymorphisms (G460W) on blood pressure regulation has recently been suggested, although its significance in the prognosis of renal function in IgA nephropathy (IgAN) has not been fully investigated. Therefore, we evaluated the clinical manifestations and renal prognosis in 276 Japanese patients with histologically proven IgAN with respect to their ACE I/D and ADD1 G460W polymorphisms. The prognosis of renal function was analyzed by Kaplan-Meier survival curves and multivariate Cox proportional-hazards regression models. Baseline data, including blood pressures, proteinuria, renal function, and incidence of hypertension, were similar for the different genotypes of ACE and ADD1. The individual genotypes taken alone were not associated with the progression of renal dysfunction. However, renal survival of patients with the 460WW polymorphism of ADD1 was significantly worse within the group with the II genotype of ACE (Kaplan-Meier, log rank test; chi2=6.062, P=0.0138) but not for those with other ACE genotypes. In the Cox proportional-hazards regression model with adjustment for clinical risk factors, including hypertension, proteinuria, and no administration of an angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, the 460WW variant of ADD1 was a highly significant and independent risk factor only for patients with the ACE II genotype, with a hazard ratio of 3.65 (P=0.0016), but not for those with other ACE genotypes (hazard ratio=0.65, P=0.2902). These findings suggest an interaction between ACE and ADD1 polymorphisms not only on blood pressure regulation but also on the progression of renal dysfunction in patients with IgAN.     

Lysophosphatidic acid transactivates both c-Met and epidermal growth factor receptor, and induces cyclooxygenase-2 expression in human colon cancer LoVo cells

AIM: To examine whether lysophosphatidic acid (LPA) induces phosphorylation of c-Met and epidermal growth factor receptor (EGFR), both of which have been proposed as prognostic markers of colorectal cancer, and whether LPA induces cyclooxygenase-2 (COX-2) expression in human colon cancer cells. METHODS: Using a human colon cancer cell line, LoVo cells, we performed immunoprecipitation analysis, followed by Western blot analysis. We also examined whether LPA induced COX-2 expression, by Western blot analysis. RESULTS: Immunoprecipitation analysis revealed that 10 umol/L LPA induced tyrosine phosphorylation of c-Met and EGFR in LoVo cells within a few minutes. We found that c-Met tyrosine phosphorylation induced by LPA was not attenuated by pertussis toxin or a matrix metalloproteinase inhibitor, in marked contrast to the results for EGFR. In addition, 0.2-40 umol/L LPA induced COX-2 expression in a dose-dependent manner. CONCLUSION: Our results suggest that LPA acts upstream of various receptor tyrosine kinases (RTKs) and COX-2, and thus may act as a potent stimulator of colorectal cancer.     

Establishment of a human nonluteinized granulosa cell line that transitions from the gonadotropin-independent to the gonadotropin-dependent status

The ovary is a complex endocrine organ responsible for steroidogenesis and folliculogenesis. Follicles consist of oocytes and two primary steroidogenic cell types, the granulosa cells, and the theca cells. Immortalized human granulosa cells are essential for researching the mechanism of steroidogenesis and folliculogenesis. We obtained granulosa cells from a 35-yr-old female and immortalized them by lentivirus-mediated transfer of several genes so as to establish a human nonluteinized granulosa cell line (HGrC1). We subsequently characterized HGrC1 and investigated its steroidogenic performance. HGrC1 expressed enzymes related to steroidogenesis, such as steroidogenic acute regulatory protein, CYP11A, aromatase, and gonadotropin receptors. Stimulation with FSH increased the mRNA levels of aromatase, which consequently induced the aromatization of androstenedione to estradiol. Activin A increased the mRNA levels of the FSH receptor, which were synergistically up-regulated with FSH stimulation. HGrC1 also expressed a series of ligands and receptors belonging to the TGF-β superfamily. A Western blot analysis showed that bone morphogenetic protein (BMP)-4, BMP-6, and BMP-7 phosphorylated small mother against decapentaplegic (Smad)1/5/8, whereas growth differentiation factor-9 phosphorylated Smad2/3. BMP-15 and anti-Müllerian hormone phosphorylated Smad1/5/8 while also weakly phosphorylating Smad2/3. These results indicate that HGrC1 may possess the characteristics of granulosa cells belonging to follicles in the early stage. HGrC1 might also be capable of displaying the growth transition from a gonadotropin-independent status to gonadotropin-dependent one.     

Impact of diabetes mellitus on characteristics of carotid plaques and outcomes after carotid endarterectomy

Background

Published results for carotid endarterectomy (CEA) in symptomatic and asymptomatic severe carotid stenosis with diabetes mellitus (DM) are contradictory. To evaluate perioperative and long-term results of CEA in patients with DM, we retrospectively analyzed data of patients with or without DM who underwent CEA in our institute.

Methods

Between January 2005 and December 2010, 281 consecutive CEAs were performed in 268 patients under general anesthesia. All patients were subject to cardiac work-ups before surgery, and coronary revascularization was performed prior to CEA if patients were diagnosed with significant coronary artery stenosis. Lesion characteristics were assessed by a duplex ultrasound scan, computed tomography angiography (CTA), and plaque imaging on magnetic resonance imaging (MRI) before surgery, and patients were followed-up by a duplex ultrasound scan at three, six, and 12 months, then yearly, after surgery.

Results

Of 281 cases, 136 had DM (48 %). Diabetic patients more frequently had a history of coronary artery disease than non-diabetic patients (48.5 % vs. 36.6 %, P?=?0.042). Coronary intervention prior to CEA was more frequently performed in diabetic patients than in non-diabetic patients (22.1 % vs. 11.0 %, P?=?0.013). The incidence of perioperative (30 day) stroke (P?=?1.000), death (P?=?1.000), and cardiac complications (P?=?0.484) did not differ among groups. Follow-up was available in 77.2 % of patients, with a median duration of 50 months (interquartile range, 32.1-67.2 months). The incidence of ipsilateral stroke (P?=?0.720), death (P?=?0.351), and severe restenosis (peak systolic velocity?>?230 cm/sec) (P?=?0.905) were not different between groups.

Conclusions

DM does not increase the risk of perioperative complications and does not influence long-term outcomes after CEA if preexisting vascular risk factors and cardiac diseases are appropriately evaluated and treated before surgery.     

Usefulness of Craniograms in Discriminating Coiled Intracranial Aneurysms Requiring Retreatment

While endovascular coil embolization has become one of the major therapeutic modalities for intracranial aneurysms, long-term imaging follow-up is required because of the higher rate of retreatment compared with surgical clipping. The purpose of this study was to show the usefulness of craniograms to discriminate coiled intracranial aneurysms that required retreatment. Under the study protocol approved by institutional review board, a retrospective review of the medical record was done regarding coil embolization for intracranial aneurysms performed between January 2014 and December 2018. Coil embolization performed as the initial treatment and followed up for more than 1 year without additional treatment, and those performed as retreatment after the initial coil embolization performed at our institution were recruited. Craniograms obtained just after the initial treatment were compared with those obtained just before the additional treatment in the retreated cases and compared with the latest ones in the non-recurrence cases. Correlation between the morphological changes in the coil mass on the craniograms and retreatments was evaluated. During the study period, 288 coil embolization procedures for intracranial aneurysms were performed. From these, 191 treatments that were followed up for more than 1 year without any additional treatments and 30 retreatments were included. Morphological change of the coil mass was observed in 4 of the 191 non-recurrence treatments and 26 of the 30 retreatments, which was significantly correlated with retreatments (p <0.001). Craniogram was a useful modality in following up the coiled intracranial aneurysms to detect those required retreatments.     

Exploratory Systematic Review and Meta-Analysis of Panax Genus Plant Ingestion Evaluation in Exercise Endurance

Background: Many studies that use food containing Panax genus plants (PGPs) have been conducted but most of them have not mentioned the effective compounds ginsenosides and their composition. Therefore, we conducted a systematic review and meta-analysis of time to exhaustion as an index of exercise endurance with ingestion of PGPs or ginsenosides to reveal their effects. Methods: We performed a systematic review with a comprehensive and structured literature search using seven literature databases, four clinical trial databases, and three general web search engines during 15–22 March 2021. A random-effects model was applied to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) as the difference between the mean in the treatment and placebo groups. We evaluated the risk of bias of individual studies along with the risk of bias tool in the Cochrane handbook. This study was funded by Maruzen Pharmaceuticals Co., Ltd. (Hiroshima, Japan). The protocol for this study was registered with the UMIN-CTR (No. UMIN000043341). Results: Five studies met the inclusion criteria. The number of total participants was 90, with 59 in the ingestion-PGPs group and 64 in the control group, because three studies were crossover-design trials. We found that ingestion of PGPs or ginsenosides significantly improved exercise endurance (SMD [95% CI]: 0.58 [0.22–0.95], I² = 0%). It was suggested that ginsenoside Rg₁ (Rg₁) and PGPs extract containing Rg₁ were significantly effective in improving exercise endurance (SMD [95% CI]: 0.70 [0.14–1.27], I² = 30%) by additional analysis. Conclusions: This systematic review suggests that the ingestion of PGPs or ginsenosides, especially Rg₁, is effective in improving exercise endurance in healthy adults. However, further high-quality randomized controlled trials are required because imprecision and publication bias cannot be ignored in this systematic review.