Pathogenesis of the Lesions of Glomerulus and Renal Arteriole in Experimental Hypertension

Rats with adrenal regeneration hypertension were divided by the degree of blood pressure, and the changes in renal glomerulus were studied mainly with electron microscope. The increase in mesangial basement membrane like material and in the mesangial cells occurred as the early changes in the glomerulus. The mesangial basement membrane like material was extremely increased with an increase in blood pressure or with time. In some cases, fibrinoid necrosis appeared. It was considered that the increased mesangial basement membrane like material was produced anew, since the silver granules which were previously labeled were not deposited into them. Fibrinoid necrosis was considered to arise mainly from the interruption of the blood circulation, such as collapse of the capillary loop and platelet thrombi, and hyperpermeability. The findings of argyrosis could be ruled out in this study, since there were no findings which were suspected to show the renal lesions caused by the oral administration of a silver nitrate solution used as a label

Topically applied tissue factor pathway inhibitor reduced intimal thickness of small arterial autografts in rabbits

AbstractPurpose: The purpose of this study was to investigate whether topically applied tissue factor pathway inhibitor (TFPI) reduces intimal thickness and increases long-term patency of small arterial autografts in rabbits. Methods: An entire 10-mm long section of the left femoral artery was harvested and immersed in saline solution (control group, n = 10), 100 IU/mL of heparin (heparin group, n = 15), or 40 μg/mL of TFPI (TFPI group, n = 15) for 15 minutes. Then the graft was interposed to the right femoral artery. Patency rates were determined by flow measurements throughout the time course of the study, and the grafts were analyzed for measurement of intimal thickness at 3 months after operation. Immunohistochemical analysis was performed to examine whether topically applied TFPI binds to endothelial cells of the grafts. Results: Three-month postoperative patency rates were 10% in the control group, 47% in the heparin group, and 73% in the TFPI group. The TFPI group had a significantly higher patency rate than that of the control group (P <.005). Compared with the heparin group, the TFPI group had a significant reduction in intimal area (0.19 ± 0.05 mm2 vs 0.30 ± 0.09 mm2, P =.0051), in percentage of stenosis (35.7% ± 7.7% vs 61.4% ± 15.8%, P <.0001), and in intimal/media areas ratio (0.64 ± 0.24 vs 1.04 ± 0.33, P =.0051). Immunohistologic analyses confirmed that topically applied TFPI bound to endothelial cells. Conclusion: These results indicate that topically applied TFPI reduces intimal thickness and increases long-term patency of small arterial autografts in rabbits. (J Vasc Surg 2001;34:151-5.

Prolactin inhibits osteoclastic activity in the goldfish scale: A novel direct action of prolactin in teleosts

In teleosts, prolactin is involved in calcium regulation, but its role in scale/bone metabolism Is unclear. Using the in-vitro system with goldfish scales developed recently, we explored the effects of teleost prolactin, growth hormone, and somatolactin on osteoclasts and osteoblasts. Addition of prolactin at concentrations of 0.01-100 ng/ml reduced osteoclastic activity, partly via osteoclast apoptosis, after 6-18 h incubation. Conversely, growth hormone and somatolactin at a concentration of 100 ng/ml increased osteoclastic activity after 18 h incubation, indicating the specificity of the inhibitory effect of prolactin on osteoclastic activity. On the other hand, these three hormones promoted osteoblastic activity at concentrations of 10-100 ng/ml. The results from this study are the first demonstration of direct effects of prolactin on scale/bone metabolism and osteoclastic activity in a teleost. © 2008 Zoological Society of Japan

Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol

金沢大学大学院医学系研究科病態検査学Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+1)-to-A mutation(Int14 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C ≥ 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene. Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products: a novel intron 14 splice donor site mutation caused by a T insertion at position +3 from the exon14/intron14 boundary (Int14 T) and a missense mutation (Asp442 to Gly) within exon 15 (D442G). The Int14 T mutation was only found in one family. However, the D442G and Int14 A mutations were highly prevalent in subjects with HDL-C ≥ 60 mg/dl, with combined allele frequencies of 9%, 12%, 21%, and 43% for HDL-C 60-79, 80-99, 100-119, and ≥ 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Int14 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively. These two mutations accounted for about 10% of the total variance of HDL-C in this population. The phenotype in a genetic compound heterozygote (Int14 T and Int14 A) was similar to that of Int14 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Int14 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86±26 mg/dl) were lower than in Int14 A homozygotes (158±35 mg/dl), reflecting residual CETP activity in plasma. In 47 D442G heterozygotes, mean HDL-C levels were 91±23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Int14 A heterozygotes (69±15 mg/dl). Thus, the D442G mutation acts differently to the null mutations with weaker effects on HDL in the homozygous state and stronger effects in the heterozygotes, suggesting dominant expression of a partially defective allele. CETP deficiency, reflecting two prevalent mutations (D442G and Int14 A), is the first example of a genetic deficiency state which is sufficiently common to explain a significant fraction of the variation in HDL-C in the general population

ADAMTS-1: A metalloproteinase-disintegrin essential for normal growth, fertility, and organ morphology and function

金沢大学医薬保健研究域医学系A disintegrin and metalloproteinase (ADAM) represents a protein family possessing both metalloproteinase and disintegrin domains. ADAMTS-1, an ADAM family member cloned from cachexigenic colon adenocarcinoma, is unusual in that it contains thrombospondin type I motifs and anchors to the extracellular matrix. To elucidate the biological role of ADAMTS-1, we developed ADAMTS-1-null mice by gene targeting. Targeted disruption of the mouse ADAMTS-1 gene resulted in growth retardation with adipose tissue malformation. Impaired female fertilization accompanied by histological changes in the uterus and ovaries also resulted. Furthermore, ADAMTS-1(-/-) mice demonstrated enlarged renal calices with fibrotic changes from the ureteropelvic junction through the ureter, and abnormal adrenal medullary architecture without capillary formation. ADAMTS-1 thus appears necessary for normal growth, fertility, and organ morphology and function. Moreover, the resemblance of the renal phenotype to human ureteropelvic junction obstruction may provide a clue to the pathogenesis of this common congenital disease

Effectiveness of Messenger RNA Coronavirus Disease 2019 Vaccines Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infections During the Delta Variant Epidemic in Japan: Vaccine Effectiveness Real-time Surveillance for SARS-CoV-2 (VERSUS)

Background. Although high vaccine effectiveness of messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines has been reported in studies in several countries, data are limited from Asian countries, especially against the Delta (B.1.617.2) variant.Methods. We conducted a multicenter test-negative case-control study in patients aged ≥16 years visiting hospitals or clinics with signs or symptoms consistent with COVID-19 from 1 July to 30 September 2021, when the Delta variant was dominant (≥90% of SARS-CoV-2 infections) nationwide in Japan. Vaccine effectiveness of BNT162b2 or mRNA-1273 against symptomatic SARS-CoV-2 infections was evaluated. Waning immunity among patients aged 16–64 years was also assessed.Results. We enrolled 1936 patients, including 396 test-positive cases and 1540 test-negative controls for SARS-CoV-2. The median age was 49 years, 53.4% were male, and 34.0% had underlying medical conditions. Full vaccination (receiving 2 doses ≥14 days before symptom onset) was received by 6.6% of cases and 38.8% of controls. Vaccine effectiveness of full vaccination against symptomatic SARS-CoV-2 infections was 88.7% (95% confidence interval [CI], 78.8%–93.9%) among patients aged 16–64 years and 90.3% (95% CI, 73.6%–96.4%) among patients aged ≥65 years. Among patients aged 16–64 years, vaccine effectiveness was 91.8% (95% CI, 80.3%–96.6%) within 1–3 months after full vaccination, and 86.4% (95% CI, 56.9%–95.7%) within 4–6 months.Conclusions. mRNA COVID-19 vaccines had high effectiveness against symptomatic SARS-CoV-2 infections in Japan during July–September 2021, when the Delta variant was dominant nationwide