Long-Term Effects of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Predictors of Treatment Response and Safety over 6 Years of Continuous Therapy.

Tolvaptan, an oral vasopressin V2 receptor antagonist, reduces renal volume expansion and loss of renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Data for predictive factors indicating patients more likely to benefit from long-term tolvaptan are lacking. Data were retrospectively collected from 55 patients on tolvaptan for 6 years. Changes in renal function, progression of renal dysfunction (estimated glomerular filtration rate [eGFR], 1-year change in eGFR [ΔeGFR/year]), and renal volume (total kidney volume [TKV], percentage 1-year change in TKV [ΔTKV%/year]) were evaluated at 3-years pre-tolvaptan, at baseline, and at 6 years. In 76.4% of patients, ΔeGFR/year improved at 6 years. The average 6-year ΔeGFR/year (range) minus baseline ΔeGFR/year: 3.024 (-8.77-20.58 mL/min/1.73 m2). The increase in TKV was reduced for the first 3 years. A higher BMI was associated with less of an improvement in ΔeGFR (p = 0.027), and family history was associated with more of an improvement in ΔeGFR (p = 0.044). Hypernatremia was generally mild; 3 patients had moderate-to-severe hyponatremia due to prolonged, excessive water intake in response to water diuresis-a side effect of tolvaptan. Family history of ADPKD and baseline BMI were contributing factors for ΔeGFR/year improvement on tolvaptan. Hyponatremia should be monitored with long-term tolvaptan administration.

Calcium intake during pregnancy is associated with decreased risk of emotional and hyperactivity problems in five-year-old Japanese children.

Background: Recently, more attention has been paid to behavioral problems in children. However, for the most part, risk factors for these problems have yet to be determined.Objective: The current prebirth cohort study investigated the relationship between maternal calcium consumption during pregnancy and behavioral problems in five-year-old Japanese children.Methods: Subjects were 1199 mother-child pairs. Dietary intake during the preceding month was assessed using a self-administered diet history questionnaire. Emotional problems, conduct problems, hyperactivity problems, and peer problems were assessed using the Strengths and Difficulties Questionnaire. Logistic regression analysis was conducted to estimate odds ratios (ORs) and 95% confidence intervals (CIs).Results: Compared with the lowest quartile of maternal calcium intake, the highest was significantly associated with decreased risk of childhood emotional problems: the adjusted OR (95% CIs) was 0.46 (0.27-0.79, P for trend = 0.01). Higher maternal calcium intake during pregnancy was also independently associated with decreased risk of childhood hyperactivity problems; the adjusted ORs (95% CIs) in the first, second, third, and fourth quartiles of maternal calcium intake during pregnancy were 1 (reference), 0.52 (0.31-0.84), 0.58 (0.35-0.93), and 0.60 (0.37-0.97), respectively (P for trend = 0.046). No such inverse associations were observed for childhood conduct problems or peer problems; the adjusted ORs (95% CIs) in the highest quartile of maternal calcium intake were 0.97 (0.64-1.47) for conduct problems and 1.11 (0.61-2.01) for peer problems.Conclusions: Maternal calcium intake during pregnancy may decrease the risk of childhood emotional and hyperactivity problems.

Trafficking of newly synthesized surfactant protein B to the lamellar body in alveolar type II cells.

Lung surfactant accumulates in the lamellar body (LB) via not only the secretory (anterograde) pathway but also the endocytic (retrograde) pathway. Our previous studies suggested that the major surfactant components, phosphatidylcholine and surfactant protein A take independent trafficking routes in alveolar type II cells. Thus, trafficking of surfactant protein B (SP-B), a major hydrophobic surfactant apoprotein, should be re-evaluated by a straightforward method. Radiolabeling of cells and subsequent cell fractionation were employed to pursue the sequential trafficking of newly synthesized SP-B in rabbit alveolar type II cells. The LB fraction was prepared by gradient ultracentrifugation. Immunoprecipitation from the culture medium, total cells, and LB fraction was carried out with anti-SP-B antibody. Newly synthesized [35S]-pro-SP-B (~ 42 kDa) was detected in the cells after 1 h. An ~ 8-kDa mature form of [35S]-SP-B was detected in the cells after 3 h and in the LB after 6 h. Mature [35S]-SP-B was predominant in the cells after 24 h, and the dominant portion was present in the LB. In contrast, only a small amount of mature [35S]-SP-B was present in the culture medium. Molecular processing of ~ 42 kDa [35S]-pro-SP-B and transport to the LB was inhibited by brefeldin A, which disassembles the Golgi apparatus. These results suggest that newly synthesized SP-B is sorted to the LB via the Golgi and stored until exocytosis. This pathway is distinct from the pathways reported for phosphatidylcholine and surfactant protein A.

Multiple cerebral infarction diagnosed as Eosinophilic Granulomatosis with Polyangiitis by autopsy.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis of unknown cause involving the brain and accompanied by prominent eosinophilia. Intracardiac thrombosis is a major cardiac complication of EGPA that may cause thromboembolism. CASE PRESENTATION: A 53-year-old man presenting with abulia (consciousness disturbance) and left upper limb paralysis was admitted to our hospital. His case was complicated by penetrating branches, small vessel infarcts, and endocardial thrombosis in the right and left ventricle. Cardiomyopathy was also observed. Sixteen days after admission, the patient died from intracranial hemorrhage. Brain autopsy revealed two major findings: 1) large hemorrhagic infarction caused by cardiac embolism; and 2) granuloma and eosinophil infiltration. Vasculitis was accompanied by eosinophil infiltration in the cortical blood vessels and granuloma. CONCLUSIONS: In this case study, we report autopsy findings of brain infarction in a patient with EGPA and endocardial thrombosis. The brain infarction was caused by the cardiac embolisms and vasculitis.

Prospective, randomized, placebo-controlled trial evaluating the efficacy and safety of propofol sedation by anesthesiologists and gastroenterologist-led teams using computer-assisted personalized sedation during upper and lower gastrointestinal endoscopy.

BACKGROUND AND AIM: No randomized controlled studies comparing propofol versus no sedation have been reported. Comparative data demonstrating the efficacy and safety of propofol sedation by anesthesiologists (ANES), and gastroenterologist-led teams (GLT) using computer-assisted personalized sedation (CAPS), during routine gastrointestinal (GI) endoscopy in Japan do not exist. We aimed to demonstrate the safety and efficacy of propofol sedation versus no sedation (PLCB) when propofol is given by ANES or GLT, during routine GI endoscopy. METHODS: Two hundred and seventy two American Society of Anesthesiologists (ASA) class I or II adults were prospectively enrolled in this multicenter study and randomized into three groups (PLCB, ANES, GLT). Ability to maintain moderate sedation, defined as MOAA/S scores of 2-4 for ≥50% of all MOAA/S measurements from scope-in to scope-out, was the primary endpoint. Secondary endpoints included patient (PSSI) and clinician (CSSI) satisfaction. RESULTS: Proportion of subjects maintained in moderate sedation by ANES (88.1%) and GLT (94.5%) was significantly higher than PLCB (21.6%; P < 0.001); there was no difference between the ANES and GLT groups (P = 0.116). Mean PSSI scores for subjects sedated by ANES (81.2 ± 12.5) and GLT (80.8 ± 14.1) were significantly higher than PLCB (65.3 ± 19.7; P < 0.001) and mean CSSI scores were also significantly higher in both active treatment groups (75.5 ± 10.2, 77.9 ± 10.3) than PLCB (60.8 ± 18.6; P < 0.001). CONCLUSION: Moderate sedation can be achieved and maintained with propofol, improving both patient and physician satisfaction, when propofol is given by an anesthesiologist or a gastroenterologist-led team using CAPS.

Roles of oxidative stress and the mineralocorticoid receptor in cardiac pathology in a rat model of metabolic syndrome.

Oxidative stress and the mineralocorticoid receptor (MR) are implicated in the pathogenesis of salt-induced left ventricular (LV) diastolic dysfunction associated with metabolic syndrome (MetS). We recently characterized DahlS.Z-Lepr(fa) /Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of MetS. We investigated the pathophysiological roles of increased oxidative stress and MR activation in cardiac injury with this model. DS/obese rats were treated with the antioxidant tempol (1 mmol/L in drinking water) or the selective MR antagonist eplerenone (15 mg/kg per day, per os) for 5 weeks beginning at 10 weeks of age. The increased systolic blood pressure and LV hypertrophy that develop in untreated DS/obese rats were substantially ameliorated by eplerenone but not by tempol. Eplerenone also attenuated LV fibrosis and diastolic dysfunction more effectively than did tempol in DS/obese rats, whereas cardiac oxidative stress and inflammation were reduced similarly by both drugs. Both the ratio of plasma aldosterone concentration to plasma renin activity and cardiac expression of the MR and serum/glucocorticoid-regulated kinase 1 genes were decreased to a greater extent by eplerenone than by tempol. Our results indicate that both increased oxidative stress and MR activation in the heart may contribute to the development of LV remodeling and diastolic dysfunction in DS/obese rats. The superior cardioprotective action of eplerenone is likely attributable to its greater antihypertensive effect, which is likely related to its greater inhibition of aldosterone-MR activity in the cardiovascular system.

Premature cardiac senescence in DahlS.Z-Lepr(fa)/Lepr(fa) rats as a new animal model of metabolic syndrome.

Aging is accelerated by metabolic and cardiovascular diseases, and the risk of these diseases increases with age. Obesity is an important risk factor for many age-related diseases and is linked to reduced telomere length in white blood cells. We investigated whether cardiac senescence might be enhanced in DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, which we recently established as a new animal model of metabolic syndrome. The heart of DS/obese rats was compared with that of homozygous lean littermates (DahlS.Z-Lepr+/Lepr+, or DS/lean, rats). DS/obese rats manifested hypertension as well as left ventricular hypertrophy, fibrosis, and diastolic dysfunction at 18 weeks of age. Myocardial oxidative stress and inflammation were increased in DS/obese rats compared with DS/lean rats. Telomere length in myocardial cells did not differ between the two rat strains, whereas telomerase activity and expression of the telomerase reverse transcriptase gene were increased in DS/obese rats. Expression of the senescence-associated genes for checkpoint kinase 2 (Chk2), p53, and p21 as well as that of genes related to the renin-angiotensin-aldosterone system were also up-regulated in the DS/obese rat heart. Our results indicate that DS/obese rats undergo premature cardiac senescence as well as cardiac remodeling in association with the development of diastolic dysfunction in these animals.

Glucocorticoids activate cardiac mineralocorticoid receptors in adrenalectomized Dahl salt-sensitive rats.

We previously showed that selective mineralocorticoid receptor (MR) blockade by eplerenone is cardioprotective in Dahl salt-sensitive (DS) rats. To clarify the consequences of glucocorticoid-mediated MR activation in these animals, we investigated the effects of exogenous corticosterone on blood pressure as well as cardiac remodeling and function after adrenalectomy. DS rats were subjected to adrenalectomy at 6 weeks of age and thereafter fed a high-salt diet and administered corticosterone (20 mg/kg per day) or vehicle. Systolic blood pressure was higher in the corticosterone group than in the vehicle group at 7 weeks and thereafter. By 11 weeks, corticosterone had reduced left ventricular (LV) mass and induced LV diastolic dysfunction. The ratio of collagen type I to type III mRNA levels in the left ventricle was increased in the corticosterone group compared with the vehicle group. Administration of a non-antihypertensive dose of the MR antagonist spironolactone (20 mg/kg per day) from 6 weeks inhibited the effects of corticosterone on both the collagen type I to type III mRNA ratio and diastolic function without affecting the decrease in LV mass. Spironolactone attenuated both the increase in NADPH oxidase activity in the left ventricle and coronary vascular inflammatory responses apparent in the corticosterone group. These results indicate that exogenous glucocorticoids induce hypertension, cardiac remodeling, and diastolic dysfunction in adrenalectomized DS rats fed a high-salt diet. The cardiac effects of exogenous glucocorticoids are likely attributable, at least in part, to myocardial oxidative stress and coronary vascular inflammation induced by glucocorticoid-activated MRs.

Increased circulating polymorphonuclear myeloid-derived suppressor cells are associated with prognosis of metastatic castration-resistant prostate cancer.

Introduction: Myeloid-derived suppressor cell (MDSC) exhibits immunosuppressive functions and affects cancer progression, but its relationship with prostate cancer remains unclear. We elucidated the association of polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC) levels of the total peripheral blood mononuclear cells (PBMCs) with prostate cancer progression and evaluated their roles as prognostic indicators. Methods: We enrolled 115 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC, n = 62), metastatic hormone-sensitive prostate cancer (mHSPC, n = 23), and metastatic castration-resistant prostate cancer (mCRPC, n = 30). Subsequently, the proportions of MDSCs in each disease progression were compared. Log-rank tests and multivariate Cox regression analyses were performed to ascertain the associations of overall survival. Results: The patients with mCRPC had significantly higher PMN-MDSC percentage than those with nmHSPC and mHSPC (P = 7.73 × 10-5 and 0.0014). Significantly elevated M-MDSC levels were observed in mCRPC patients aged <70 years (P = 0.016) and with a body mass index (BMI) <25 kg/m2 (P = 0.043). The high PMN-MDSC group had notably shorter median survival duration (159 days) than the low PMN-MDSC group (768 days, log-rank P = 0.018). In the multivariate analysis including age, BMI, and MDSC subset, PMN-MDSC was significantly associated with prognosis (hazard ratios, 3.48; 95% confidence interval: 1.05-11.56, P = 0.042). Discussion: PMN-MDSC levels are significantly associated with mCRPC prognosis. Additionally, we highlight the remarkable associations of age and BMI with M-MDSC levels in mCRPC, offering novel insights into MDSC dynamics in prostate cancer progression.

Glucocorticoid-induced hypertension and cardiac injury: effects of mineralocorticoid and glucocorticoid receptor antagonism.

Glucocorticoids are widely administered for the treatment of various disorders, although their long-term use results in adverse effects associated with glucocorticoid excess. We investigated the pathophysiological roles of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the cardiac changes induced by exogenous corticosterone in rats. Corticosterone or vehicle was injected twice daily in rats from 8 to 12 weeks of age. The effects of the GR antagonist RU486, the MR antagonist spironolactone, or both agents on corticosterone action were also determined. Corticosterone induced hypertension, left ventricular (LV) fibrosis, and LV diastolic dysfunction. Neither RU486 nor spironolactone affected corticosterone-induced hypertension, whereas spironolactone, but not RU486, attenuated the effects of corticosterone on LV fibrosis and diastolic function. Corticosterone also increased cardiac oxidative stress and inflammation in a manner sensitive to spironolactone but not to RU486. The corticosterone-induced LV atrophy was not affected by either RU486 or spironolactone. Our results implicate MRs in the cardiac fibrosis and diastolic dysfunction, but not MRs or GRs in the cardiac atrophy, induced by corticosterone. Neither MRs nor GRs appear to contribute to corticosterone-induced hypertension.

Germ Cell Neoplasia in Situ Recognized Incidentally with Complaining of Discomfort in the Right Testis: A Case Report.

A 27-year-old man experienced discomfort in his right testis in early September, 2021, and visited the hospital five days later. Physical examination did not detect any abnormalities in the scrotum. However, an ultrasound revealed a tumor in the central part of the right testis, and a Magnetic Resonance Imaging (MRI) showed a tumor 2.7cm in diameter with clear boundaries and a marginally smooth surface. The level of alpha-fetoprotein, human chorionic gonadotropin, human chorionic gonadotropin-ß subunit, and lactate dehydrogenase were within normal limits. A Computed Tomography (CT) scan showed no abnormalities. We can't rule out the possibility of malignancy, right radical orchiectomy was performed with a diagnosis of right testicular tumor in mid-September 2021. The macroscopic lesion was 1.5×1.3 cm in size, and no viable tumorous cells were found pathologically. Atypical cells were observed in the seminiferous tubules from the spermatic cord, which were positively stained with immune-histochemical staining CD117 (c-kit), D2-40, and MIB-1 but negatively with alpha-fetoprotein, human chorionic gonadotropin, and human chorionic gonadotropin-ß subunit. The pathological diagnosis was germ cell neoplasia in situ, and no continuity was observed between these cells and bleeding necrosis. The patient has been followed up for 1 year and 4 months after surgery, with no recurrence or metastasis observed.

Non-operative treated spontaneous spinal epidural hematoma in a 12-year-old boy.

Spontaneous spinal epidural hematoma (SSEH) has been reported as a rare condition especially in childhood. Because its symptoms are atypical, it is not easy to diagnose the onset of SSEH. However, with wider use of magnetic resonance imaging (MRI), several SSEH cases, especially not requiring surgical intervention, have been reported. We report on a 12-year-old boy who presented with a 5-day history of progressive pain in his back and extremities and numbness of his lower legs. An MRI of the spine demonstrated a dorsal epidural hematoma extending from C4 to T4, and the axial scan of the MRI revealed a posterior hematoma. Neurological deficit was estimated as not severe and not progressive, therefore surgery was postponed, and the patient was discharged without surgical intervention. Seven months later, MRI and myelography were performed, and we confirmed that the spinal epidural hematoma was absorbed. There have been some cases showing spontaneous regression of SSEH, and in younger than 18 years old, most of those cases that were treated with hematopathy such as hemophilia and spontaneous regression after SSEH correlated to larger size of hematoma. Because of bleeding tendencies in these cases the spinal cord was not pressed by the hematoma; this contributed conclusively to the prognosis. On the contrary, the 12-year-old boy, not having bleeding tendency, had the larger lesion of SSEH and recovered spontaneously without surgical intervention. Evaluation of MRI findings and neurological deficits in SSEH cases is important for deciding the indication of surgical intervention.

Maternal Consumption of Dairy Products during Pregnancy Is Associated with Decreased Risk of Emotional Problems in 5-Year-Olds: The Kyushu Okinawa Maternal and Child Health Study.

Milk is a good source of fats, minerals, and vitamins. The present prebirth cohort study examined the association between maternal dairy product intake during pregnancy and the risk of childhood behavioral problems in 5-year-old Japanese children. Study subjects were 1199 mother-child pairs. Dietary intake was assessed using a diet history questionnaire. Emotional problems, conduct problems, hyperactivity problems, peer problems, and low prosocial behavior were assessed using the parent-reported version of the Strengths and Difficulties Questionnaire. Adjustments were made for a priori selected non-dietary confounders and potentially related dietary factors. A significant inverse exposure-response association was observed between maternal total dairy intake during pregnancy and the risk of childhood emotional problems (adjusted odds ratio [OR] between extreme quartiles, 0.62; 95% confidence interval [CI]: 0.36-1.03, p for trend, 0.04). The greater maternal consumption of cow's milk, but not yogurt or cheese, during pregnancy was independently related to a reduced risk of emotional problems in children (adjusted OR between extreme quartiles, 0.41; 95% CI: 0.23-0.70, p for trend, 0.003). Higher maternal consumption levels of total dairy products, especially cow's milk, during pregnancy may be associated with a decreased risk of emotional problems in 5-year-old children.

Angiotensin-converting enzyme inhibition promotes coronary angiogenesis in the failing heart of Dahl salt-sensitive hypertensive rats.

BACKGROUND: The biologic response to angiotensin-converting enzyme (ACE) inhibitors may be influenced by the local environment. The effect of ACE inhibition on coronary angiogenesis was investigated in a rat model of hypertensive heart failure. METHODS AND RESULTS: Dahl salt-sensitive (DS) rats fed a high-salt diet from 6 weeks of age were treated with a nonantihypertensive dose of the ACE inhibitor perindopril or vehicle from 9 to 18 weeks. Treatment of rats with perindopril attenuated the heart failure as well as cardiac hypertrophy and fibrosis that were manifest in the vehicle-treated animals. Myocardial capillary density as well as the expression of the bradykinin B(2) receptor, endothelial nitric oxide synthase, and vascular endothelial growth factor were reduced in the heart of vehicle-treated rats compared with that of nonhypertensive control rats, and all of these changes were attenuated by treatment with perindopril. CONCLUSIONS: These results indicate that ACE inhibition by perindopril promotes myocardial capillary formation as well as attenuates cardiac remodeling and failure in a manner independent from the antihypertensive effect of the drug in DS hypertensive rats. The beneficial cardiac effects of perindopril were associated with activation of the bradykinin-nitric oxide pathway in the heart.

Miniaturized high-resolution time-of-flight mass spectrometer MULTUM-S II with an infinite flight path.

A new miniature multiturn time-of-flight (TOF) analyzer "MULTUM-S II" has been designed and constructed. This instrument consists of an electron ionization source, the multiturn TOF ion optics, a detector, vacuum system, and electronic circuits. The multiturn TOF analyzer consists of four electrostatic toroidal sectors and two additional electric toroidal sectors for the purpose of ion injection/ejection. The size and weight of the system is less than 50 cm × 57 cm × 30 cm and 35 kg (including vacuum pumps and electronic circuits). The multiturn TOF analyzer is capable of high mass resolution because of its infinite flight path utilizing perfect space and time focused closed flight orbit. To evaluate the resolution in MULTUM-S II, separation of pyridine (¹²C5H5N) and the isotopic component of benzene (¹³C¹²C5H6) was performed at a mass resolution of about 20,000. Another performance characteristic of the MULTUM-S II was demonstrated by the separation of the greenhouse gas doublet CO2 and N2O (Δm = 0.0113 Da). While the mass difference is a mere 0.01 Da, the instrument could easily separate the two peaks at a calculated mass resolution of 31,600. The MULTUM-S II offers high mass resolution mass spectrometry in a miniaturized/portable enclosure.

The design and optimization of a series of 2-(pyridin-2-yl)-1H-benzimidazole compounds as allosteric glucokinase activators.

The optimization of a series of benzimidazole glucokinase activators is described. We identified a novel and potent achiral benzimidazole derivative as an allosteric GK activator. This activator was designed and synthesized via removal of the chiral center of the lead compound, 6-(N-acylpyrrolidin-2-yl)benzimidazole. The activator exhibited good PK profiles in rats and dogs, and significant hypoglycemic efficacy at 1 mg/kg po dosing in a rat OGTT model. The binding site and binding mode of the benzimidazole class of GKA with GK protein was confirmed by X-ray crystallographic analysis.

Safety and efficacy of intravenous ferric carboxymaltose in Japanese patients with iron-deficiency anemia caused by digestive diseases: an open-label, single-arm study.

Iron-deficiency anemia (IDA) accounts for majority of anemia. Although iron replacement therapy is effective, in Japan, conventional iron formulations have disadvantages such as gastrointestinal side effects for oral formulations and issues of frequent administration for intravenous (IV) formulations. Ferric carboxymaltose (FCM), which overcomes these limitations, is widely used as an IV iron source overseas. In this multi-center, open-label, single-arm study, we investigated the safety and efficacy of FCM up to 12 weeks after the start of administration in patients with IDA caused by digestive diseases. Thirty-nine patients diagnosed with IDA based on hemoglobin and serum ferritin levels were included. Eligible subjects were administered FCM until the total calculated iron dose (1000 or 1500 mg) was achieved over intervals of at least 1 week. A single iron dose was 500 mg. In the full analysis set (n = 39), the incidence of adverse events and adverse drug reactions was 71.8 and 48.7%, respectively. All events were as expected from the safety profile of IV iron. The mean change from baseline (10.39 g/dL) to the highest observed hemoglobin level was 3.31 g/dL. These results indicate the safety and efficacy of FCM for treating IDA caused by digestive diseases in Japanese patients.

Cellular kinetics and K-ras codon 12 mutations according to histomorphometric type of colorectal polyps with epithelial serrated proliferation.

Recent studies have examined cellular kinetics and genetic abnormalities in colorectal polyps with epithelial serrated proliferation (CP-ESP), including hyperplastic polyps, serrated adenomas, and tubulovillous adenomas. However, difficulty in histologically classifying these lesions and the lack of clear-cut diagnostic criteria have led to inconsistent findings. Some 60 cases of CP-ESP and 6 cases of CP-ESP with malignant transformation were studied. When nuclear size progressively decreased from the bottom and middle layers to the surface layer of the crypts, maturation gradient was considered positive. CP-ESP and CP-ESP adjacent to carcinoma were morphologically classified as being positive or negative for maturation gradient and inferior and lateral glandular branching. Cellular kinetics were evaluated using Ki-67 immunostaining, and polymerase chain reaction (PCR)-dependent preferential homoduplex formation assay was performed to detect the presence or absence of K-ras codon 12-point mutations. CP-ESPs were morphologically classified into five types. In CP-ESP of types 1 to 4, the proliferation zone was confined to the bottom layer of the crypts or extended from the bottom to middle layers. In contrast, the proliferation zone extended throughout the crypts in most type 5 lesions. K-ras codon 12 mutations were detected in only types 3 and 5 CP-ESP. The five histomorphologic types of CP-ESP have distinct patterns of cellular kinetics. Histomorphologically, type 3 CP-ESP is considered an atypical hyperplastic polyp, occasionally associated with an elongated proliferation zone or K-ras mutations. Preliminary evidence indicates some relation between K-ras mutations and structural atypia associated with lateral branching of the crypts.

Blockade of glucocorticoid receptors with RU486 attenuates cardiac damage and adipose tissue inflammation in a rat model of metabolic syndrome.

Glucocorticoids are stress hormones that modulate metabolic, inflammatory and cardiovascular processes. We recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive (DS) and Zucker rats, as a new animal model of metabolic syndrome (MetS). We have now investigated the effects of glucocorticoid receptor (GR) blockade on cardiac and adipose tissue pathology and gene expression, as well as on glucose metabolism in this model. DS/obese rats were treated with the GR blocker RU486 (2 mg kg(-1) per day, subcutaneous) for 4 weeks beginning at 9 weeks of age. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+), or DS/lean) littermates of DS/obese rats served as controls. Treatment of DS/obese rats with RU486 attenuated left ventricular (LV) fibrosis and diastolic dysfunction, as well as cardiac oxidative stress and inflammation, without affecting hypertension or LV hypertrophy. Administration of RU486 to DS/obese rats also inhibited the upregulation of GR and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) expression at the mRNA and protein levels in the heart; it attenuated adiposity and adipose tissue inflammation, as well as the upregulation of GR and 11ß-HSD1 mRNA and protein expression in adipose tissue; it ameliorated fasting hyperinsulinemia as well as insulin resistance and glucose intolerance. Our results thus implicate the glucocorticoid-GR axis in the pathophysiology of MetS, and they suggest that GR blockade has therapeutic potential for the treatment of this condition.

Comparative effects of valsartan in combination with cilnidipine or amlodipine on cardiac remodeling and diastolic dysfunction in Dahl salt-sensitive rats.

Angiotensin receptor blockers (ARBs) are often supplemented with calcium channel blockers (CCBs) for treatment of hypertension. We recently showed that the L/N-type CCB cilnidipine has superior cardioprotective effects compared with the L-type CCB amlodipine in Dahl salt-sensitive (DS) rats. We have now compared the effects of the ARB valsartan combined with cilnidipine or amlodipine on cardiac pathophysiology in DS rats. DS rats fed a high-salt diet from 6 weeks of age were treated with vehicle, valsartan alone (10 mg kg(-1) per day), or valsartan combined with either cilnidipine (1 mg kg(-1) per day) or amlodipine (1 mg kg(-1) per day) from 7 to 11 weeks. The salt-induced increase in systolic blood pressure apparent in the vehicle group was attenuated similarly in the three drug treatment groups. Valsartan-cilnidipine attenuated left ventricular (LV) fibrosis and diastolic dysfunction as well as cardiac oxidative stress and inflammation to a greater extent than did valsartan alone or valsartan-amlodipine. In addition, the increases in urinary excretion of dopamine and epinephrine as well as in cardiac renin-angiotensin-aldosterone-system (RAAS) gene expression apparent in vehicle-treated rats were attenuated to a greater extent by valsartan-cilnidipine than by the other two treatments. Valsartan-cilnidipine thus attenuated LV remodeling and diastolic dysfunction more effectively than did valsartan or valsartan-amlodipine in rats with salt-sensitive hypertension, and this superior cardioprotective action of valsartan-cilnidipine compared with valsartan-amlodipine is likely attributable, at least in part, to the greater antioxidant and antiinflammatory effects associated with both greater inhibition of cardiac RAAS gene expression and N-type calcium channel blockade.