Angiotensin-converting enzyme (ACE) 2, a newly emerging component of the renin-angiotensin system, is presumed to be a counterregulator against ACE in generating and degrading angiotensin II. It remains to be elucidated how mRNA levels of these two genes are quantitatively regulated in the kidney and also what kind of clinicopathological characteristics could influence the gene expressions in humans. Seventy-eight cases of biopsy-proven renal conditions were examined in detail. Total RNA from a small part of each renal cortical biopsy specimen was reverse transcribed, and the resultant cDNA was amplified for ACE, ACE2, and glyceraldehyde-3-phosphate dehydrogenase with a real-time PCR system. Then we investigated the relationship between clinicopathological variables and mRNA levels adjusted for glyceraldehyde-3-phosphate dehydrogenase. Statistically significant correlation was not observed between any clinicopathological variables and either of the gene expressions by pairwise comparison. However, a strong correlation was observed between the gene expressions of ACE and those of ACE2. Moreover, the ACE to ACE2 ratio was significantly higher in subjects with hypertension (HT) than that in subjects without HT. Whereas parameters of renal function, e.g. urinary protein excretion (UPE) and creatinine clearance (Ccr), are not significantly related to the ACE to ACE2 ratio as a whole, the HT status may reflect disease-induced deterioration of renal function. That is, UPE and Ccr of subjects with HT are significantly different from those without HT, in which a significant correlation is also observed between UPE and Ccr. Finally, stepwise regression analysis further revealed that only the HT status is an independent confounding determinant of the ACE to ACE2 ratio among the variables tested. Our data suggest that ACE2 might play an important role in maintaining a balanced status of local renin-angiotensin system synergistically with ACE by counterregulatory effects confounded by the presence of hypertension. Thus, ACE2 may exert pivotal effects on cardiovascular and renal conditions.

OBJECTIVE -Recent studies have proved that blockade of the renin-angiotensin system (RAS) retards the progression of diabetic nephropathy, whereas hyporeninemia is known as a typical state in diabetic subjects. The purpose of this study is to determine whether expression levels of RAS differ between nondiabetic and diabetic renal tissues with accurate quantitative method.RESEARCH DESIGN AND METHODS -Subjects were 66 nondiabetic and 8 diabetic patients with biopsy-proven renal diseases. The eight diabetic subjects suffered from type 2 diabetes with overt proteinuria. Renal histology revealed typical diffuse or nodular lesions with linear IgG deposit on immunofluorescent staining and thickened basement membrane on electronic microscopy. Total RNA from a small part of the renal cortical biopsy specimens was reverse-transcribed, and the resultant cDNA was amplified for new major components of RAS (i.e., renin, renin receptor, angiotensinogen, ACE, ACE2, angiotensin II type 1 receptor, and angiotensin II type 2 receptor) and measured.RESULTS -Among these components, a significant upregulation was observed in the ACE gene in diabetic renal tissue.CONCLUSIONS -The results suggest that renal tissue RAS might be activated in the respect that ACE gene expression is upregulated in spite of a tendency to low renin expression in type 2 diabetic nephropathy. Diabetes Care 29:848 -852, 2006R ecently proposed mechanisms for the development of diabetic nephropathy include glomerular hyperfiltration (1), disorientation of intracellular signal transduction (2), and involvement of advanced glycation end products (3). Activation of the reninangiotensin system (RAS) by high glucose, mechanical stress, and proteinuria has been implicated in the major changes associated with diabetic nephropathy (4). Thus, renal tissue activation of RAS is thought to contribute to deterioration in renal function of diabetic nephropathy. Recently, a number of large-scale prospective studies have proven that blockade of the system with ACE inhibitors and angiotensin II receptor blockers (ARBs) retards the progression of diabetic nephropathy (5-11). Actually, several studies suggest that the RAS is activated especially at the early stage (12,13). However, from early studies, hyporeninemia has been well known as a typical state of circulatory RAS in diabetic subjects at the late stage (14,15). Although the tissue RAS is thought to be controlled independently of the circulatory RAS, this apparent paradox is still difficult to interpret. It is supposed that the tissue RAS is activated in contrast to the circulatory RAS, and several non-or semiquantitative evaluations were made. However, direct or quantitative evidence in human diabetic nephropathy is very scarce so far. Furthermore, new major components for RAS, renin receptor (RER) (16), and ACE2 (17) have emerged recently.The purpose of this study is to determine whether expression levels of RAS including RER and ACE2 differ between nondiabetic and diabetic human renal tissues with full quantitative evalua...

OBJECTIVERecent studies have proven the favorable effects of angiotensin receptor blockers (ARBs) on cardiovascular and renal disorders. However, determinants of the response to ARBs remain unclear. We substantiated the hypothesis that genetic variants of the renin-angiotensin system (RAS) have significant impacts on the response to ARBs.RESEARCH DESIGN AND METHODSSubjects comprised 231 consecutively enrolled hypertensive individuals including 45 type 2 diabetic subjects. Five genetic variants of the RAS, i.e., renin (REN) C-5312T, ACE insertion/deletion, angiotensinogen M235T, angiotensin II type 1 receptor A1166C, and angiotensin II type 2 receptor C3123A were assayed by PCR and restriction fragment-length polymorphism. A dose of 40–160 mg/day of valsartan was administered for 3 months as a monotherapy.RESULTSChanges in diastolic blood pressure significantly differed between genotypes of REN C-5312T: 10.7-mmHg reduction (from 95.9 ± 12.9 to 85.2 ± 11.4) in CC versus 7.0-mmHg reduction (from 94.7 ± 14.0 to 87.7 ± 12.6) in CT/TT (P = 0.02 for interactive effects of valsartan and genotype). Responder rates also differed between the genotypes: 72.8% in CC versus 58.0% in CT/TT (P = 0.03). Univariate analysis indicated a significant association of response to valsartan with blood pressure, diabetes, plasma aldosterone concentration, and CC homozygotes of REN C-5312T. Finally, multiple logistic regression analysis revealed that systolic blood pressure, CC homozygotes of REN C-5312T, and diabetes were independent predictors for responders with odds ratios (95% CI) of 2.49 (1.41–4.42), 2.03 (1.10–3.74), and 0.48 (0.24–0.96), respectively.CONCLUSIONSThis study provides strong support that a genetic variant of REN C-5312T and diabetes contribute to the effects of ARBs and are independent predictors for responder. Thus, in treatment of hypertension with ARBs, a new possibility for personalized medicine has been shown.

Background: Tracheal intubation (TI) practice across pediatric emergency departments (EDs) has not been comprehensively reported. We aim to describe TI practice and outcomes in pediatric EDs in contrast to those in intensive are units (ICUs) and use the data to identify quality improvement targets. Methods: Consecutive TI encounters from pediatric EDs and ICUs in the National Emergency Airway Registry for Children (NEAR4KIDS) database from 2015 to 2018 were analyzed for patient, provider, and practice characteristics and outcomes: adverse TI-associated events (TIAEs), oxygen desaturation (SpO 2 < 80%), and procedural success. A multivariable model identified factors associated with TIAEs in the ED. Results: A total of 756 TIs in 13 pediatric EDs and 12,512 TIs in 51 pediatric/cardiac ICUs were reported. Median (interquartile range [IQR]) patient age for ED TIs was higher (32 [7-108] months) than that for ICU TIs (15 [3-91] months; p < 0.001).

Background and objectiveMany surveys of neural integrity of the cerebral white matter with psychiatric diseases on diffusion tensor imaging have recently been performed, but these mainly utilize fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) values, and the results were inconsistent and not fully applied clinically. In this study, we investigated the possibility of differentiating between Alzheimer’s disease (AD) and elderly major depressive disorder (MDD) patients in whom early-stage symptoms are difficult to diagnose, by visually evaluating cerebral nerve fascicles utilizing diffusion tensor tractography. We also measured and evaluated FA and ADC values at the same time.Subjects and methodsThe subjects included 13 AD patients (age: 69.5 ± 5.1 years), 19 MDD patients (65.8 ± 5.7 years), and 22 healthy control (HC) subjects (67.4 ± 4.8 years). Images were acquired using a 1.5T magnetic resonance imaging device and analyzed by diffusion tensor tractography analysis software.ResultsDepiction of the anterior thalamic radiation (ATR) tended to be poor in AD patients unlike in MDD patients and HC subjects. The FA values in the left superior longitudinal fasciculus and fornix (FX) in AD patients were significantly different from those in MDD patients and HC subjects. The ADC values in the bilateral ATR and left superior and inferior longitudinal fasciculi, left inferior fronto-occipital fasciculus, and FX in AD patients were significantly different from those in MDD patients and HC subjects.ConclusionVisual evaluation of the ATR in combination with the FA values of the left superior longitudinal fasciculus and FX and ADC values of the bilateral ATR, left superior and inferior longitudinal fasciculi, left inferior fronto-occipital fasciculus, and FX is useful for differentiating between AD and MDD patients, which further suggests that it may become a useful auxiliary diagnostic tool.