Usefulness of magnetic resonance imaging in the assessment of endomyocardial disease

Endomyocardial disease is a restrictive cardiomyopathy that includes L?ffler endocarditis, which is characterized by hypereosinophilia, and endomyocardial fibrosis, which is not. Echocardiography enables cardiac function and anatomy to be assessed and the differential diagnosis of other causes of restrictive disease, but magnetic resonance imaging provides information about the tissue itself. Furthermore, paramagnetic contrast agents are useful in detecting myocardial abnormalities. We report three cases of endomyocardial disease and the typical findings of magnetic resonance imaging.     

Role of superoxide in modulating the renal effects of angiotensin II

Angiotensin II is known to stimulate NADPH oxidase-dependent superoxide (O2-) generation, which may contribute to the acute renal vasoconstrictor and antinatriuretic actions of this peptide. To evaluate this hypothesis, the effects of a superoxide dismutase mimetic (tempol) or a NADPH inhibitor (apocynin) on the angiotensin renal actions were studied. Renal cortical nitric oxide (NO) was measured electrochemically in vivo. Tempol increased sodium excretion and NO levels. Apocynin raised renal blood flow, glomerular filtration rate, sodium excretion, and NO levels. These results indicate the presence of an endogenous NADPH oxidase-dependent O2- generation that may modulate renal function by scavenging NO. Angiotensin II infusion reduced renal blood flow, glomerular filtration, sodium excretion, and NO levels in a dose-dependent manner. The angiotensin receptor antagonist valsartan, tempol, or apocynin blunted the angiotensin effects on renal excretion and NO, suggesting that angiotensin receptors stimulation induces the NADPH oxidase-dependent O2- generation that might reduce NO bioavailability. This idea is supported by the finding that angiotensin increased O2- generation in renal homogenates, and this effect was prevented by valsartan, apocynin, or tempol. These results indicate that some of the acute renal effects of angiotensin II may be enhanced by an increased NADPH oxidase-derived O2- production that reduces renal NO bioavailability.     

Association between the A1166C polymorphism of the angiotensin II receptor type 1 and progression of chronic renal insufficiency

BACKGROUND: In some studies genetic variation in the renin-angiotensin-aldosterone system (RAAS) has been associated with hypertension and rapid progression of renal insufficiency to end-stage renal disease (ESRD). Most of these studies do not take into account covariables influencing progression. We studied retrospectively the role of angiotensinogen (AGT) M235T, angiotensin converting enzyme (ACE) insertion/deletion (I/D), angiotensin II type 1 receptor (AT1R) A1166C, aldosterone syntase (CYP11B2) -344C/T and intron 2 W/C polymorphisms in conjunction with clinical and biochemical covariables on the rate of progression of renal insufficiency in a group of patients with ESRD of various etiologies. METHODS: Genotyping was performed by polymerase chain reaction (PCR) in 104 ESRD patients (62 males and 42 females), aged 64 +/- 14 years (mean +/- SD) with mean initial serum creatinine of 2.6 +/- 1.1 mg/dL and a mean time to reach ESRD of 52 +/- 38 months. RESULTS: The univariate analysis showed that there was a significant difference in the values of the slopes among the AT1R A1166C polymorphism genotypes: AA -4.87 +/- 0.22, AC -5.09 +/- 0.65 and CC -5.52 +/- 0.66 (p<0.05). None of the remainder polymorphisms showed significant association with progression. Stepwise multiple regression analysis including all the clinical, biochemical and genetic variables showed that only systolic blood pressure (SBP), serum PTHi and AT1R genotype were independently associated with the rate of progression, excluding the other variables from the model. CONCLUSIONS: These results indicate that susceptibility to faster progression to ESRD is associated with the AT1R A1166C polymorphism. This association remains significant after adjustment for relevant covariates, highlighting the importance of analyzing genetic risk factors in the context of clinical and biochemical variables.     

Contributions of Electromigration and Electroosmosis to Iontophoretic Drug Delivery

Purpose. To determine the electromigration and electroosmotic contributions to the iontophoretic delivery of lidocaine hydrochloride, in addition to the more-lipophilic quinine and propranolol hydrochlorides, in the presence and absence of background electrolyte.Methods: In vitro experiments, using excised pig ear skin and both vertical and side-by-side diffusion cells, were performed as a function of drug concentration and with and without background electrolytes in the anodal formulation. Concomitantly, the contribution of electroosmosis in each experimental configuration was monitored by following the transport of the neutral, polar marker molecule, mannitol. Results. Electromigration was the dominant mechanism of drug iontophoresis (typically representing 90% of the total flux). In the presence of background electrolyte, lidocaine delivery increased linearly with concentration as it competed more and more effectively with Na⁺ to carry the charge across the skin. However, iontophoretic delivery of quinine and propranolol increased non-linearly with concentration. Without electrolytes, on the other hand, electrotransport of the three drugs was essentially independent of concentration over the range 1-100 mM. Transport efficiency of lidocaine was 10%, whereas that of the more lipophilic compounds was significanly less, with the major charge carrier being Cl^– moving from beneath the skin into the anodal chamber. Both quinine and propranolol induced a concentration-dependent attenuation of electroosmotic flow in the normal anode-to-cathode direction. Conclusion. Dissecting apart the mechanistic contributions to iontophoretic drug delivery is key to the optimization of the formulation, and to the efficient use of the drug substance.     

Beta-amyloid25-35 inhibits glutamate uptake in cultured neurons and astrocytes: modulation of uptake as a survival mechanism

Glutamate transporters are vulnerable to oxidants resulting in reduced uptake function. We have studied the effects of beta-amyloid(25-35) (beta A(25-35)) on [(3)H]-glutamate uptake on cortical neuron or astrocyte cultures in comparison with a scrambled peptide (SCR) and dihydrokainic acid (DHK), a prototypic uptake inhibitor. beta A(25-35) was more potent than DHK in inhibiting glutamate uptake and the effects of both were more marked on astrocytes than on neurons. At 24 h, beta A(25-35) dose-dependently (0.5-15 microM) increased glutamate levels in media from neuron cultures. DHK only enhanced extracellular glutamate at the highest concentration tested (2500 microM). beta A(25-35) induced gradual neurotoxicity (0.1-50 microM) over time. Exposure to beta A(25-35) resulted in increased uptake in astrocytes (0.25-5 microM) and neurons (0.5-15 microM) surviving its toxic effects. However, exposure to DHK (2.5-2500 microM) did not induce neurotoxicity nor modulated uptake. These results indicate that, while inhibition of glutamate uptake may be involved in the neurotoxic effects of beta A(25-35), enhancement of uptake may be a survival mechanism following exposure to beta A(25-35).     

A multicentre observational study of the effectiveness,safety and economic impact of nivolumab on non-small-cell lung cancer in real clinical practice

International Journal of Clinical Pharmacy - Background Immunotherapy has become a standard treatment for lung cancer; however, the high cost makes it necessary to assess health outcomes. Objective...