Hypertension caused by transgenic overexpression of Rac1

Reactive oxygen species, including superoxide, are important mediators of the pathophysiology of hypertension. In the vasculature, superoxide antagonizes nitric oxide (NO*), resulting in increased vascular tone. The GTP binding protein Rac regulates a wide variety of cellular functions, including the activation of NADPH oxidase, the major source of O2*-in the blood vessel wall. An hypothesis is that Rac1 may act as an important regulator of vascular O2*- production, contributing to the balance between O2*- and NO* and maintaining consequent homeostasis of blood pressure. To alter the activity of vascular NADPH oxidase, the authors developed a transgenic animal model that overexpresses the human cDNA of the constitutively active mutant of Rac1 (RacCA) in smooth muscle cells using the smooth muscle +/--actin promoter. The RacCA transgenic had excessive amounts of O2*- in the vessel wall that, which led to heightened production of peroxynitrite, as detected by increased protein nitration and reduced NO* levels. RacCA mice developed moderate hypertension, which was corrected by N-acetyl-L-cysteine (NAC). RacCA transgenic mice also developed left ventricular hypertrophy as a secondary effect of pressure overload. The data suggest that Rac1 is a critical regulator of the redox state of blood vessels and homeostasis of blood pressure.     

Transfusion-induced malaria from an asymptomatic carrier

An asymptomatic malaria carrier who satisfied the currently recommended standards and criteria of the American Association of Blood Banks for blood donation was the source of the transfusion-induced malaria in this study. The risk of transfusion-induced malaria remains a very real threat in the United States. Any case of unexplained fever following transfusion should be considered as possibly caused by malaria. Delay of the proper diagnosis may be due to unfamiliarity of medical personnel with diagnostic criteria for malaria. Persons who give a history of having resided for long periods in malarious regions, even though they have remained asymptomatic for many years while residing in a malaria free area may still carry the more persistent malarial species and, therefore, should be rejected as donors of whole blood.     

Binasal visual field defects from simultaneous bilateral retinal infarctions in sickle cell disease

PURPOSE: To report a case of retinal occlusive disease producing binasal visual field defects in a patient with sickle cell (SC) disease. DESIGN: Retrospective case report. METHODS: A 21-year-old man with SC disease presented with binasal field defects and 20/20 acuity in each eye. RESULTS: Initial ophthalmoscopy and fluorescein angiography revealed no abnormalities. Optical coherence tomography (OCT) demonstrated bilateral temporal inner retinal hyperreflectivity, and multifocal electroretinography (mfERG) confirmed retinal dysfunction. Several weeks later, ophthalmoscopy and angiography demonstrated macular arteriolar occlusive disease. CONCLUSIONS: Simultaneous bilateral macular occlusive events are uncommon in patients particularly with SC disease. Although the binasal field defects raised the suspicion of a process affecting the optic nerves, the OCT and mfERG proved essential in diagnosing retinal rather than optic nerve disease.     

Recurrent vitreous hemorrhage secondary to haptic-induced chafing

CASE REPORT: After cataract extraction and placement of a posterior chamber intraocular lens, a 70-year-old man had 5 vitreous hemorrhages over 3 years. Iris transillumination defects and apposition of the nasal haptic and ciliary body were found. COMMENTS: Iris chafing is a rare complication of cataract extraction. Vitreous hemorrhage presumably resulted from iris erosion caused by the IOL haptic.     

Cardiovascular antioxidant therapy: a review of supplements, pharmacotherapies, and mechanisms

Oxidant stress plays an important role in the pathogenesis of atherosclerosis. In the late 1980s, biological studies demonstrated that oxygen-free radicals oxidize low-density lipoprotein-cholesterol, resulting in the creation of foam cells and inciting the cascade of biological events that ultimately result in the formation of atherosclerosis. In vitro studies showed the ability of antioxidant vitamins to scavenge free radicals and block the oxidation of low-density lipoprotein. This data was supported in vivo by early observational studies suggesting the benefit of antioxidants, particularly vitamin E, in the prevention of coronary artery disease. On the basis of these studies, the use of antioxidant supplements by the general population increased substantially and became a multibillion dollar industry. Despite strong biological evidence and promising observational data, more rigorous scientific evaluation did not support a causational relationship between vitamin supplements and lowering coronary artery disease risk. Several prospective, double-blind, placebo-controlled trials showed no benefit and possibly harmful effects. Therapies such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and statins, which are known to have benefit in preventing and treating atherosclerosis by reducing blood pressure and cholesterol, also have a "pleiotropic" effect in reducing the formation of reactive oxygen species (ROS). Advances in molecular biology and the study of ROS led to a better understanding of the mechanisms that govern their production and role in atherogenesis. This progress identified unforeseen pathways by which these drugs favorably alter the balance in ROS production, and have raised possibilities for future targeted therapies in the prevention of atherosclerosis.     

High prevalence of multidrug-resistant Gram-negative bacteria carriage in children screened prospectively for multidrug resistant organisms at admission to a paediatric hospital,Hamburg, Germany,September 2018 to May 2019

BackgroundIncreasing resistance to antibiotics poses medical challenges worldwide. Prospective data on carriage prevalence of multidrug resistant organisms (MDRO) in children at hospital admission are limited and associated risk factors are poorly defined.AimTo determine prevalence of MDRO carriage in children at admission to our paediatric hospital in Hamburg and to identify MDRO carriage risk factors.MethodsWe prospectively obtained and cultured nasal/throat and inguinal/anal swabs from children (≤ 18 years) at admission between September 2018 and May 2019 to determine prevalence of meticillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Gram-negative bacteria (MRGN) and vancomycin-resistant enterococcus (VRE) and associated species. We collected medical histories using a questionnaire and evaluated 31 risk factors using logistic regression models.ResultsMDRO carriage prevalence of 3,964 children was 4.31% (95% confidence interval (CI): 3.69–5.00). MRSA carriage prevalence was 0.68% (95% CI: 0.44–0.99), MRGN prevalence was 3.64% (95% CI: 3.07–4.28) and VRE prevalence 0.08% (95% CI: 0.02–0.22). MDRO carriage was associated with MRGN history (odds ratio (OR): 6.53; 95% CI: 2.58–16.13), chronic condition requiring permanent care (OR: 2.67; 95% CI: 1.07–6.13), antibiotic therapy (OR: 1.92, 95% CI: 1.24–2.94), living in a care facility (OR: 3.34; 95% CI: 0.72–12.44) and refugee status in previous 12 months (OR: 1.91; 95% CI: 0.27–8.02). Compared to established practice, screening using risk-factors had better diagnostic sensitivity (86.13%; 95% CI: 80.89–91.40) and specificity (73.54%; 95% CI: 72.12–74.97).ConclusionMRGN carriage was higher than MRSA and VRE. Extended risk-factor-based admission screening system seems warranted.     

Determination of intestinal viability by Doppler ultrasound.

The Doppler ultrasonic flowmeter was used to determine intestinal serosal and mesenteric blood flows in 130 patients who underwent abdominal aortic vascular procedures and in 14 patients who underwent general surgical procedures. Temporary occlusion of the inferior mesenteric artery (IMA) during aortic surgery resulted in the absence or marked diminution of collateral blood flow over the left side of the colon in eight patients. One patient had the flow in the IMA preserved by proper placement of an end-to-side aortofemoral Dacron prosthesis, whereas the other seven patients underwent replantation of the IMA into the Dacron prosthesis. All patients did well postoperatively. In the 14 general surgical patients, intestinal viability and collateral mesenteric blood flows were determined, which demonstrated that the presence of audible arterial blood flow correlated with ultimate bowel viability. We recommend the use of the Doppler ultrasonic flowmeter in abdominal aortic revascularization procedures to determine the need for IMA reconstruction as well as in general surgical procedures where the surgeon desires a more objective assessment of intestinal viability.     

The effect of selective antihypertensive drugs on the vascular remodeling-associated hypertension: insights from a profilin1 transgenic mouse model

Thienopyridines (ticlopidine, clopidogrel, and prasugrel) require in vivo metabolism to exhibit a critical thiol group in the active form that binds to the P2Y12 platelet receptor to inhibit platelet activation. We hypothesized that formation of thienopyridine-derived nitrosothiols (ticlopidine-SNO, clopidogrel-SNO, and prasugrel-SNO) occurs directly from the respective parent drug. Pharmaceutical-grade thienopyridine (ticlopidine, clopidogrel chloride, clopidogrel sulfate, clopidogrel besylate, or prasugrel) was added to nitrite in aqueous solution to form the respective thienopyridine-SNO (Th-SNO). An isolated aortic ring preparation was used to test vasoactivity of the Th-SNO derivatives. Increasing nitrite availability resulted in increased Th-SNO formation for all drugs (other than ticlopidine). Th-SNO induced significant endothelium-independent relaxation of preconstricted aortic rings. Clopidogrel-chloride-SNO displayed rapid-release kinetics in a chemical environment, which was reflected by immediate and transient vasorelaxation when compared with the SNO derivatives of the other thienopyridines. Accounting for differences in yield, clopidogrel-chloride-SNO exhibited the greatest propensity to immediately relax vascular tissue. Th-SNO derivatives exhibit nitrovasodilator properties by supplying NO that can directly activate vascular soluble guanylate cyclase to induce vasorelaxation. Differences in SNO yield and vasoactivity exist between thienopyridine preparations that might be important to our understanding of the direct pharmacological effectiveness of thienopyridines on vascular and platelet function.     

Association of preoperative parameters with postoperative mortality and long-term survival after liver transplantation

Background

The ability of Child–Turcotte–Pugh (CTP) or Model for End-Stage Liver Disease (MELD) scores to predict recipient survival after liver transplantation is controversial. This analysis aims to identify preoperative parameters that might be associated with early postoperative mortality and long-term survival after liver transplantation.

Methods

We studied a total of 15 parameters, using both univariate and multivariate models, among adults who underwent primary liver transplantation.

Results

A total of 458 primary adult liver transplants were performed. Fifty-seven (12.44%) patients died during the first 3 postoperative months and composed the early mortality group. The remaining 401 patients composed the long-term patient survival group. The parameters that were identified through univariate analysis to be associated with early postoperative mortality were CTP score, MELD score, bilirubin, creatinine, international normalized ratio and warm ischemia time (WIT). In all multivariate models, WIT retained its statistical significance. The 10-year long-term survival was 65%. The parameters that were identified to be independent predictors of long-term survival were the recipient’s sex (improved survival in women, p = 0.005), diagnosis of hepatocellular cancer (p = 0.015) and recipient’s age (p = 0.024).

Conclusion

Either CTP or MELD score, in conjunction with WIT, might have a role in predicting early postoperative mortality after liver transplantation, whereas the recipient’s sex and the absence of hepatocellular cancer are associated with improved long-term survival.