Melatonin reduces oxidative stress and improves vascular function in pulmonary hypertensive newborn sheep

Pulmonary hypertension of the newborn (PHN) constitutes a critical condition with severe cardiovascular and neurological consequences. One of its main causes is hypoxia during gestation, and thus, it is a public health concern in populations living above 2500 m. Although some mechanisms are recognized, the pathophysiological facts that lead to PHN are not fully understood, which explains the lack of an effective treatment. Oxidative stress is one of the proposed mechanisms inducing pulmonary vascular dysfunction and PHN. Therefore, we assessed whether melatonin, a potent antioxidant, improves pulmonary vascular function. Twelve newborn sheep were gestated, born, and raised at 3600 meters. At 3 days old, lambs were catheterized and daily cardiovascular measurements were recorded. Lambs were divided into two groups, one received daily vehicle as control and another received daily melatonin (1 mg/kg/d), for 8 days. At 11 days old, lung tissue and small pulmonary arteries (SPA) were collected. Melatonin decreased pulmonary pressure and resistance for the first 3 days of treatment. Further, melatonin significantly improved the vasodilator function of SPA, enhancing the endothelial‐ and muscular‐dependent pathways. This was associated with an enhanced nitric oxide‐dependent and nitric oxide independent vasodilator components and with increased nitric oxide bioavailability in lung tissue. Further, melatonin reduced the pulmonary oxidative stress markers and increased enzymatic and nonenzymatic antioxidant capacity. Finally, these effects were associated with an increase of lumen diameter and a mild decrease in the wall of the pulmonary arteries. These outcomes support the use of melatonin as an adjuvant in the treatment for PHN.     

Magnetic Resonance Cisternography in the Diagnosis of Delayed Iatrogenic Cerebrospinal Fistula: A Case Report

A 52–year–old woman presented with a clinical picture consistent with bacterial meningitis 3 years after functional endoscopic sinus surgery. Diagnosis of a cerebrospinal fluid (CSF) fistula was made clinically, and the site of the fistula was confirmed using magnetic resonance cisternography. The utilization of this technique in the diagnosis of CSF disorders is gaining popularity. Its usefulness in the context of other imaging modalities is discussed.     

Tube feeding in mechanically ventilated critically ill patients: a prospective clinical audit.

BACKGROUND: When and whether early enteral nutrition (EN) benefits critically ill patients is debatable. This prospective clinical audit aimed to evaluate the feasibility of an early EN protocol and to identify factors that may hinder EN delivery in critically ill patients. METHODS: Thirty-six medical patients with severe respiratory failure under invasive ventilation and scheduled to receive early EN, with a length of ICU stay >72 hours, were included. As asserted by the Society of Critical Care Medicine, 8% of patients were priority 1, 72% priority 2, and 20% priority 3 for intensive therapeutic and vital support interventions. RESULTS: Overall, because of gastrointestinal complications, only 39% of the prescribed EN was administered; only 8 (22%) patients did tolerate EN within the first 48 hours after admission and did achieve their minimum nutritional requirements. The most frequent complication (78%) was high volume of gastric residuals followed by abdominal distention (61%), both associated with hemodynamic instability (HI). Gastrointestinal dysfunction was associated with high Acute Physiologic and Chronic Health Evaluation II score (p = .01), total calorie intake (p = .02), total carbohydrate intake (p = .02), HI (p = .03), malnutrition (p = .04), volume of IV saline (p = .04), and concurrent vasoactive drug administration (p = .05). CONCLUSIONS: This audit in extremely severe intensive care patients identified several factors that impair gastrointestinal function and preclude EN at any stage, namely early EN. Nutrition management must take into account concurrent therapies, given their potential interference with nutrition and organ function.     

In vitro effects of Nd:YAG laser radiation on blood: A quantitative and morphologic analysis

Use of the Neodymium: yttrium -aluminum -garnet (Nd:YAG) laser to recanalize stenosed arteries may require delivery of the beam through blood. To assess the degree of hemolysis and debris formation, 54 samples of citrated whole blood were exposed to Nd:YAG laser radiation of varying powers (10, 20 and 30 watts) and duration (1, 2.5 and 5 seconds). Compared to control samples which were not subjected to laser light, there was no significant decrease in hematocrit (41 to 40.5 +/- 5%), hemoglobin concentration (13.8 to 13.8 +/- .06 g/1OO ml), or increase in "free" hemoglobin concentration. Debris weight (from .45 +/- .002 to .45 +/- .002 mg), as well as the white blood cell count, was also not significantly changed (from 5,400 to 5,200 +/- 240 WBC/cm). Light microscopy examination of debris from samples of whole blood, washed erythrocytes, and platelet-rich plasma subjected to the laser at 30 watts for five seconds failed to demonstrate the presence of membrane denaturation of blood elements, as compared with the morphologic changes observed in whole blood samples exposed to a "hot tip" rather than Nd:YAG laser radiation. Nd:YAG laser can be used intravascularly without fear of hemolysis or debris "micro-embolization" up to a power of 30 watts for five seconds.     

Massive pulmonary embolism: triple-armed therapy

Many patients who suffer a massive pulmonary embolus die despite emergent therapy. In these desperately ill patients an aggressive, combined method of management was initiated to improve their chances and quality of survival. During a 5-year period 10 patients were treated with (1) low-dose topical, intrapulmonary thrombolytic therapy to dissolve thrombus, (streptokinase or urokinase); (2) anticoagulation to prevent thrombus propagation (heparin); and (3) the simultaneous insertion of a Greenfield filter to prevent the early, recurrent, and therefore potentially fatal pulmonary embolus--"triple-armed therapy." Thrombolytic therapy was administered through a Swan-Ganz catheter wedged against the pulmonary embolus. During the same interval 10 other patients also sustained massive pulmonary emboli but were treated only with systemic heparin. Serial pulmonary arteriography was performed daily. The patients treated by triple-armed therapy responded favorably with a rapid (less than 6 hours), significant improvement in PaO2, pulmonary artery pressure, cardiac output, pulmonary vascular resistance, and blood pressure, compared with patients treated with continuous heparin alone. Nine patients in the triple-armed therapy group survived whereas only six in the heparin group survived. Two additional patients were treated by triple-armed therapy and had thrombolysis with triple-armed therapy with tissue plasminogen activator; these patients demonstrated the most rapid improvement in cardiorespiratory dynamics and arteriographic clearance of emboli. This management protocol shows promise for patients who sustain a massive pulmonary embolus, because it reduces the morbidity associated with pulmonary embolectomy while avoiding the hazards associated with systemic thrombolytic therapy.     

Delayed effects of thallium in the rat brain: regional changes in lipid peroxidation and behavioral markers, but moderate alterations in antioxidants, after a single administration.

Thallium (Tl+) toxicity has been related with the generation of reactive oxygen species (ROS) and oxidative stress (OS) in the central nervous system. Since changes in endogenous antioxidant systems might contribute to acute Tl+-induced OS and neurotoxicity, in this study we measured the metal concentration and the levels of lipid peroxidation (LP) in different brain regions (hypothalamus (Ht); cerebellum (Ce); striatum (S); hippocampus (Hc) and frontal cortex (Cx)) in possible correlation with the content of reduced glutathione (GSH), the activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD), and the animal performance in behavioral tests, all evaluated after a single administration of thallium acetate (8 or 16 mg/kg, i.p.) to rats. Seven days after Tl+ administration, the metal was homogeneously and dose-dependently accumulated in all regions evaluated. LP was increased in Ht, Ce and S, while GSH was depleted in S. Cu,Zn-SOD activity was also decreased in Ht and S. All these changes occurred with 16 mg/kg dose and at 7 days after treatment, but not at 1 or 3 days. In addition, Tl+-treated animals exhibited general hypokinesis, but no changes were observed in spatial learning. Our findings suggest that a delayed response of the brain to Tl+ may be the result of its residual levels. Also, despite the regional alterations produced by Tl+ in LP and the limited changes in endogenous antioxidants, there is a correlation between the Tl+-induced oxidative damage and the affected behavioral tasks, suggesting that, although still moderate, Tl+ evokes neurotoxic patterns under the experimental conditions tested.     

Cross-neutralization of the neurotoxicity of Crotalus durissus terrificus and Bothrops jararacussu venoms by antisera against crotoxin and phospholipase A2 from Crotalus durissus cascavella venom.

We have previously demonstrated that rabbit antisera raised against crotoxin from Crotalus durissus cascavella venom (cdc-crotoxin) and its PLA2 (cdc-PLA2) neutralized the neurotoxicity of this venom and its crotoxin. In this study, we examined the ability of these antisera to neutralize the neurotoxicity of Crotalus durissus terrificus and Bothrops jararacussu venoms and their major toxins, cdt-crotoxin and bothropstoxin-I (BthTX-I), respectively, in mouse isolated phrenic nerve-diaphragm preparations. Immunoblotting showed that antiserum to cdc-crotoxin recognized cdt-crotoxin and BthTX-I, while antiserum to cdc-PLA2 recognized cdt-PLA2 and BthTX-I. ELISA corroborated this cross-reactivity. Antiserum to cdc-crotoxin prevented the neuromuscular blockade caused by C. d. terrificus venom and its crotoxin at a venom/crotoxin:antiserum ratio of 1:3. Antiserum to cdc-PLA2 also neutralized the neuromuscular blockade caused by C. d. terrificus venom or its crotoxin at venom or toxin:antiserum ratios of 1:3 and 1:1, respectively. The neuromuscular blockade caused by B. jararacussu venom and BthTX-I was also neutralized by the antisera to cdc-crotoxin and cdc-PLA2 at a venom/toxin:antiserum ratio of 1:10 for both. Commercial equine antivenom raised against C. d. terrificus venom was effective in preventing the neuromuscular blockade typical of B. jararacussu venom (venom:antivenom ratio of 1:2), whereas for BthTX-I the ratio was 1:10. These results show that antiserum produced against PLA2, the major toxin in C. durissus cascavella venom, efficiently neutralized the neurotoxicity of C. d. terrificus and B. jararacussu venoms and their PLA2 toxins.     

Fixed-dose combination therapy of nebivolol and valsartan for the treatment of hypertension

Recent large clinical trials have refuted earlier suggestions from the Joint National Committee 8 committee that less aggressive targets for blood pressure control were all that could be justified in most hypertensive patients. It now does appear that in fact “lower is better,” with blood pressure targets < 120/80 mm Hg appropriate for many hypertensive patients. Two drug combinations are often indicated as initial therapy if a 20/10 mm Hg or greater blood pressure reduction is necessary to reach target. Combinations consisting of β-blockers and renin-angiotensin-aldosterone system inhibitors have previously been deemed “less effective,” based on partially overlapping mechanisms of action and limited clinical trial evidence. Nebivolol is a vasodilating β₁-selective blocker and β₃- adrenoceptor agonist; β₃-adrenoceptor activation increases nitric oxide concentrations and thus explains the vasodilatory effect. A recent 8-week randomized trial (N=4,161) in individuals with stage 1-2 hypertension demonstrated that single-pill fixed dose combinations (FDC) of nebivolol and valsartan, an angiotensin II subtype 1 receptor blocker, were more effective in reducing blood pressure than the corresponding monotherapies, with comparable tolerability. In addition, an ABPM-biomarkers substudy from that trial (n=805) demonstrated that the FDC prevented a valsartan-induced increase in plasma renin activity, and that the nebivolol/valsartan 20/320 mg/day dose reduced plasma aldosterone concentration significantly more than valsartan 320 mg/day. This article will describe the properties of nebivolol that make it unique and separate it from other β-blockers, and will further support the pharmacological advantages of this particular combination.     

One- and two-stage surgical revision of peri-prosthetic joint infection of the hip: a pooled individual participant data analysis of 44 cohort studies

One-stage and two-stage revision strategies are the two main options for treating established chronic peri-prosthetic joint infection (PJI) of the hip; however, there is uncertainty regarding which is the best treatment option. We aimed to compare the risk of re-infection between the two revision strategies using pooled individual participant data (IPD). Observational cohort studies with PJI of the hip treated exclusively by one- or two-stage revision and reporting re-infection outcomes were retrieved by searching MEDLINE, EMBASE, Web of Science, The Cochrane Library, and the WHO International Clinical Trials Registry Platform; as well as email contact with investigators. We analysed IPD of 1856 participants with PJI of the hip from 44 cohorts across four continents. The primary outcome was re-infection (recurrence of infection by the same organism(s) and/or re-infection with a new organism(s)). Hazard ratios (HRs) for re-infection were calculated using Cox proportional frailty hazards models. After a median follow-up of 3.7 years, 222 re-infections were recorded. Re-infection rates per 1000 person-years of follow-up were 16.8 (95% CI 13.6–20.7) and 32.3 (95% CI 27.3–38.3) for one-stage and two-stage strategies respectively. The age- and sex-adjusted HR of re-infection for two-stage revision was 1.70 (0.58–5.00) when compared with one-stage revision. The association remained consistently absent after further adjustment for potential confounders. The HRs did not vary importantly in clinically relevant subgroups. Analysis of pooled individual patient data suggest that a one-stage revision strategy may be as effective as a two-stage revision strategy in treating PJI of the hip.