Melatonin attenuates hypochlorous acid-mediated heme destruction, free iron release, and protein aggregation in hemoglobin

Abstract: In inflammatory diseases, where hypochlorous acid (HOCl) is elevated, iron homeostasis is disturbed, resulting in accumulation of free iron. Free iron is toxic by virtue of its ability to generate free radicals through the Fenton reaction. HOCl is generated by myeloperoxidase, (MPO) using chloride and hydrogen peroxide as substrates. Recent studies demonstrate that HOCl binds to the heme moiety of hemoglobin (Hb), which generates a transient ferric species whose formation and decay kinetics indicate it participates in protein aggregation, heme destruction, and free iron release. Here, we show that melatonin prevents HOCl‐mediated Hb heme destruction and protein aggregation, using a combination of UV‐vis spectrophotometry, ferrozine colorimetric assay, and in‐gel heme staining. We also show that melatonin treatment prevents HOCl‐mediated loss of red blood cell (RBC) viability, indicating biologic relevance of this finding. The mechanism by which melatonin prevents HOCl‐mediated Hb heme destruction is by direct scavenging of HOCl and/or through the destabilization of the higher Hb oxidative states intermediates, ferryl porphyrin radical cation Hb‐Fe(IV)=O^+π? and Hb‐Fe(IV)=O, which are formed through the reaction of HOCl with Hb. Our work establishes a direct mechanistic link between melatonin and its protective effect in chronic inflammatory diseases. Collectively, in addition to acting as an antioxidant and as a MPO inhibitor, melatonin can also exert its protective effect by inhibiting HOCl‐mediated heme destruction of hemoproteins and subsequent free iron release.     

Positive impact of hepatitis C virus (HCV) treatment on antiretroviral treatment adherence in human immunodeficiency virus-HCV coinfected patients: one more argument for expanded access to HCV treatment for injecting drug users

Aims Treatment for the hepatitis C virus (HCV) may be delayed significantly in human immunodeficiency virus (HIV)/HCV coinfected patients on antiretroviral treatment (ART) for fear that its burden could compromise ART adherence. However, the effect such treatment has on ART adherence in observational settings remains largely unknown. Longitudinal data were used to investigate the relationship between initiating HCV treatment and adherence to ART in HIV/HCV coinfected patients. Design The French national prospective cohort of patients coinfected with HIV and HCV (ANRS‐CO‐13‐HEPAVIH) is a multi‐centre cohort. Setting Seventeen out‐patient hospital services delivering HIV and HCV care in France. Participants HIV/HCV coinfected patients on ART (n = 593 patients, 976 visits). Measurements Self‐administered questionnaires and medical records. A mixed logistic regression model based on generalized estimates equations (GEE) to identify factors associated with non‐adherence to ART. Findings Among the 593 patients, 36% were classified as non‐adherent to ART at the enrolment visit and 12% started HCV treatment during follow‐up. ART adherence was not associated statistically with HCV treatment initiation. The proportion of patients maintaining adherence or becoming adherent to ART for those starting HCV treatment was higher than in the rest of the sample (P = 0.07). After multiple adjustment for known correlates, such as poor housing conditions, binge drinking, recent drug use and depressive symptoms, patients who initiated HCV treatment were less likely to be non‐adherent to ART [odds ratio (95% confidence interval) = 0.41 (0.24–0.71)]. Conclusions Engaging human immunodeficiency virus/hepatitis C virus coinfected individuals in hepatitis C virus treatment is associated with high adherence to antiretroviral treatment. Physicians should prioritize hepatitis C virus treatment as part of a multi‐disciplinary approach.     

Disease patterns and causes of death of hospitalized HIV-positive adults in West Africa: a multicountry survey in the antiretroviral treatment era

Objective

We aimed to describe the morbidity and mortality patterns in HIV-positive adults hospitalized in West Africa.

Method

We conducted a six-month prospective multicentre survey within the IeDEA West Africa collaboration in six adult medical wards of teaching hospitals in Abidjan, Ouagadougou, Cotonou, Dakar and Bamako. From April to October 2010, all newly hospitalized HIV-positive patients were eligible. Baseline and follow-up information until hospital discharge was recorded using standardized forms. Diagnoses were reviewed by a local event validation committee using reference definitions. Factors associated with in-hospital mortality were studied with a logistic regression model.

Results

Among 823 hospitalized HIV-positive adults (median age 40 years, 58% women), 24% discovered their HIV infection during the hospitalization, median CD4 count was 75/mm³ (IQR: 25–177) and 48% had previously received antiretroviral treatment (ART). The underlying causes of hospitalization were AIDS-defining conditions (54%), other infections (32%), other diseases (8%) and non-specific illness (6%). The most frequent diseases diagnosed were: tuberculosis (29%), pneumonia (15%), malaria (10%) and cerebral toxoplasmosis (10%). Overall, 315 (38%) patients died during hospitalization and the underlying cause of death was AIDS (63%), non-AIDS-defining infections (26%), other diseases (7%) and non-specific illness or unknown cause (4%). Among them, the most frequent fatal diseases were: tuberculosis (36%), cerebral toxoplasmosis (10%), cryptococcosis (9%) and sepsis (7%). Older age, clinical WHO stage 3 and 4, low CD4 count, and AIDS-defining infectious diagnoses were associated with hospital fatality.

Conclusions

AIDS-defining conditions, primarily tuberculosis, and bacterial infections were the most frequent causes of hospitalization in HIV-positive adults in West Africa and resulted in high in-hospital fatality. Sustained efforts are needed to integrate care of these disease conditions and optimize earlier diagnosis of HIV infection and initiation of ART.     

Strategies in the management of post-burn breast deformities

Background

Burn injuries to the chest area may end up with severe breast deformity and asymmetry. They are frequently complex and unique to each case, affecting parenchymal development, breast implantation on chest wall, nipple areola complex position, infra-mammary fold definition, and skin envelope. Furthermore, contractures affecting adjacent territories may occur and add to the deformity. Surgical correction should address all the deformity components. Thus, a structured reconstructive plan that recruits different mammaplasty techniques and deals with adjacent territories is needed. This work presents different strategies used in treating severe post-burn breast deformities. Elaborate analyses of the deformities, surgical techniques, and outcomes are presented and a structured reconstructive plan is proposed.

Methods

Sixteen deformed breasts in 11 patients (mean age, 22 years) were managed. The techniques used included a variety of mastopexy techniques, prosthesis-based endoscopic breast reconstruction, and autologous breast augmentation with fat grafting or local flaps in some hypoplastic cases. Ancillary procedures to the neck, axilla, and abdomen were carried out to release the breast when tethered by their contractures.

Results

Considerable improvement and reasonable symmetry were achieved in most cases. All patients were satisfied with the results, tolerated the need for multiple procedures, and accepted residual minor asymmetries.

Conclusions

A post-burn breast deformity has a complex nature that may be addressed on multiple stages with different techniques of mastopexy, augmentation, and reconstruction. Ancillary procedures to a contracted adjacent territory may be needed to release the breast if tethered. Adopting a structured reconstructive plan may help obtain reproducible constant results. Level of Evidence: Level IV, therapeutic study.     

The efficacy of non-fasting ketogenic diet protocol in the management of intractable epilepsy in pediatric patients: a single center study from Saudi Arabia

ObjectiveTo review the characteristics and outcomes of pediatric patients on a ketogenic diet (KD), an established treatment option for individuals with intractable epilepsy, in a tertiary epilepsy center.MethodsThis retrospective study included pediatric patients diagnosed with intractable epilepsy who had experienced no benefits from at least two appropriately chosen antiseizure medications. All patients were hospitalized, started a KD without fasting, and were observed for complications and tolerance. The etiology of epilepsy, side effects, and KD efficacy on seizure outcomes were also examined.ResultsOf 16 children included in the study, nine (56%) experienced significant seizure improvement, with three becoming seizure-free during the KD. Ten patients were fed orally, and six were fed through gastrostomy feeding tubes. Most were on a 3:1 ratio, and nine reached ketosis within the first three days of KD initiation. Initial recurrent hypoglycemia was documented in four patients, and four experienced vomiting and acidosis. Most families complied with the diet, and all of the children gained weight during the study period.ConclusionKetogenic diets are an established and effective treatment for childhood epilepsy, with reversible mild adverse effects. A non-fasting KD protocol is a safe and effective option for children with intractable epilepsy.     

Evidence for a potent antiinflammatory effect of rosiglitazone

We have recently demonstrated a potent antiinflammatory effect of troglitazone, an agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) and a partial agonist of PPARalpha in both the nondiabetic obese and diabetic obese subjects. We have now investigated the antiinflammatory actions of rosiglitazone, a selective PPARgamma agonist. Eleven nondiabetic obese subjects and 11 obese diabetic subjects were each given 4 mg of rosiglitazone daily for a period of 6 wk. Fasting blood samples were obtained at 0, 1, 2, 4, 6, and 12 wk (6 wk after the cessation of rosiglitazone). Eight obese subjects and five obese diabetic subjects were also included in the study as control groups. Fasting blood samples were obtained from the control groups at 0, 1, 2, 4, and 6 wk only. Nuclear factor kappaB (NFkappaB)-binding activity in mononuclear cells, plasma monocyte chemoattractant protein-1 (MCP-1), TNF-alpha, soluble intercellular adhesion molecule-1, C-reactive protein (CRP), and serum amyloid A (SAA) were measured. Blood glucose concentration changed significantly at 6 wk only in the obese diabetic subjects after rosiglitazone treatment for 6 wk, whereas insulin concentration decreased significantly at 6 wk in both groups. NFkappaB-binding activity in mononuclear cell nuclear extract fell in both obese and obese diabetic subjects (P < 0.02). Rosiglitazone treatment resulted in a reduction in plasma MCP-1 and CRP in both groups (P < 0.05). Plasma TNF-alpha and SAA concentrations were inhibited significantly in the obese group (P < 0.05) but not in the obese diabetic subjects. NFkappaB-binding activity and plasma MCP-1, CRP, SAA, and TNF-alpha did not change in the obese and obese diabetic control groups. We conclude that rosiglitazone, a selective PPARgamma agonist, exerts an antiinflammatory effect at the cellular and molecular level, and in plasma. These observations may have implications for atherogenesis in the long term in subjects treated with rosiglitazone and possibly other thiazolidinediones.     

The Saudi Critical Care Society extracorporeal life support chapter guidance on utilization of veno-venous extracorporeal membrane oxygenation in adults with acute respiratory distress syndrome and special considerations in the era of coronavirus disease 2019

Extracorporeal membrane oxygenation (ECMO) is considered as a supportive treatment that provides circulatory and ventilatory support and can be thought off as a bridge to organ recovery. Since 2009, it has been applied as a rescue treatment for patients with severe adult respiratory distress syndrome (ARDS) mainly due to viral causes. In December 2019, several patients presented with a constellation of symptoms of viral pneumonia in China. A new strain of the corona virus family, called COVID-19, has been discovered to be the cause of this severe mysterious illness that was named severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2). This new virus continued to spread across the globe leading to the World Health Organization announcing it as a pandemic in the early 2020. By the end of March 2021, the number of COVID-19 cases worldwide exceeded 126 million cases. In Saudi Arabia, the first confirmed case of COVID-19 was reported in the 2nd March 2020. By the end of March 2021, the total number of confirmed COVID-19 cases in Saudi Arabia is just above 360,000. In anticipation of the need of ECMO for the treatment of patients with SARS‑CoV‑2 based on the previous Middle East respiratory syndrome coronavirus pandemic experience, the Saudi Extra-Corporeal Life Support (ECLS) chapter that is under the umbrella of the Saudi Critical Care Society (SCCS) convened a working group of ECMO experts. The mission of this group was to formulate a guidance for the use of ECMO as a last resort for patients with severe ARDS, especially with COVID-19 based on available evidence. The ECLS-SCCS chapter wanted to generate a document that can be used to simple guide, with a focus on safety, to provide ECMO service for patients with severe ARDS with a special focus on SARS‑CoV‑2.