Strategies to Treat Pulmonary Hypertension Using Programmed Cell Death-Inducing Anti-Cancer Drugs without Damaging the Heart

Pulmonary arterial hypertension (PAH) is a fatal disease without a cure. By the time patients are diagnosed with PAH, thickening of pulmonary arterial (PA) walls and the narrowing of vascular lumen have already developed due to the abnormal growth of pulmonary vascular cells, contributing to the elevated pulmonary vascular resistance and the right ventricle (RV) damage. Therefore, agents that eliminate excess pulmonary vascular wall cells have therapeutic potential, and the apoptosis-based therapy using anti-cancer drugs may be promising for the treatment of PAH. However, cell death agents could also exert adverse effects including cardiotoxicity, complicating the development of such therapies for PAH patients who already have the damaged heart. We tested the concept that programmed cell death-inducing anti-cancer drugs may reduce the PA wall thickening using rat models of PAH. We found that: (i) The treatment of PAH animals with anthracycline-, proteasome inhibitor- or Bcl-2 inhibitor-classes of anti-cancer drugs after the pulmonary vascular remodeling had already developed resulted in the reversal of PA wall thickening and opened up the lumen; (ii) These effects were accompanied by the apoptosis of PA wall cells in PAH rats, but not in normal healthy rats, suggesting the anti-cancer drugs selectively kill remodeled vascular cells; (iii) The RV affected by PAH was not further damaged by anthracyclines or proteasome inhibitors; (iv) While the left ventricle (LV) was damaged by these drugs, we identified cardioprotective agents that protect the heart against drug-induced cell death without affecting the efficacy to reverse the PA remodeling; and (v) docetaxel, not only reversed pulmonary vascular remodeling without exerting RV or LV toxicity, but also repaired the RV damage caused by PAH. Thus, the inclusion of programmed cell death-inducing anti-cancer drugs should be considered for treating PAH patients

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

3D-MRI Brain Tumor Detection Model Using Modified Version of Level Set Segmentation Based on Dragonfly Algorithm

Accurate brain tumor segmentation from 3D Magnetic Resonance Imaging (3D-MRI) is an important method for obtaining information required for diagnosis and disease therapy planning. Variation in the brain tumor&rsquo;s size, structure, and form is one of the main challenges in tumor segmentation, and selecting the initial contour plays a significant role in reducing the segmentation error and the number of iterations in the level set method. To overcome this issue, this paper suggests a two-step dragonfly algorithm (DA) clustering technique to extract initial contour points accurately. The brain is extracted from the head in the preprocessing step, then tumor edges are extracted using the two-step DA, and these extracted edges are used as an initial contour for the MRI sequence. Lastly, the tumor region is extracted from all volume slices using a level set segmentation method. The results of applying the proposed technique on 3D-MRI images from the multimodal brain tumor segmentation challenge (BRATS) 2017 dataset show that the proposed method for brain tumor segmentation is comparable to the state-of-the-art methods

Simultaneous Brucella breast and pacemaker infection

Infection with Brucella spp. is endemic to the Middle East and the eastern Mediterranean basin. Brucellosis can mimic infectious and non-infectious febrile illnesses and therefore it can pose a diagnostic challenge. A wide range of deep-seated infections have been ascribed to brucellosis including breast abscesses and infections of prosthetic endovascular devices. The latter are usually rare but difficult to treat short of excision of the infected device. Here, we present the case of a middle-aged Lebanese woman who presented with simultaneous breast abscesses and a pacemaker infection due to brucellosis. To our knowledge, a similar manifestation has not been reported in the literature. Keywords: Brucella, Pacemaker, Endocarditis, Breast absces

Diacerein protects rats with liver ischemia/reperfusion damage: Down-regulation of TLR4/ NFκ-B signaling pathway

Purpose: Liver ischemia-reperfusion (I/R) injury is an inescapable problem. Diacerein, a chondro-protective drug, has antioxidant and anti-inflammatory effects. Its effect on liver I/R injury has not yet been fully clarified. Therefore, the current study aimed to detect its hepatic protective effect with the explanation of possible underlying mechanisms. Methods: Adult male albino rats were assigned to 4 groups: sham group, diacerein pretreated sham group, I/R non-treated group, and I/R diacerein pretreated group. Serum liver enzymes, hepatic tissue oxidative stress parameters, inflammatory biomarkers mainly Toll-like receptors-4 (TLR4), and liver fatty acid binding protein (L-FABP) levels were determined. Histopathological examination of liver tissues and immunohistochemical studies of heat shock protein 70, nuclear factor-kappa B, and Cluster of Differentiation 68 were also done. Results: Diacerein pretreatment has the ability to restore the hepatic I/R damaging effect, proved by the reduction of serum liver enzymes, the decrease of the oxidative stress and hepatic inflammation via down-regulation of TLR4/ NFκ-B signaling pathway together with the restoration of L-FABP level and improvement of the histopathological and immunohistochemical study findings in the hepatic tissue. Conclusion: These results suggested the hepatoprotective effect of diacerein relies on its antioxidant and anti-inflammatory effects reducing TLR4/ NFκ-B signaling pathway

Tau Protein in Lung Smooth Muscle Cells

Tau, a microtubule-associated protein, plays a critical role in the pathophysiology of neurons. However, whether tau protein is expressed in smooth muscle cells is unknown. Thus, we tested the hypothesis that tau protein is expressed in the primary cultures of smooth muscle cells. Here, we report that tau protein is expressed and constitutively phosphorylated at threonine 181 in various smooth muscle cell types, including human pulmonary artery smooth muscle cells, bronchial airway smooth muscle cells, and cerebral artery smooth muscle cells. Immunofluorescence staining revealed that phosphorylated tau at threonine 181 is more organized in the cell than is total tau protein. A protein phosphatase inhibitor, calyculin A, induced the formation of higher molecular weight species of phosphorylated tau, as visualized by Western blotting, indicating the occurrence of tau aggregation. Immunofluorescence analysis also showed that calyculin A caused the aggregation of phosphorylated tau and disrupted the cytoskeletal organization. These results demonstrate the existence of tau protein in smooth muscle cells, and that smooth muscle tau is susceptible to protein phosphorylation and aggregation. Lung smooth muscle tau may therefore play an important role in pulmonary pathophysiology

Paeonol Attenuates Hepatic Ischemia/Reperfusion Injury by Modulating the Nrf2/HO-1 and TLR4/MYD88/NF-κB Signaling Pathways

Hepatic ischemia/reperfusion (HIR) is the most common type of liver injury following several clinical situations. Modulating oxidative stress and inflammation by Nrf2/HO-1 and TLR4/MYD88/NF-κB pathways, respectively, is involved in alleviating HIR injury. Paeonol is a natural phenolic compound that demonstrates significant antioxidant and anti-inflammatory effects. The present study explored the possible protective effect of paeonol against HIR injury and investigated its possible molecular mechanisms in rats. Rats were randomly divided into four groups: sham-operated control, paeonol-treated sham-operated control, HIR untreated, and HIR paeonol-treated groups. The results confirmed that hepatic injury was significantly aggravated biochemically by elevated serum levels of alanine transaminase and aspartate transaminase, as well as by histopathological alterations, while paeonol reduced the increase in transaminases and alleviated pathological changes induced by HIR. Additionally, paeonol inhibited the HIR-induced oxidative stress in hepatic tissues by decreasing the upraised levels of malondialdehyde and nitric oxide and enhancing the suppressed levels of reduced glutathione and superoxide dismutase activity. Furthermore, paeonol activated the protective antioxidative Nrf2/HO-1 pathway. The protective effect of paeonol was associated with inhibiting the expression of the inflammatory key mediators TLR4, MYD88, NF-κB, and TNF-α. Finally, paeonol inhibited the increased mRNA levels of the pro-apoptotic marker Bax and enhanced the reduced mRNA levels of the anti-apoptotic marker Bcl-2. Taken together, our results proved for the first time that paeonol could protect against HIR injury by inhibiting oxidative stress, inflammation, and apoptosis

Pentoxifylline Effects on Hospitalized COVID-19 Patients with Cytokine Storm Syndrome: A Randomized Clinical Trial

COVID-19 is a fatal, fast-spreading pandemic, and numerous attempts are being made around the world to understand and manage the disease. COVID-19 patients may develop a cytokine-release syndrome, which causes serious respiratory diseases and, in many cases, death. The study examined the feasibility of employing legally available anti-inflammatory pentoxifylline (PTX), a low toxicity and cost medication, to mitigate the hyper-inflammation caused by COVID-19. Thirty adult patients who tested positive for SARS-CoV2 were hospitalized owing to the cytokine storm syndrome. They were given 400 mg of pentoxifylline orally TID according to the standard COVID-19 protocol of the Egyptian Ministry of Health. Besides this, a group of thirty-eight hospitalized COVID-19 patients who received the standard COVID-19 protocol was included in the study as a control group. The outcomes included laboratory test parameters, clinical improvements, and number of deaths in both groups. After receiving PTX, all patients showed a significant improvement in C reactive protein (CRP), and interleukin-6 (IL-6) levels at p p = 0.004, respectively, while there was an increase in total leukocyte count (TLC) and neutrophil-to-leucocyte ratio (NLR) at p p < 0.01, while showing no statistically significant difference in the control group. The median initial ALT (42 U/L) in the treatment group showed a decrease compared to the control group (51 U/L). No statistical significance was reported regarding clinical improvement, length of stay, and death percentages between the two groups. Our results showed no significant improvement of PTX over controls in clinical outcomes of hospitalized COVID-19 patients. Nevertheless, PTX displayed a positive effect on certain inflammatory biomarkers