Search

biBackground:/i/bBreastfeeding has various benefits for infants and mothers. However, if not performed in the correct posture, prolonged breastfeeding could cause musculoskeletal-related symptoms such as shoulder, neck, and upper back pain. In Jordan, nursing mothers do not have access to a breastfeeding midwifery team, a breastfeeding dietician, or a breastfeeding nurse for advice and education. The primary aim of this study was to explore nursing mothers' experiences of breastfeeding-related musculoskeletal pain; secondary aims were to explore nursing mothers' awareness of recommended breastfeeding postures and their experience of education and advice about breastfeeding postures.biMethods:/i/bA cross-sectional mixed methods study was conducted with nursing mothers in Jordan who have breastfed their babies for 6 months or more following normal delivery, using an online survey questionnaire and semi-structured interviews. Participants were recruited through general practitioner clinics.biResults:/i/bFour hundred ninety-three nursing mothers submitted the online questionnaire, and 12 interviews were completed. Nursing mothers reported experiencing nonspecific pain in lower back, neck, shoulder, and hand, attributed to breastfeeding. Pain in these joints affected mood, sleep, working ability, and quality of life by limiting activities of daily living. Findings showed that the majority of Jordanian nursing mothers did not receive education about safe or optimal breastfeeding positioning from health professionals.biConclusions:/i/bNursing mothers in Jordan are not receiving appropriate education or advice about optimal postures for breastfeeding and have reported experiencing musculoskeletal pain, attributed to breastfeeding, that interferes with activities of daily living and affects quality of life. Postural education and advice should be provided to nursing mothers to prevent or avoid development of musculoskeletal pain.

To assess survival and prognostic factors among women with epithelial ovarian cancer in Western Saudi Arabia.A retrospective cohort study was carried out between October 2000 and May 2018, reviewing clinical and pathology data of all women who underwent staging or debulking surgery for epithelial ovarian cancer. Analysis of disease-free survival (DFS), overall survivals (OS) and the associated factors used Kaplan-Meier method in addition to cox multivariate regression.A total of 144 patients were included (median age=49.5 years), with a median follow-up time was 3.4 years. Majority (59.7%) of the patients were diagnosed at an advanced stage (III or IV). The mean (95% CI) DFS was 82.3 (67.8-96.8) months, OS was 96.2 (81.3-111.2) months, and the 5-year survival rate was estimated as 38.9%. Univariate analysis showed that older age, clear cell or papillary carcinoma subtypes, serous type, advanced International Federation of Gynecology and Obstetrics (FIGO) stage and the presence of residual disease were associated with poorer DFS and OS (log rank0.05). Cox regression showed FIGO stage and residual disease1cm as the strongest prognostic factors independently associated with DFS and OS.Improving early diagnosis and achieving optimal cytoreduction are the most critical challenges to achieve significant positive impact on survival of women with epithelial ovarian cancer.

ObjectivesThis study aims to estimate the prevalence and longevity of detectable SARS-CoV-2 antibodies as well as memory cells T and B after recovery. In addition, the prevalence of COVID-19 reinfection, and the preventive efficacy of previous infection with SARS-CoV-2 were investigated.Methods and analysesA synthesis of existing research was conducted. The Cochrane Library for COVID-19 resources, the China Academic Journals Full Text Database, PubMed, and Scopus as well as preprint servers were searched for studies conducted between 1 January 2020 to 1 April 2021. We included studies with the relevant outcomes of interest. All included studies were assessed for methodological quality and pooled estimates of relevant outcomes were obtained in a meta-analysis using a bias adjusted synthesis method. Proportions were synthesized with the Freeman-Tukey double arcsine transformation and binary outcomes using the odds ratio (OR). Heterogeneity between included studies was assessed using the I2 and Cochran’s Q statistics and publication bias was assessed using Doi plots.ResultsFifty-four studies, from 18 countries, with around 12 000 000 individuals, followed up to 8 months after recovery were included. At 6-8 months after recovery, the prevalence of SARS-CoV-2 specific immunological memory remained high; IgG – 90.4% (95%CI 72.2-99.9, I2=89.0%, 5 studies), CD4+ - 91.7% (95%CI 78.2 – 97.1, one study), and memory B cells 80.6% (95%CI 65.0-90.2, one study) and the pooled prevalence of reinfection was 0.2% (95%CI 0.0 – 0.7, I2 = 98.8, 9 studies). Individuals previously infected with SARS-CoV-2 had an 81% reduction in odds of a reinfection (OR 0.19, 95% CI 0.1 - 0.3, I2 = 90.5%, 5 studies).ConclusionAround 90% of people previously infected with SARS-CoV-2 had evidence of immunological memory to SARS-CoV-2, which was sustained for at least 6-8 months after recovery, and had a low risk of reinfection.RegistrationPROSPERO: CRD42020201234What is already known on this topicIndividuals who recover from COVID-19 may have immunity against future infection but the proportion who develop immunity is uncertain. Further, there is uncertainty about the proportion of individuals who get reinfected with COVID-19.What this study addsUsing data from 54 studies with follow up time up to 8 months after recovery, during the period February 2020-February 2021, we found that, post-COVID-19, up to 90% of individuals had antibodies and memory T and B cells against SARS-CoV-2. We also found a pooled prevalence of reinfection of 0.2%, and that infection conferred an 81% decrease in odds of reinfection with SARS-CoV-2, compared to unimmunized individuals without previous COVID-19.This review of 12 million individuals presents evidence that most individuals who recover from COVID-19 develop immunological memory to SARS-CoV-2, which was still detectable for up to 8 months. Further, reinfection after recovery from COVID-19 was rare during the first 8 months after recovery, with a prevalence below 1%, while prior infection confers protection with an odds ratio of 0.19 and a preventive efficacy of 80% at a baseline prevalence of 5% for COVID-19 in a community.Implications of all the available evidenceIndividuals with a history of COVID-19 infection have immunity against the disease for up to 8 months, although this period could be longer. These individuals could be prioritized last for COVID-19 vaccinations or considered for single dose vaccinations.StrengthsThis comprehensive review addresses key questions on prevalent immunological memory and risk of reinfection in individuals with prior confirmed COVID-19 using robust systematic review methods.LimitationsSome of the included studies which examined prevalent immunological memory were small studies which were affected by loss to follow up. The review did not examine evidence for immunity against the new divergent variants, which may be more likely to have immune evasion behaviour and may present a higher risk of reinfection. Lastly, the review did not examine the effect of the severity of COVID-19 on both immunological memory and the risk of reinfection.

BackgroundThe transition to residency is competitive with more medical students applying for residency positions than slots available, and some will face challenges securing a position in their desired specialty. Our institution created a transitional year (TY) residency program in 2016 to help meet the needs of our medical students who did not initially secure a position in the main residency Match.ObjectiveThis report provides a brief overview of the TY program and analysis of the program's value from the inaugural 3 years (2017–2020).MethodsThe TY program is based at a midsized, urban, academic health center and features a tailorable curriculum emphasizing preparation for residents' specialty career plans. We used participatory action research and appreciative inquiry strategies as part of the annual program evaluation to examine TY residents' perceptions of the program's value. Stakeholder perceptions were also elicited from a purposive selection of 4 program directors and 2 key medical school education leaders.ResultsInternal evaluations revealed a high rate of resident satisfaction with the TY program and self-reported benefits such as increased confidence, clinical proficiency, and professional enculturation. Stakeholders valued the program as a potential pipeline for increasing physicians in the state and providing valuable direction to students' career trajectories.ConclusionsCreating a TY residency program to meet the needs of unmatched medical students was feasible to implement, acceptable to residents in meeting their academic and career needs, and provided a sustainable institutional solution with benefits to multiple stakeholders.

The aim of this quality improvement project was to look into the hospital prescriptions and to identify and record the type and number of errors, to implement measures to reduce the risk of these errors and then to reaudit to assess the impact of changes implemented. The initial audit was conducted prospectively over a eleven-week period. Prescriptions written by doctors of all grades and members of the staff, such as optometrists and nurses, were analysed. A glaucoma prescription guide along with more training at prescribing for doctors was introduced with a view to reducing these errors. A reaudit later demonstrated a significant reduction in these errors. After the introduction of a glaucoma prescription guide and more training for all grades of staff members, prescription errors reduced to 73/2342 (3.1%). Reaudit showed a reduction in both prescription writing errors 50/73(68.4%) and drug-related errors 23/73(31.6%). Prescription errors are avoidable. This audit demonstrated that providing an accessible, easy to read and understand glaucoma prescription guide in the outpatient department along with targeted training for medical staff in prescribing can help in minimising these errors and can lead to safer practice.

Phytochemical investigation of Penicillium sp. RO-11 strain, collected from the sediments of a hydrothermal spring located in the southwestern area of Saudi Arabia, afforded, along with previously isolated compounds, the undescribed polyketides penicillactonin (1), penipyranicin D (4) and isopyrenulin B (5) and the undescribed meroterpenoid preaustinoid C (7). The structures of these compounds were elucidated based on data from mass spectrometry, 1D and 2D NMR, and comparison between experimental and calculated ECD spectra. Penicillactonin and preaustinoid C bring unprecedented structural features, for which a biosynthetic rationale is proposed, further extending the chemodiversity associated to Penicillium fungi. Preaustinoid C showed significant activity against LPS-induced NO production and selective effect on IL-2 and IFN-γ gene regulation in activated Jurkat cells.

Renal artery calcifications can be associated with insufficient stent expansion and in-stent restenosis. Intravascular lithotripsy (IVL) uses shockwaves to disrupt calcium and treat calcific renal in-stent restenosis. Herein, the authors present a case to treat resistant reno-vascular hypertension and in-stent restenosis of an inadequately expanded renal stent in a patient with severe calcific renal artery stenosis. The patient was treated with IVL and stent dilation. The patient was followed subsequently, and her home blood pressure was well controlled on anti-hypertensive medications. In conclusion, IVL promises pronounced success in the modification of severely calcified renal artery lesions and can be used to treat renal artery stenosis even in the context of inadequately expanding renal artery stents.Extensive calcifications can contribute to the blockages of the arteries of the kidney. These can be associated with insufficient stent expansion in patients undergoing stent placement. Intravascular lithotripsy uses high-energy shockwaves to disrupt calcium deposits of renal arteries. Herein, the authors present a case of high blood pressure refractory to four blood pressure medications associated with blockage of previously placed stent of the artery of the left kidney. This case demonstrates that lithotripsy is an effective procedure to modify calcifications in order to facilitate expansion of the stent to restore blood flow to kidneys.

Objective To investigate local short‐term neuroplasticity elicited by subthalamic, thalamic, and pallidal deep brain stimulation (DBS) for movement disorders. Methods During DBS surgery, we delivered pairs of stimulus pulses with both circular and directional leads across 90 interstimulus intervals in 17 participants and recorded local field potentials from unused contacts on the implanted electrode array. We removed the stimulus artifact, validated the neural origin of the underlying signals, and examined short‐term plasticity as a function of interstimulus interval and DBS target, using linear mixed effects models. Results DBS evokes short latency local field potentials that are readily detected with both circular and directional leads at all stimulation targets (0.31 ± 0.10 msec peak latency, mean ± SD). Peak amplitude, area, and latency are modified strongly by interstimulus interval (P

Melittin is vital for the endosomal escape of nanoparticles, but its excessive cytotoxicity in mammalian cells limits its value as a potential therapeutic agent. Several novel analogs of melittin have been optimized and characterized to establish a non-toxic melittin-based gene delivery system, in which the sequences of the melittin peptides were altered to reduce their cytotoxic activity. This review focusses on the involvement of melittin in nanoparticle endosomal escape and on the construction of melittin conjugates to boost gene delivery. Endosomal escape mechanisms for melittin, as well as the development of melittin as a therapeutic agent and its potential applications in nanomedicine, are discussed.

Background While injuries experienced during hurricanes and other tropical cyclones have been relatively well- characterized through traditional surveillance, less is known about tropical cyclones' impacts on non-injury morbidity, which can be triggered through pathways that include psychosocial stress or interruption in medical treatment. Methods We investigated daily emergency Medicare hospitalizations (1999-2010) in 180 United States counties, drawing on an existing cohort of high-population counties. We classified counties as exposed to tropical cyclones when storm-associated peak sustained winds were ≥ 21 m/s at the county center; secondary analyses considered other wind thresholds and hazards. We matched storm-exposed days to unexposed days by county and seasonality. We estimated change in tropical cyclone-associated hospitalizations over a storm period from 2 days before to 7 days after the storm's closest approach, compared to unexposed days, using generalized linear mixed-effect models. Results For 1999-2010, 175 study counties had at least one tropical cyclone exposure. Cardiovascular hospitalizations decreased on the storm day, then increased following the storm, while respiratory hospitalizations were elevated throughout the storm period. Over the 10-day storm period, cardiovascular hospitalizations increased 3% (95% confidence interval [CI]: 2%, 5%) and respiratory hospitalizations increased 16% (95% CI: 13%, 20%) compared to matched unexposed periods. Relative risks varied across tropical cyclone exposures, with strongest association for the most restrictive wind-based exposure metric. Conclusions In this study, tropical cyclone exposures were associated with a short-term increase in cardiorespiratory hospitalization risk among the elderly, based on a multi-year/multi-site investigation of US Medicare beneficiaries ≥ 65 years.

Many quinazoline derivatives with pharmacological properties, such as anticancer activity, have been synthesized. Fourteen quinazoline derivatives bearing a substituted sulfonamide moiety (4a–n) were previously synthesized and fully characterized. These compounds exerted antiproliferative activity against cell lines derived from solid tumors. Herein, the antileukemic activities of these compounds (4a–n) against two different leukemia cell lines (Jurkat acute T cell and THP-1 acute monocytic) were investigated. Our investigation included examining their activity in vivo in a zebrafish embryo model. Remarkably, compounds 4a and 4d were the most potent in suppressing cell proliferation, with an IC50 value range of 4–6.5 µM. Flow cytometry analysis indicated that both compounds halted cell progression at the G2/M phase and induced apoptosis in a dose-dependent manner. RT-PCR and Western blot analyses also showed that both compounds effectively induced apoptosis by upregulating the expression of proapoptotic factors while downregulating that of antiapoptotic factors. In vivo animal toxicity assays performed in zebrafish embryos indicated that compound 4d was more toxic than compound 4a, with compound 4d inducing multiple levels of teratogenic phenotypes in zebrafish embryos at a sublethal concentration. Moreover, both compounds perturbed the hematopoiesis process in developing zebrafish embryos. Collectively, our data suggest that compounds 4a and 4d have the potential to be used as antileukemic agents.

Dystonia is an understudied motor feature of Parkinson's disease (PD). Although considerable efforts have focused on brain oscillations related to the cardinal symptoms of PD, whether dystonia is associated with specific electrophysiological features is unclear.The objective of this study was to investigate subcortical and cortical field potentials at rest and during contralateral hand and foot movements in patients with PD with and without dystonia.We examined the prevalence and distribution of dystonia in patients with PD undergoing deep brain stimulation surgery. During surgery, we recorded intracranial electrophysiology from the motor cortex and directional electrodes in the subthalamic nucleus (STN) both at rest and during self-paced repetitive contralateral hand and foot movements. Wavelet transforms and mixed models characterized changes in spectral content in patients with and without dystonia.Dystonia was highly prevalent at enrollment (61%) and occurred most commonly in the foot. Regardless of dystonia status, cortical recordings display beta (13-30 Hz) desynchronization during movements versus rest, while STN signals show increased power in low frequencies (6.0 ± 3.3 and 4.2 ± 2.9 Hz peak frequencies for hand and foot movements, respectively). Patients with PD with dystonia during deep brain stimulation surgery displayed greater M1 beta power at rest and STN low-frequency power during movements versus those without dystonia.Spectral power in motor cortex and STN field potentials differs markedly during repetitive limb movements, with cortical beta desynchronization and subcortical low-frequency synchronization, especially in patients with PD with dystonia. Greater knowledge on field potential dynamics in human motor circuits can inform dystonia pathophysiology in PD and guide novel approaches to therapy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Xenogeneic sources of collagen type I remain a common choice for regenerative medicine applications due to ease of availability. Human and animal sources have some similarities, but small variations in amino acid composition can influence the physical properties of collagen, cellular response, and tissue remodeling. The goal of this work is to compare human collagen type I-based hydrogels versus animal-derived collagen type I-based hydrogels, generated from commercially available products, for their physico-chemical properties and for tissue engineering and regenerative medicine applications. Specifically, we evaluated whether the native human skin type I collagen could be used in the three most common research applications of this protein: as a substrate for attachment and proliferation of conventional 2D cell culture; as a source of matrix for a 3D cell culture; and as a source of matrix for tissue engineering. Results showed that species and tissue specific variations of collagen sources significantly impact the physical, chemical, and biological properties of collagen hydrogels including gelation kinetics, swelling ratio, collagen fiber morphology, compressive modulus, stability, and metabolic activity of hMSCs. Tumor constructs formulated with human skin collagen showed a differential response to chemotherapy agents compared to rat tail collagen. Human skin collagen performed comparably to rat tail collagen and enabled assembly of perfused human vessels in vivo. Despite differences in collagen manufacturing methods and supplied forms, the results suggest that commercially available human collagen can be used in lieu of xenogeneic sources to create functional scaffolds, but not all sources of human collagen behave similarly. These factors must be considered in the development of 3D tissues for drug screening and regenerative medicine applications.

This study aimed to investigate the adhesion ofTwenty-five samples of polymethyl methacrylate (PMMA) and 25 samples of urethane dimethacrylate (UDMA) (10 mm × 10 mm × 2 mm) were prepared and allocated to 10 groups (five samples in each group). For each type of denture base materials, four test groups were immersed for 30 days in four commercially available DAs in addition to water as control group. Specimens were thenThe results showed that the mean number of CA per specimen in the adhesive-exposed groups was higher than that in the control group for both UDMA and PMMA resins. However, this difference was not statistically significant. No association between the type of denture base material andThe study found no association between the type of denture base materials and CA adhesion. No clear impact was identified for the type of DA on CA adhesion to acrylic denture bases.Using DAs would likely not increase the incidence of denture stomatitis in completely edentulous patients.

The construction field is considered one of the most dangerous industries. Accidents and fatalities take place on a daily basis in construction projects. Globally, different levels of government have implemented strict rules and regulations to protect workers on job sites. However, despite the efforts to implement the rules and regulations, accidents occur frequently. Falling from heights is considered the most common cause of death in construction. This study developed a novel system integrating deep learning and drones to monitor workers in real-time when performing at-height activities.Specifically, a pre-trained deep learning model was used to detect Personal Fall Arrest System components (e.g., safety harness, lifeline, and helmet). The drone was utilized to take images and videos from the construction site, and the data were relayed to the model to detect safety violations. The system was tested and validated in real construction sites and in a controlled lab environment to verify the model's effectiveness under different light and weather conditions.The overall accuracy of the system was 90%. The model's precision and recall were 97.2 % and 90.2%, respectively. The average time taken to detect a violation was around 12 seconds.Moreover, the Area Under Curve - Receiver Operating Characteristics chart showed that the trained model was very good and precise in detecting and differentiating the desired objects.This fast, reliable, and economical system can aid in saving many lives if implemented and utilized properly in real construction sites.

Centaurea bruguierana, of the Asteraceae family, has a long history of use in traditional medicines for the treatment of various ailments. However, the anticancer activity and underlying mechanisms have not yet been assessed. The C. bruguierana was extracted with methanol and fractionated into four different fractions. Different cancer cells and one non-cancerous were used to examine the cytotoxic effects of these fractions using MTT assay. The most potent fraction, C. bruguierana ethyl acetate fraction (CB EtOAc), was explored for its effects on cell cycle progression and apoptosis induction by Hoechst staining and annexin V-PI double staining in MCF-7 cells. The expression of apoptosis-related genes was quantified by RT-PCR. Of all fractions, CB EtOAc was found to have the strongest antiproliferative activity (IC50 = 10 μg/mL) against MCF-7 cells. The antiproliferative activity of the CB EtOAc fraction against MCF-7 was correlated with arrested of cell cycle in the G1 phase, nuclear fragmentation, and the exposure of phosphatidylserine. The induction of apoptosis by CB EtOAc in MCF-7 cells was also associated with an increase in the Bax/Bcl-2 ratio and higher expression of caspases. Overall, our results demonstrated that CB EtOAc showed apoptosis-inducing effects, suggesting that C. bruguierana may be a promising source for a novel chemotherapeutic agents for the treatment of breast cancer.

The current pandemic of 2019 novel coronavirus disease (COVID-19) caused by a novel virus strain, 2019-nCoV/SARS-CoV-2 have posed a serious threat to global public health and economy. It is largely unknown how the human immune system responds to this infection. A better understanding of the immune response to SARS-CoV-2 will be important to develop therapeutics against COVID-19. Here, we have used transcriptomic profile of human alveolar adenocarcinoma cells (A549) infected with SARS-CoV-2 and employed a network biology approach to generate human-virus interactome. Network topological analysis discovers 15 SARS-CoV-2 targets, which belongs to a subset of interferon (IFN) stimulated genes (ISGs). These ISGs (IFIT1, IFITM1, IRF7, ISG15, MX1, and OAS2) can be considered as potential candidates for drug targets in the treatments of COVID-19. We have identified significant interaction between ISGs and TLR3 agonists, like poly I: C, and imiquimod, and suggests that TLR3 agonists can be considered as a potential drug for drug repurposing in COVID-19. Our network centric analysis suggests that moderating the innate immune response is a valuable approach to target COVID-19., Highlights • Differential gene expression analysis of SARS-CoV-2 infected transcriptome • Network based Human-SRAS-CoV-2 interactome analysis • Interferon (IFN) stimulated genes (ISGs) are the most important targets. • TLR3 agonists, like poly I:C, and imiquimod are identified as potential drugs. • Targeting the innate immune response is a valuable approach against COVID-19.

Extracellular vesicles have an important function in cellular communication. Here, we show that human and mouse monocytes release TGF-β1-transporting vesicles in response to the pathogenic fungus Candida albicans. Soluble β-glucan from C. albicans binds to complement receptor 3 (CR3, also known as CD11b/CD18) on monocytes and induces the release of TGF-β1-transporting vesicles. CR3-dependence is demonstrated using CR3-deficient (CD11b knockout) monocytes generated by CRISPR-CAS9 genome editing and isolated from CR3-deficient (CD11b knockout) mice. These vesicles reduce the pro-inflammatory response in human M1-macrophages as well as in whole blood. Binding of the vesicle-transported TGF-β1 to the TGF-β receptor inhibits IL1B transcription via the SMAD7 pathway in whole blood and induces TGFB1 transcription in endothelial cells, which is resolved upon TGF-β1 inhibition. Notably, human complement-opsonized apoptotic bodies induce production of similar TGF-β1-transporting vesicles in monocytes, suggesting that the early immune response might be suppressed through this CR3-dependent anti-inflammatory vesicle pathway., Extracellular vesicles can carry immunoregulatory cytokines such as TGF-β. Here the authors use CD11b-deficient mice and macrophages to show that such vesicles carrying TGF-β are produced in response to Candida albicans infections and can limit the proinflammatory response partly via a positive feedback on TGF-β production by endothelial cells.

Purpose: To report the outcomes in eyes with noninfectious uveitis receiving dexamethasone implant at the time of pars plana vitrectomy (PPV).Methods: Retrospective analysis of visual acuity (VA), ...

Apolipoprotein A-I (apoA-I) is cross-linked and dysfunctional in human atheroma. Although multiple mechanisms of apoA-I cross-linking have been demonstrated in vitro, the in vivo mechanisms of cross-linking are not well-established. We have recently demonstrated the highly selective and efficient modification of high-density lipoprotein (HDL) apoproteins by endogenous oxidized phospholipids (oxPLs), including γ-ketoalkenal phospholipids. In the current study, we report that γ-ketoalkenal phospholipids effectively cross-link apoproteins in HDL. We further demonstrate that cross-linking impairs the cholesterol efflux mediated by apoA-I or HDL3 in vitro and in vivo. Using LC-MS/MS analysis, we analyzed the pattern of apoprotein cross-linking in isolated human HDL either by synthetic γ-ketoalkenal phospholipids or by oxPLs generated during HDL oxidation in plasma by the physiologically relevant MPO-H(2)O(2)-NO(2)(−) system. We found that five histidine residues in helices 5–8 of apoA-I are preferably cross-linked by oxPLs, forming stable pyrrole adducts with lysine residues in the helices 3–4 of another apoA-I or in the central domain of apoA-II. We also identified cross-links of apoA-I and apoA-II with two minor HDL apoproteins, apoA-IV and apoE. We detected a similar pattern of apoprotein cross-linking in oxidized murine HDL. We further detected oxPL cross-link adducts of HDL apoproteins in plasma and aorta of hyperlipidemic LDLR(−/−) mice, including cross-link adducts of apoA-I His-165–apoA-I Lys-93, apoA-I His-154–apoA-I Lys-105, apoA-I His-154–apoA-IV Lys-149, and apoA-II Lys-30–apoE His-227. These findings suggest an important mechanism that contributes to the loss of HDL's atheroprotective function in vivo.

Strong opioid analgesics, including morphine, are the mainstays for treating moderate to severe acute pain and alleviating chronic cancer pain. However, opioid-related adverse effects, including nausea or vomiting, sedation, respiratory depression, constipation, pruritus (itch), analgesic tolerance, and addiction and abuse liability, are problematic. In addition, the use of opioids to relieve chronic noncancer pain is controversial due to the "opioid crisis" characterized by opioid misuse or abuse and escalating unintentional death rates due to respiratory depression. Hence, considerable research internationally has been aimed at the "Holy Grail" of the opioid analgesic field, namely the discovery of novel and safer opioid analgesics with improved opioid-related adverse effects. In this Perspective, medicinal chemistry strategies are addressed, where structurally diverse nonmorphinan-based opioid ligands derived from natural sources were deployed as lead molecules. The current state of play, clinical or experimental status, and novel opioid ligand discovery approaches are elaborated in the context of retaining analgesia with improved safety and reduced adverse effects, especially addiction liability.

Pharmacological interventions of diabetic gastroparesis (DG) constitute an essential element of a patient's management. This article aimed to systematically review the available pharmacological approaches of DG, including their efficacy and safety. A total of 24 randomised clinical trials (RCTs) that investigated the efficacy and/or safety of medications targeting DG symptoms were identified using several online databases. Their results revealed that metoclopramide was the only approved drug for accelerating gastric emptying and improving disease symptoms. However, this medication may have several adverse effects on the cardiovascular and nervous systems, which might be resolved with a new intranasal preparation. Acceptable alternatives are oral domperidone for patients without cardiovascular risk factors or intravenous erythromycin for hospitalised patients. Preliminary data indicated that relamorelin and prucalopride are novel candidates that have proven to be effective and safe. Future RCTs should be conducted based on unified guidelines using universal diagnostic modalities to reveal reliable and comprehensive outcomes.

We synthesised a new series of sulphonamide-bearing quinazolinone derivatives 5-18 and evaluated their in vitro cytotoxicity in various cancer cell lines (A549, HepG-2, LoVo and MCF-7) and in normal human cells (HUVEC). Compounds 6 and 10 exhibited the higher activity against all the cancer cell lines compared with 5-flourourcil as positive control. The ability of the most promising compounds 6 and 10 to induce cell cycle arrest and apoptosis in breast cancer (MCF-7) cells was evaluated by flow cytometry. Reverse transcriptase-polymerase chain reaction and western blotting were used to evaluate the expression of apoptosis-related markers. We found that the 2-tolylthioacetamide derivative 6 and the 3-ethyl phenyl thioacetamide derivative 10 exhibited cytotoxic activity comparable to that of 5-fluorouracil as reference drug in MCF-7 and LoVo colon cancer cells. Cell cycle analysis showed a concentration-dependent accumulation of cells in the sub-G1 phase upon treatment with both compounds. The Annexin V-fluorescein isothiocyanate/propidium iodide assay showed that the compounds 6 and 10 increased the early and late apoptosis cell death modes in a dose-dependent manner. These compounds downregulated the expression of B-cell lymphoma-2 (Bcl-2), while increasing that of p53, Bcl-2-like protein 4, and caspase-7, at the mRNA and protein levels. Molecular docking of compounds 6 and 10 with Bcl-2 predicted them to show moderate − high binding affinity (6: −7.5 kcal/mol, 10: −7.9 kcal/mol) and interactions with key central substrate cavity residues. Overall, compounds 6 and 10 were found to be promising anticancer and apoptosis-inducing agents.

The ataxia-telangiectasia mutated (ATM) protein regulates cell cycle checkpoints, the cellular redox state, and double-stranded DNA break repair. ATM loss causes the disorder ataxia-telangiectasia (A-T), distinguished by ataxia, telangiectasias, dysregulated cellular redox and iron responses, and an increased cancer risk. We examined the sulfur pool in A-T cells, with and without an ATM expression vector. While free and bound sulfide levels were not changed with ATM expression, the acid-labile sulfide faction was significantly increased. ATM expression also increased cysteine desulfurase (NFS1), NFU1 iron-sulfur cluster scaffold homolog protein, and several mitochondrial complex I proteins' expression. Additionally, ATM expression suppressed cystathionine β-synthase and cystathionine γ-synthase protein expression, cystathionine γ-synthase enzymatic activity, and increased the reduced to oxidized glutathione ratio. This last observation is interesting, as dysregulated glutathione is implicated in A-T pathology. As ATM expression increases the expression of proteins central in initiating 2Fe-2S and 4Fe-4S cluster formation (NFS1 and NFU1, respectively), and the acid-labile sulfide faction is composed of sulfur incorporated into Fe-S clusters, our data indicates that ATM regulates aspects of Fe-S cluster biosynthesis, the transsulfuration pathway, and glutathione redox cycling. Thus, our data may explain some of the redox- and iron-related pathologies seen in A-T.

Background Visceral leishmaniasis (VL), caused by the protozoan parasite Leishmania donovani (L. donovani), is the most severe form of leishmaniasis. It is largely responsible for significant morbidity and mortality in tropical and subtropical countries. Currently, available therapeutics have lots of limitations including high-cost, adverse side-effects, painful route of administration, less efficacy, and resistance. Therefore, it is time to search for cheap and effective antileishmanial agents. In the present work, we evaluated the antileishmanial potential of sesamol against promastigotes as well as intracellular amastigotes. Further, we tried to work out its mechanism of antileishmanial action on parasites through different assays. Methodology In vitro and ex vivo antileishmanial assays were performed to evaluate the antileishmanial potential of sesamol on L. donovani. Cytotoxicity was determined by MTT assay on human THP-1-derived macrophages. Sesamol-induced morphological and ultrastructural changes were determined by electron microscopy. H2DCFDA staining, JC-1dye staining, and MitoSOX red staining were performed for reactive oxygen assay (ROS), mitochondrial membrane potential, and mitochondrial superoxide, respectively. Annexin V/PI staining for apoptosis, TUNEL assay, and DNA laddering for studying sesamol-induced DNA fragmentation were performed. Conclusions Sesamol inhibited the growth and proliferation of L. donovani promastigotes in a dose-dependent manner. It also reduced the intracellular parasite load without causing significant toxicity on host-macrophages. Overall, it showed antileishmanial effects through induction of ROS, mitochondrial dysfunction, DNA fragmentation, cell cycle arrest, and apoptosis-like cell death to parasites. Our results suggested the possible use of sesamol for the treatment of leishmaniasis after further in vivo validations.

Brittle cornea syndrome (BCS) is a rare recessive condition characterised by extreme thinning of the cornea and sclera. BCS results from loss-of-function mutations in the poorly understood genes ZNF469 or PRDM5. In order to determine the function of ZNF469 and to elucidate pathogenic mechanisms, we used genome editing to recapitulate a human ZNF469 BCS mutation in the orthologous mouse gene Zfp469. Ophthalmic phenotyping showed that homozygous Zfp469 mutation causes significant central and peripheral corneal thinning arising from reduced stromal thickness. Expression of key components of the corneal stroma in primary keratocytes from Zfp469BCS/BCS mice is affected, including decreased Col1a1 and Col1a2 expression. This alters the collagen type I/collagen type V ratio and results in collagen fibrils with smaller diameter and increased fibril density in homozygous mutant corneas, correlating with decreased biomechanical strength in the cornea. Cell-derived matrices generated by primary keratocytes show reduced deposition of collagen type I, offering an in vitro model for stromal dysfunction. Work remains to determine whether modulating ZNF469 activity will have therapeutic benefit in BCS or in conditions such as keratoconus in which the cornea thins progressively. This article has an associated First Person interview with the first author of the paper., Summary: A mouse model of brittle cornea syndrome was created to elucidate molecular mechanisms underlying the pathology of this rare connective tissue disorder in which extremely thin corneas rupture, causing irreversible blindness.

Cigarette smoking has a negative effect on respiratory and skeletal muscle function and is a risk factor for various chronic diseases. To assess the effects of 14 days of smoking cessation on respiratory and skeletal muscle function, markers of inflammation and oxidative stress in humans. Spirometry, skeletal muscle function, circulating carboxyhaemoglobin levels, advanced glycation end products (AGEs), markers of oxidative stress and serum cytokines were measured in 38 non-smokers, and in 48 cigarette smokers at baseline and after 14 days of smoking cessation. Peak expiratory flow (p = 0.004) and forced expiratory volume in 1 s/forced vital capacity (p = 0.037) were lower in smokers compared to non-smokers but did not change significantly after smoking cessation. Smoking cessation increased skeletal muscle fatigue resistance (p p p p

The present review aimed to summarize and evaluate the available literature regarding the survival rate and outcomes of dental implants in patients with Papillon-Lefèvre syndrome (PLS).An extensive search of the literature was conducted on PubMed, Scopus and Web of Science databases for all data published from January 1996 till April 2020 using a combination of the following keywords: 'Papillon Lefévre Syndrome', 'prosthodontic rehabilitation' and 'dental implant' according to the PRISMA guidelines for the focused research question constructed using the PICO criteria. Clinical trials and observational studies on implant placement in PLS patients reported in English language were included in the study.A total of 10 studies (nine case reports and one case series) comprising 124 dental implants placed in 13 PLS patients were included. The follow-up period ranged from 4 months to 9 years. With regard to implant loading, 9 studies reported delayed loading, while one study did not provide any information regarding the nature of implant loading. The design of prosthodontic superstructure was either a removable or fixed prosthesis. Out of the 124 inserted implants, 20 (16%) were reported as failed. The overall survival rate was 84%.The limited available evidence suggests that the survival rate of dental implants in patients with PLS is lower than that among healthy individuals. Nevertheless, no strict contraindication for implant-supported prosthesis seems to be justified in this group of patients. Further longitudinal studies with adequate follow-up periods are highly warranted.The prognosis of implant treatment for PLS patients has not yet been established. Dental practitioners should follow a careful approach in planning the dental implant treatment for this cohort of patients.

Fine particulate matter (PM(2.5)) is a well-established risk factor for public health. To support both health risk assessment and epidemiological studies, data are needed on spatial and temporal patterns of PM(2.5) exposures. This review article surveys publicly available exposure datasets for surface PM(2.5) mass concentrations over the contiguous U.S., summarizes their applications and limitations, and provides suggestions on future research needs. The complex landscape of satellite instruments, model capabilities, monitor networks, and data synthesis methods offers opportunities for research development, but would benefit from guidance for new users. Guidance is provided to access publicly available PM(2.5) datasets, to explain and compare different approaches for dataset generation, and to identify sources of uncertainties associated with various types of datasets. Three main sources used to create PM(2.5) exposure data are: ground-based measurements (especially regulatory monitoring), satellite retrievals (especially aerosol optical depth, AOD), and atmospheric chemistry models. We find inconsistencies among several publicly available PM(2.5) estimates, highlighting uncertainties in the exposure datasets that are often overlooked in health effects analyses. Major differences among PM(2.5) estimates emerge from the choice of data (ground-based, satellite, and/or model), the spatiotemporal resolutions, and the algorithms used to fuse data sources.

Skin cancer is the most common type of cancer in the United States, the majority of which is caused by overexposure to ultraviolet (UV) irradiance, which is one component of sunlight. National Environmental Public Health Tracking Program at CDC has collaborated with partners to develop and disseminate county-level daily UV irradiance (2005–2015) and total solar irradiance (1991–2012) data for the contiguous United States. UV irradiance dataset was derived from the Ozone Monitoring Instrument (OMI), and solar irradiance was extracted from National Solar Radiation Data Base (NSRDB) and SolarAnywhere data. Firstly, we produced daily population-weighted UV and solar irradiance datasets at the county level. Then the spatial distributions and long-term trends of UV irradiance, solar irradiance and the ratio of UV irradiance to solar irradiance were analyzed. The national average values across all years are 4300 Wh/m2, 2700 J/m2 and 130 mW/m2 for global horizontal irradiance (GHI), erythemally weighted daily dose of UV irradiance (EDD) and erythemally weighted UV irradiance at local solar noon time (EDR), respectively. Solar, UV irradiances and the ratio of UV to solar irradiance all increased toward the South and in some areas with high altitude, suggesting that using solar irradiance as indicator of UV irradiance in studies covering large geographic regions may bias the true pattern of UV exposure. National annual average daily solar and UV irradiances increased significantly over the years by about 0.3% and 0.5% per year, respectively. Both datasets are available to the public through CDC's Tracking network. The UV irradiance dataset is currently the only publicly-available, spatially-resolved, and long-term UV irradiance dataset covering the contiguous United States. These datasets help us understand the spatial distributions and temporal trends of solar and UV irradiances, and allow for improved characterization of UV and sunlight exposure in future studies.

Purpose Respiratory and musculoskeletal function decline with age, irrespective of physical activity levels. Previous work has suggested that the age-related rate of decline in function of these two systems might be similar, but it is not known to what extent each system contributes to decreasing performance in ageing master cyclists. Therefore, the purposes of this study are (1) whether the age-related rate of decline in respiratory function, respiratory muscle strength, muscle architecture, muscle function, haemoglobin concentration, haematocrit and performance in master cyclists is uniform and (2) which parameters contribute most to the reduction in performance with age. Methods Master cyclists were recruited during the Track Cycling Masters World Championship 2019 in Manchester. Respiratory function and respiratory muscle strength were determined using spirometry and a mouth pressure device, respectively. Muscle architecture was determined using ultrasonography, and muscle function by countermovement jump. Results Forced expiratory volume in the first second, forced vital capacity, fascicle length, muscle thickness, take-off velocity, jump power, jump power per body mass, handgrip strength, haemoglobin concentration and performance correlated negatively with age (p ≤ 0.043). The age-related rate of decline did not differ significantly between parameters (p = 0.124), but it was slower for haemoglobin concentration (p = 0.041). Take-off velocity was the major determinant of performance in 200, 500 and 2000 m track cycling disciplines (R2adj = 0.675, 0.786 and 0.769, respectively; p Conclusion Age-related decline in respiratory and muscle system is accompanied by a similar rate of decline in performance. The major contribution to the age-related decline of performance is reduced muscle function, specifically take-off velocity.

Background The pathophysiology of deep vein thrombosis (DVT) is considered as multifactorial, where thrombus formation is an interplay of genetic and acquired risk factors. Little is known about the expression profile and roles of long noncoding RNAs (lncRNAs) in human subjects developing DVT at high altitude. Methods Using RNAseQ, we compared peripheral blood mRNA and lncRNA expression profile in human high-altitude DVT (HA-DVT) patients with high-altitude control subjects. We used DESeq to identify differentially expressed (DE) genes. We annotated the lncRNAs using NONCODE 3.0 database. In silico putative lncRNA–miRNA association study unravels the endogenous miRNA sponge associated with our candidate lncRNAs. These findings were validated by small-interfering RNA (siRNA) knockdown assay of the candidate lncRNAs conducted in primary endothelial cells. Results We identified 1,524 DE mRNAs and 973 DE lncRNAs. Co-expressed protein-coding gene analysis resulted in a list of 722 co-expressed protein-coding genes with a Pearson correlation coefficients >0.7. The functional annotation of co-expressed genes and putative proteins revealed their involvement in the hypoxia, immune response, and coagulation cascade. Through its miRNA response elements to compete for miR-143 and miR-15, lncRNA-LINC00659 and UXT-AS1 regulate the expression of prothrombotic genes. Furthermore, in vitro RNA interference (siRNA) simultaneously suppressed lncRNAs and target gene mRNA level. Conclusion This transcriptome profile describes novel potential mechanisms of interaction between lncRNAs, the coding genes, miRNAs, and regulatory transcription factors that define the thrombotic signature and may be used in establishing lncRNAs as a biomarker in HA-DVT.

Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV2) is responsible for fetal pneumonia called COVID19. SARS-CoV2 emerged in Wuhan, Hubei Province of China in December 2019. The COVID19 pandemic has now gripped the entire world with more than 70 million cases and over 1.5 million deaths so far. There no treatment option for COVID19 is in term of a drug or vaccine is currently available. Therefore drug repurposing may only provide a quick method for utilizing existing drugs for a therapeutic option. The virus genome contains several non-structural proteins (NSP) which serve as target for designing of antiviral agents. NSP9 of SARS-CoV2 encodes for a replicase enzyme which is essential for the virus replication in the host cell. In search of potent inhibitors, we have screened FDA approved drugs against NSP9 using in silico methods. Five drugs fluspirilene, troglitazone, alvesco, dihydroergotoxine and avodart were found to have highest affinities with the replicase. The molecular dynamics simulation (MDS) studies demonstrated strong drugs binding and stable NSP9-drugs complexes formation. The findings are also strongly supported by root-mean-square deviation, root-mean-square fluctuation, radius of gyration, and hydrogen bond analysis of the complexes. Principal component analysis showed the stable conformation of NSP9 upon drug binding. It could be inferred that these five drugs individually or in combinations may be used as potential inhibitors of NSP9 of SARS-CoV-2 after exploring their in vivo antiviral potential.Communicated by Ramaswamy H. Sarma.

Recent evidence has revealed that exposing cells to exogenous H 2 S or inhibiting cellular H 2 S synthesis can modulate cell cycle checkpoints, DNA damage and repair, and the expression of proteins involved in the maintenance of genomic stability, all suggesting that H 2 S plays an important role in the DNA damage response (DDR). Here we review the role of H 2 S in the DRR and maintenance of genomic stability. Treatment of various cell types with pharmacologic H 2 S donors or cellular H 2 S synthesis inhibitors modulate the G 1 checkpoint, inhibition of DNA synthesis, and cause p21, and p53 induction. Moreover, in some cell models H 2 S exposure induces PARP-1 and g-H2AX foci formation, increases PCNA, CHK2, Ku70, Ku80, and DNA polymerase-d protein expression, and maintains mitochondrial genomic stability. Our group has also revealed that H 2 S bioavailability and the ATR kinase regulate each other with ATR inhibition lowering cellular H 2 S concentrations, whereas intracellular H 2 S concentrations regulate ATR kinase activity via ATR serine 435 phosphorylation. In summary, these findings have many implications for the DDR, for cancer chemotherapy, and fundamental biochemical metabolic pathways involving H 2 S., Highlights • Inhibition of the ATR kinase lowers intracellular H2S concentrations. • Inhibition of H2S synthesis activates the ATR kinase and increases its kinase activity. • Inhibition of H2S synthesis combined with low-level oxidative stress increases genomic instability. • These findings may have applications the cancer chemotherapeutics.

In order to investigate for a new effective and safe anticancer drug, we synthesized a novel series of quinazoline containing biologically active substituted-sulfonamide moiety at 3- position 4a–n. The structure of the newly prepared compounds was proved by microanalysis, IR, 1H-NMR, 13C-NMR and mass spectral data. All the synthesized compounds were evaluated for their in vitro cytotoxic activity in numerous cancer cell lines including A549, HepG-2, LoVo and MCF-7 and normal HUVEC cell line. The two most active compounds 4d and 4f were then tested for their apoptosis induction using DNA content and Annexin V-FITC/PI staining. Moreover, apoptosis initiation was also confirmed using RT-PCR and Western blot. To further understand the binding preferences of quinazoline sulfonamides, docking simulations were used. Among the fourteen new synthesized compounds, we found that compounds 4d and 4f exerted the strongest cytotoxicity against MCF-7 cells with an IC50 value of 2.5 and 5 μM, respectively. Flow cytometry data revealed the ability of compounds 4d and 4f to mediate apoptosis and arrest cell cycle growth at G1 phase. Furthermore, RT-PCR and Western blot results suggested that both 4d and 4f activates apoptotic cell death pathway in MCF-7 cells. Molecular docking assessments indicated that compounds 4d and 4f fit perfectly into Bcl2’s active site. Based on the biological properties, we conclude that both compounds 4d and 4f could be used as a new type of anticancer agent, which provides a scientific basis for further research into the treatment of cancer.

Background: The emergence and spread of SARS-CoV-2 throughout the world has created an enormous socioeconomic impact. Although there are several promising drug candidates in clinical trials, none is available clinically. Thus, the drug repurposing approach may help to overcome the current pandemic. Methods: The main protease (Mpro) of SARS-CoV-2 is crucial for cleaving nascent polypeptide chains. Here, FDA-approved antiviral and anti-infection drugs were screened by high-throughput virtual screening (HTVS) followed by re-docking with standard-precision (SP) and extra-precision (XP) molecular docking. The most potent drug's binding was further validated by free energy calculations (Prime/MM-GBSA) and molecular dynamics (MD) simulation. Results: Out of 1397 potential drugs, 157 showed considerable affinity toward Mpro. After HTVS, SP, and XP molecular docking, four high-affinity lead drugs (Iodixanol, Amikacin, Troxerutin, and Rutin) with docking energies −10.629 to −11.776 kcal/mol range were identified. Among them, Amikacin exhibited the lowest Prime/MM-GBSA energy (−73.800 kcal/mol). It led us to evaluate other aminoglycosides (Neomycin, Paramomycin, Gentamycin, Streptomycin, and Tobramycin) against Mpro. All aminoglycosides were bound to the substrate-binding site of Mpro and interacted with crucial residues. Altogether, Amikacin was found to be the most potent inhibitor of Mpro. MD simulations of the Amikacin-Mpro complex suggested the formation of a complex stabilized by hydrogen bonds, salt bridges, and van der Waals interactions. Conclusion: Aminoglycosides may serve as a scaffold to design potent drug molecules against COVID-19. However, further validation by in vitro and in vivo studies is required before using aminoglycosides as an anti-COVID-19 agent.

Collagen type I, commonly derived from xenogenic sources, is extensively used as a biomaterial for tissue engineering applications. However, the use of xenogenic collagen is typically associated with species specific variation in mechanical, structural, and biological properties that are known to influence cellular response and remodeling. In addition, immunological complications and risks of disease transmission are also major concerns. The goal of this study is to characterize a new xeno-free human skin-derived collagen and assess its applicability as a bioink for cell-laden 3 D bioprinting. Four different concentrations of human collagen (i.e., 0.5 mg/mL, 1 mg/mL, 3 mg/mL and 6 mg/mL) were employed for the synthesis of collagen hydrogels. In addition, bovine collagen was used as a xenogenic control. Results from SDS-PAGE analysis showed the presence of α1, α2, and β chains, confirming that the integrity of type I human collagen is maintained post isolation. Polymerization rate and compressive modulus increased significantly with increase in the concentration of human collagen. When comparing two different sources of collagen, the polymerization rate of xenogenic collagen was significantly faster (p −1, indicating a dense and supraorganized fibrillar structure in human collagen hydrogels. Conversely, Amide I band intensity for xenogenic collagen was comparable to that of Amide II and Amide III bands. Further, the use of 6 mg/mL human collagen as a bioink yielded 3 D printed constructs with high shape fidelity and cell viability. On the other hand, xenogenic collagen failed to yield stable 3 D printed constructs. Together, the results from this study provides an impetus for using human-derived collagen as a viable alternative to xenogenic sources for 3 D bioprinting of clinically relevant scaffolds for tissue engineering applications.

This perspective from a Regenerative Medicine Manufacturing Society working group highlights regenerative medicine therapeutic opportunities for fighting COVID-19. This article addresses why SARS-CoV-2 is so different from other viruses and how regenerative medicine is poised to deliver new therapeutic opportunities to battle COVID-19. We describe animal models that depict the mechanism of action for COVID-19 and that may help identify new treatments. Additionally, organoid platforms that can recapitulate some of the physiological properties of human organ systems, such as the lungs and the heart, are discussed as potential platforms that may prove useful in rapidly screening new drugs and identifying at-risk patients. This article critically evaluates some of the promising regenerative medicine-based therapies for treating COVID-19 and presents some of the collective technologies and resources that the scientific community currently has available to confront this pandemic.

Background The frequency of the alpha thalassemia trait is approximately 40% in the Kuwaiti population, but there has been no comprehensive study of the prevalent alleles. This is a report of patients who were referred for molecular diagnosis over a 20-year period. Methods This is a retrospective study of the α-globin genotypes obtained in the Hemoglobin Research Laboratory of the Department of Pediatrics, Kuwait University from 1994 to 2015. Genotyping was performed by a combination of PCR, allele-specific oligonucleotide hybridization and reverse dot blot hybridization (Vienna Lab Strip Assay). Results Four hundred samples were characterized and analyzed from individuals aged PA-1α/α PA-1α) in 33.3% of the samples, followed by heterozygosity (αα/α PA-1α) for the same mutation in 32.3%. PA-1 was therefore the most frequent allele (0.59). The frequency of the α0 (−-MED) allele was 0.017. Rare alleles that were found in very low frequencies included α0 (−-FIL) in a Filipino child, Hb Constant Spring, Hb Adana, and Hb Icaria. Conclusion There is a wide variety of alpha thalassemia alleles among Kuwaitis, but nondeletional PA-1 is by far the most common cause of the moderate to severe HbH (β4 tetramer) disease phenotype. The α0 (−MED) allele is also encountered, which has implications for premarital counseling, especially for the possibility of having babies with alpha thalassemia major (Barts hydrops fetalis).

Overexpression of epithelial cell adhesion molecule (EpCAM) has been associated with chemotherapeutic resistance, leads to aggressive tumor behavior, and results in an adverse clinical outcome. The molecular mechanism by which EpCAM enrichment is linked to therapeutic resistance via Nrf2, a key regulator of antioxidant genes is unknown. We have investigated the link between EpCAM and the Nrf2 pathway in light of therapeutic resistance using head and neck squamous cell carcinoma (HNSCC) patient tumor samples and cell lines. We report that EpCAM was highly expressed in Nrf2-positive and HPV-negative HNSCC cells. In addition, cisplatin-resistant tumor cells consisted of a higher proportion of EpCAMhigh cells compared to the cisplatin sensitive counterpart. EpCAMhigh populations exhibited resistance to cisplatin, a higher efficiency in colony formation, sphere growth and invasion capacity, and demonstrated reduced reactive oxygen species (ROS) activity. Furthermore, Nrf2 expression was significantly higher in EpCAMhigh populations. Mechanistically, expression of Nrf2 and its target genes were most prominently observed in EpCAMhigh populations. Silencing of EpCAM expression resulted in the attenuation of expressions of Nrf2 and SOD1 concomitant with a reduction of Sox2 expression. On the other hand, silencing of Nrf2 expression rendered EpCAMhigh populations sensitive to cisplatin treatment accompanied by the inhibition of colony formation, sphere formation, and invasion efficiency and increased ROS activity. The molecular mechanistic link between EpCAM expression and activation of Nrf2 was found to be a concerted interaction of interleukin-6 (IL-6) and p62. Silencing of p62 expression in EpCAMhigh populations resulted in the attenuation of Nrf2 pathway activation suggesting that Nrf2 pathway activation promoted resistance to cisplatin in EpCAMhigh populations. We propose that therapeutic targeting the Nrf2-EpCAM axis might be an excellent approach to modulate stress resistance and thereby survival of HNSCC patients enriched in EpCAMhigh populations.

(1) Background: Cardio-metabolic diseases (CMD), including cardiovascular disease, stroke, and diabetes, have numerous common individual and environmental risk factors. Yet, few studies to date have considered how these multiple risk factors together affect CMD disparities between Blacks and Whites. (2) Methods: We linked daily fine particulate matter (PM2.5) measures with survey responses of participants in the Southern Community Cohort Study (SCCS). Generalized linear mixed modeling (GLMM) was used to estimate the relationship between CMD risk and social-demographic characteristics, behavioral and personal risk factors, and exposure levels of PM2.5. (3) Results: The study resulted in four key findings: (1) PM2.5 concentration level was significantly associated with reported CMD, with risk rising by 2.6% for each &micro, g/m3 increase in PM2.5, (2) race did not predict CMD risk when clinical, lifestyle, and environmental risk factors were accounted for, (3) a significant variation of CMD risk was found among participants across states, and (4) multiple personal, clinical, and social-demographic and environmental risk factors played a role in predicting CMD occurrence. (4) Conclusions: Disparities in CMD risk among low social status populations reflect the complex interactions of exposures and cumulative risks for CMD contributed by different personal and environmental factors from natural, built, and social environments.

Background: Congenital kyphosis results from the failed formation of the vertebrae during the embryonic period and may be associated with cardiac, urogenital, or spinal cord anomalies. Surgical treatment is the best choice through anterior, posterior, or both approaches. Objectives: This study aims to evaluate the effect of posterior gradual correction using the “in situ” bender to correct severe thoracolumbar congenital kyphosis with or without osteotomy or excision of the vertebra. Methods: Twenty-five patients with an age range of 2–23 (mean ± SD = 12.58 ± 6.03) years with severe thoracolumbar kyphosis were treated surgically at our institution between 2004 and 2013. Pedicle screwing, osteotomy, and gradual “in situ” bending through the single posterior approach were the choices of treatment. Cobb’s angle, patient’s height, and SRS-22r were used to evaluate the patients preoperatively and postoperatively. Follow-up periods were 35–136 months. Result: Cobb’s angle pre-surgery range was 35–180 (81.48 ± 39.1) degrees improved post-surgery to 0–45 (21.72 ± 13.47) degrees ( p-value Conclusion: Gradual correction with the “in situ” bender with or without osteotomy through the single posterior approach can give satisfying clinical (patients’ standing height and SRS-22r scores) and radiological (Cobb’s angle) results to treat severe congenital thoracolumbar kyphosis.

Calcitonin gene-related peptide (CGRP) antagonists have recently grabbed the attention of clinicians for migraine prophylaxis. The present meta-analysis aimed to assess the efficacy and safety of CGRP monoclonal antibodies (mAbs) in patients with chronic and episodic migraine using a systematic therapeutic regimen. More specifically, double-blind placebo-controlled randomized clinical trials (RCTs) which assessed the therapeutic potential of monthly subcutaneous injections were included. The primary outcomes entailed changes in monthly migraine days (MMDs) and treatment-related adverse events (TRAEs) for: Erenumab 70 mg, fremanezumab 225 mg, and galcanezumab 120 mg. No eligible studies have investigated eptinezumab. A total of 13 RCTs were eligible (6979 patients, 84.81% females, 42.94% received active medications). Compared to placebo, the selected doses of mAbs reduced the MMDs significantly after four weeks (mean difference [MD] -2.07, 95% CI -2.47 to -1.66, P 0.001), eight weeks (MD -1.78, 95% CI -2.26--1.49, P 0.001), and 12 weeks (-1.80, 95% CI -2.16 to -1.43, P 0.001). These effects remained significant with each individual medication across all treatment cycles. In addition, the number of days using acute migraine medications decreased and the proportion of 50% responders increased significantly with mAbs use compared to placebo. No significant differences between groups were noted in TRAEs. CGRP mAbs provide highly efficacious and safe outcomes which start early after the first injection. The tolerability of these medications surpasses that of other small-molecule CGRP antagonists.

Purpose: To audit and analyse the accuracy of current biometric formulae on refractive outcomes following cataract surgery in patients with axial length less than 22 mm. Methods: A total of 84 eyes from 84 patients with axial length Results: The mean axial length was 21.00 ± 0.55 mm. Mean error was greatest for Hoffer Q at −0.57 dioptres. There was no significant difference in mean absolute error between formulae. SRK/T achieved the highest percentage of outcomes within 0.5 dioptres (45.2%) and 1 dioptre (76.2%) of target. Shallower anterior chamber depth was associated with higher mean absolute error for SRK/T (p = 0.028), Hoffer Q (p = 0.003) and Haigis (p = 0.016) but not Holladay (p = 0.111). Conclusion: SRK/T had the highest proportion of patients achieving refractive results close to predicted outcomes. However, there was a significant association between a shallower anterior chamber depth and higher mean absolute error for all formulae except Holladay 1. This suggests that anterior chamber depth with axial length should be considered when counselling patients about refractive outcome.

Leishmania is a protozoan parasite that resides and replicates in macrophages and causes leishmaniasis. The parasite alters the signaling cascade in host macrophages and evades the host machinery. Small G-proteins are GTPases, grouped in 5 different families that play a crucial role in the regulation of cell proliferation, cell survival, apoptosis, intracellular trafficking, and transport. In particular, the Ras family of small G-proteins has been identified to play a significant role in the cellular functions mentioned before. Here, we studied the differential expression of the most important small G-proteins during Leishmania infection. We found major changes in the expression of different isoforms of Ras, mainly in N-Ras. We observed that Leishmania donovani infection led to enhanced N-Ras expression, whereas it inhibited K-Ras and H-Ras expression. Furthermore, an active N-Ras pull-down assay showed enhanced N-Ras activity. L donovani infection also increased extracellular signal-regulated kinase 1/2 phosphorylation and simultaneously decreased p38 phosphorylation. In contrast, pharmacological inhibition of Ras led to reduction in the phosphorylation of extracellular signal-regulated kinase 1/2 and enhanced the phosphorylation of p38 in Leishmania-infected cells, which could lead to increased interleukin-12 expression and decreased interleukin-10 expression. Indeed, farnesylthiosalicyclic acid (a Ras inhibitor), when used at the effective level in L donovani-infected macrophages, reduced amastigotes in the host macrophages. Thus, upregulated N-Ras expression during L donovani infection could be a novel immune evasion strategy of Leishmania and would be a potential target for antileishmanial immunotherapy.

Background Pediatric chest injuries were infrequent in our practice, but the outbreak of the Syrian crisis resulted in an increase in number and a change in the pattern of thoracic trauma incidents. We compared our experience of pediatric chest injuries before and during the crisis. Methods We reviewed the records of 256 children aged 12.8 ± 5 years who were admitted to our hospital with the diagnosis of chest trauma over a 12-year period. Collected data included mechanism of injury, associated injuries, method of management, length of hospital stay, complications, and mortality. Results The incidence of pediatric chest injuries increased significantly following the outbreak of the crisis, and penetrating injuries prevailed, mainly due to shrapnel, bullets, and stab wounds. Forty percent of patients with blunt injuries and 20% of those with penetrating injuries were managed conservatively, whereas urgent thoracotomies were indicated in 10%, mostly in patients with penetrating injuries. Associated injuries were more frequent in patients with blunt injuries and resulted in a longer hospital stay and an increased mortality rate. The overall mortality rate was 7.8% and it was higher in children younger than 7 years of age and in patients who had been subjected to blunt injuries. Conclusions There has been a recent substantial upsurge in the incidence of pediatric thoracic trauma, with a predominance of penetrating injuries. Most patients could be managed nonoperatively, but a small subset required an open thoracotomy. The presence of associated injuries constitutes the main determinant of prognosis in this group of patients.

Janerin is a cytotoxic sesquiterpene lactone that has been isolated and characterized from different species of the Centaurea genus. In this study, janerin was isolated form Centaurothamnus maximus, and its cytotoxic molecular mechanism was studied in THP-1 human leukemic cells. Janerin inhibited the proliferation of THP-1 cells in a dose-dependent manner. Janerin caused the cell cycle arrest at the G2/M phase by decreasing the CDK1/Cyclin-B complex. Subsequently, we found that janerin promoted THP-1 cell death through apoptosis as indicated by flow cytometry. Moreover, apoptosis induction was confirmed by the upregulation of Bax, cleaved PARP-1, and cleaved caspase 3 and the downregulation of an anti-apoptotic Bcl-2 biomarker. In addition, immunoblotting indicated a dose dependent upregulation of P38-MAPK and ERK1/2 phosphorylation during janerin treatment. In conclusion, we have demonstrated for the first time that janerin may be capable of inducing cell cycle arrest and apoptosis through the MAPK pathway, which would be one of the mechanisms underlying its anticancer activity. As a result, janerin has the potential to be used as a therapeutic agent for leukemia.

Accumulating evidence suggests an association between immune dysfunction and autism disorders in a significant subset of children. In addition, an imbalance between pro- and anti-inflammatory pathways has been proposed to play an important role in the pathogenesis of several neurodevelopmental disorders including autism; however, the role of anti-inflammatory molecules IL-27 and CTLA-4 and pro-inflammatory cytokines IL-21 and IL-22 has not previously been explored in autistic children. In the current study, we investigated the expression of IL-21, IL-22, IL-27, and CD152 (CTLA-4) following an in-vitro immunological challenge of peripheral blood mononuclear cells (PBMCs) from children with autism (AU) or typically-developing children (TD) with phorbol-12-myristate 13-acetate (PMA) and ionomycin. In our study, cells from children with AU had increased IL-21 and IL-22 and decreased CTLA-4 expression on CD4+ T cells as compared with cells from the TD control. Similarly, AU cells showed decreased IL-27 production by CD14+ cells compared to that of TD control cells. These results were confirmed by real-time PCR and western blot analyses. Our study shows dysregulation of the immune balance in cells from autistic children as depicted by enhanced pro-inflammatory cytokines, 'IL-21/IL-22' and decreased anti-inflammatory molecules, 'IL-27/CTLA-4'. Thus, further study of this immune imbalance in autistic children is warranted in order to facilitate development of biomarkers and therapeutics.