Morus Alba Fruit Extract and its Fractions Ameliorate Streptozotocin Induced Cognitive Deficit in Mice via Modulating Oxidative and Cholinergic Systems.

Increased oxidative stress and acetylcholinesterase (AChE) activity are key pathological characters contributing to the memory disorders. Thus, drugs targeting both oxidative stress and AChE are being explored for the management of cognitive dysfunction. Morus alba fruits (commonly consumed for its high nutritious value) are known to have antioxidant and AChE inhibitory effects. However, the role of Morus alba fruits in the management of memory disorders has not reported yet. This investigation was conducted to assess the antioxidant and AChE inhibitory potential of Morus alba fruit extracts in-vitro and to identify the components responsible for such effects. Further, the obtained bioactive component was studied for possible memory improvement effects against streptozotocin (STZ) induced dementia. To isolate the bioactive component in-vitro DPPH and AChE assays guided fractionation was performed. Memory functions in mice were determined using Morris Water Maze test while brain biochemical parameters were measured to understand the mechanism of action. In-vitro assays revealed strong AChE and DPPH inhibitory potential of methanol extract (ME), therefore, it was further fractionated. Among various fractions obtained, ethyl-acetate fraction (EAF) was found to possess marked AChE and DPPH inhibitory activities. On subsequent fractionation of EAF, bioactivity of obtained sub-fractions was found to be inferior to EAF. Further, both ME and EAF improved STZ (intracerebroventricular) induced cognitive dysfunction in animals by restoring endogenous antioxidant status (superoxide dismutase and reduced glutathione) and reducing thiobarbituric acid reactive species and nitric oxide levels along with brain AChE and myeloperoxidase activity. TLC densitometric studies showed appreciable levels of phenolic acids and quercetin in both EAF and ME. It can be concluded that Morus alba fruit extract has the ability to modulate cholinergic and oxidative system due to presence of phenolic and flavonoid compounds and hence, could aid in the management of memory disorders.

Genome and secretome insights: unravelling the lignocellulolytic potential of Myceliophthora verrucosa for enhanced hydrolysis of lignocellulosic biomass.

Lignocellulolytic enzymes from a novel Myceliophthora verrucosa (5DR) strain was found to potentiate the efficacy of benchmark cellulase during saccharification of acid/alkali treated bagasse by ~ 2.24 fold, indicating it to be an important source of auxiliary enzymes. The De-novo sequencing and analysis of M. verrucosa genome (31.7 Mb) revealed to encode for 7989 putative genes, representing a wide array of CAZymes (366) with a high proportions of auxiliary activity (AA) genes (76). The LC/MS QTOF based secretome analysis of M. verrucosa showed high abundance of glycosyl hydrolases and AA proteins with cellobiose dehydrogenase (CDH) (AA8), being the most prominent auxiliary protein. A gene coding for lytic polysaccharide monooxygenase (LPMO) was expressed in Pichia pastoris and CDH produced by M. verrucosa culture on rice straw based solidified medium were purified and characterized. The mass spectrometry of LPMO catalyzed hydrolytic products of avicel showed the release of both C1/C4 oxidized products, indicating it to be type-3. The lignocellulolytic cocktail comprising of in-house cellulase produced by Aspergillus allahabadii strain spiked with LPMO & CDH exhibited enhanced and better hydrolysis of mild alkali deacetylated (MAD) and unwashed acid pretreated rice straw slurry (UWAP), when compared to Cellic CTec3 at high substrate loading rate.

A thermostable and inhibitor resistant ß-glucosidase from Rasamsonia emersonii for efficient hydrolysis of lignocellulosics biomass.

The present study reports a highly thermostable ß-glucosidase (GH3) from Rasamsonia emersonii that was heterologously expressed in Pichia pastoris. Extracellular ß-glucosidase was purified to homogeneity using single step affinity chromatography with molecular weight of ~ 110 kDa. Intriguingly, the purified enzyme displayed high tolerance to inhibitors mainly acetic acid, formic acid, ferulic acid, vanillin and 5-hydroxymethyl furfural at concentrations exceeding those present in acid steam pretreated rice straw slurry used for hydrolysis and subsequent fermentation in 2G ethanol plants. Characteristics of purified ß-glucosidase revealed the optimal activity at 80 °C, pH 5.0 and displayed high thermostability over broad range of temperature 50-70 °C with maximum half-life of ~ 60 h at 50 °C, pH 5.0. The putative transglycosylation activity of ß-glucosidase was appreciably enhanced in the presence of methanol as an acceptor. Using the transglycosylation ability of ß-glucosidase, the generated low cost mixed glucose disaccharides resulted in the increased induction of R. emersonii cellulase under submerged fermentation. Scaling up the recombinant protein production at fermenter level using temporal feeding approach resulted in maximal ß-glucosidase titres of 134,660 units/L. Furthermore, a developed custom made enzyme cocktail consisting of cellulase from R. emersonii mutant M36 supplemented with recombinant ß-glucosidase resulted in significantly enhanced hydrolysis of pretreated rice straw slurry from IOCL industries (India). Our results suggest multi-faceted ß-glucosidase from R. emersonii can overcome obstacles mainly high cost associated enzyme production, inhibitors that impair the sugar yields and thermal inactivation of enzyme.

Scrutinizing the Therapeutic Potential of PROTACs in the Management of Alzheimer's Disease.

Finding an effective cure for Alzheimer's disease has eluded scientists despite intense research. The disease is a cause of suffering for millions of people worldwide and is characterized by dementia accompanied by cognitive and motor deficits, ultimately culminating in the death of the patient. The course of the disease progression has various underlying contributing pathways, with the first and foremost factor being the development and accumulation of aberrant and misfolded proteins exhibiting neurotoxic functions. The impairment of cellular clearance mechanisms adds to their accumulation, resulting in neuronal death. This is where the PROteolysis TArgeting Chimera (PROTAC) technology comes into play, bringing the UPS degradation machinery in the proximity of the target protein for initiating its degradation and clearing abnormal protein debris with unparalleled precision demonstrating an edge over traditional protein inhibitors in many respects. The technology is widely explored in cancer research and utilized in the treatment of various tumors and malignancies, and is now being applied in treating AD. This review explores the application of PROTAC technology in developing lead compounds for managing this deadly disease along with detailing the pieces of evidence justifying its utility and efficacy.

Neurologic Complications in Patients With Lymphoreticular Malignancy: A Descriptive Cohort Study.

OBJECTIVES: The objectives of this study were to study the spectrum of neurologic complications in children with lymphoreticular malignancy (acute lymphoblastic leukemia, Hodgkin, and non-Hodgkin lymphoma) at diagnosis and during treatment and to determine the etiology of these complications. MATERIALS AND METHODS: In this descriptive cohort study, conducted between November 2018 and March 2020, 204 children with a diagnosis of lymphoreticular malignancy were enrolled. The baseline investigations were done in all the cases. Those who developed neurological symptoms were evaluated with cerebrospinal fluid examination and radiologic and electrophysiologic studies as per indication and were managed according to standard management guidelines. RESULTS: Of the 204 patients, 30 (14.7%) developed neurological complications. The majority of these complications (n=20/30; 87%) occurred during the intensive chemotherapy period. Common complications included acute methotrexate neurotoxicity (n=7), vincristine-induced neurotoxicity (n=7), central nervous system (CNS) relapse (n=4), and posterior reversible encephalopathy syndrome (n=2). L-asparaginase-induced thrombosis (n=1), intramedullary compression syndrome (n=1), CNS infection (n=2), CNS hemophagocytic lymphohistiocytosis (n=1), and steroid-induced myopathy (n=1) were also observed. The complications resolved in 21/30 (70%) patients after receiving appropriate treatment while the neurological complication persisted in 2/30 (6.7%) patients. Three patients (10%) abandoned the treatment, and 4 (13.3%) patients expired. CONCLUSIONS: Neurologic complications in patients with lymphoreticular malignancy are quite variable, having common presenting symptoms but varying imaging abnormalities. By close follow-up and effective treatment, the morbidity and mortality of these complications can be minimized.

Morus alba fruit diet ameliorates cognitive deficit in mouse model of streptozotocin-induced memory impairment.

Mounting evidence shows that dietary intake of fruits with polyphenols is beneficial to improve impaired memory functions. This study explored the preventive as well as therapeutic effects of diet enriched with Morus alba fruits extract (DEMA) in streptozotocin (STZ) induced mouse model of memory impairment. The study consisted of two facets: one aspect consisted of pretreatment of animals with DEMA for two weeks followed by STZ (i.c.v) intervention and the second phase involved induction of dementia with STZ (i.c.v) followed by treatment with DEMA for 14 days. Cognitive functions of animals were measured by Morris Water Maze test and to delineate the associated mechanism of action, brain biochemical estimations (acetyl-cholinesterase activity, myeloperoxidase activity, thiobarbituric acid reactive species, superoxide dismutase activity, reduced glutathione and nitrite/nitrate) and histopathological studies (haematoxylin and eosin staining) were performed. Pre- and post- treatment with DEMA significantly prevented and attenuated, respectively, the detrimental effects of STZ on mice brain. The results demonstrated that dietary modification, by incorporation of M. alba fruits, reduces the incidence and aids in treatment of memory disorder in mice by reducing central cholinergic activity, decreasing oxidative stress and preventing neurodegeneration.

Computational Studies to Understand the Neuroprotective Mechanism of Action Basil Compounds.

Neurodegenerative diseases, such as Alzheimer's and Parkinson's, pose a significant global health challenge, emphasizing the need for novel neuroprotective agents. Basil (Ocimum spp.) has been recognized for its therapeutic potential, and numerous studies have reported neuroprotective effects. In this manuscript, we present a computational protocol to extricate the underlying mechanism of action of basil compounds in neuroprotective effects. Molecular docking-based investigation of the chemical interactions between selected bioactive compounds from basil and key neuroprotective targets, including AChE, GSK3ß, γ-secretase, and sirtuin2. Our results demonstrate that basil compound myricerone caffeoyl ester possesses a high affinity of -10.01 and -8.85 kcal/mol against GSK3ß and γ-secretase, respectively, indicating their potential in modulating various neurobiological processes. Additionally, molecular dynamics simulations were performed to explore the protein-ligand complexes' stability and to analyze the bound basil compounds' dynamic behavior. This comprehensive computational investigation enlightens the putative mechanistic basis for the neuroprotective effects of basil compounds, providing a rationale for their therapeutic use in neurodegenerative disorders after further experimental validation.

Recent Development of Novel Aminoethyl-Substituted Chalcones as Potential Drug Candidates for the Treatment of Alzheimer's Disease.

No drug on the market, as a single entity, participates in different pathways involved in the pathology of Alzheimer's disease. The current study is aimed at the exploration of multifunctional chalcone derivatives which can act on multiple targets involved in Alzheimer's disease. A series of novel aminoethyl-substituted chalcones have been developed using in silico approaches (scaffold morphing, molecular docking, and ADME) and reported synthetic methods. The synthesized analogs were characterized and evaluated biologically using different in vitro assays against AChE, AGEs, and radical formation. Among all compounds, compound PS-10 was found to have potent AChE inhibitory activity (IC50 = 15.3 nM), even more than the standard drug (IC50 = 15.68 nM). Further, the in vivo evaluation of PS-10 against STZ-induced dementia in rats showed memory improvement (Morris Water Maze test) in rats. Also, PS-10 inhibited STZ-induced brain AChE activity and oxidative stress, further strengthening the observed in vitro effects. Further, the molecular dynamic simulation studies displayed the stability of the PS-10 and AChE complex. The novel aminoethyl-substituted chalcones might be considered potential multifunctional anti-Alzheimer's molecules.

Scaffold Morphing and In Silico Design of Potential BACE-1 (ß-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics.

Alzheimer's disease (AD) is the prime cause of 65-80% of dementia cases and is caused by plaque and tangle deposition in the brain neurons leading to brain cell degeneration. ß-secretase (BACE-1) is a key enzyme responsible for depositing extracellular plaques made of ß-amyloid protein. Therefore, efforts are being applied to develop novel BACE-1 enzyme inhibitors to halt plaque build-up. In our study, we analyzed some Elenbecestat analogues (a BACE-1 inhibitor currently in clinical trials) using a structure-based drug design and scaffold morphing approach to achieve a superior therapeutic profile, followed by in silico studies, including molecular docking and pharmacokinetics methodologies. Among all the designed compounds, SB306 and SB12 showed good interactions with the catalytic dyad motifs (Asp228 and Asp32) of the BACE-1 enzyme with drug-likeliness properties and a high degree of thermodynamic stability confirmed by the molecular dynamic and stability of the simulated system indicating the inhibitory nature of the SB306 and SB12 on BACE 1.

Lossy Micromaser Battery: Almost Pure States in the Jaynes-Cummings Regime.

We consider a micromaser model of a quantum battery, where the battery is a single mode of the electromagnetic field in a cavity, charged via repeated interactions with a stream of qubits, all prepared in the same non-equilibrium state, either incoherent or coherent, with the matter-field interaction modeled by the Jaynes-Cummings model. We show that the coherent protocol is superior to the incoherent one, in that an effective pure steady state is achieved for generic values of the model parameters. Finally, we supplement the above collision model with cavity losses, described by a Lindblad master equation. We show that battery performances, in terms of stored energy, charging power, and steady-state purity, are slightly degraded up to moderated dissipation rate. Our results show that micromasers are robust and reliable quantum batteries, thus making them a promising model for experimental implementations.

Geographic information system-based mapping of air pollution & emergency room visits of patients for acute respiratory symptoms in Delhi, India (March 2018-February 2019).

Background & objectives: Studies assessing the spatial and temporal association of ambient air pollution with emergency room visits of patients having acute respiratory symptoms in Delhi are lacking. Therefore, the present study explored the relationship between spatio-temporal variation of particulate matter (PM)2.5 concentrations and air quality index (AQI) with emergency room (ER) visits of patients having acute respiratory symptoms in Delhi using the geographic information system (GIS) approach. Methods: The daily number of ER visits of patients having acute respiratory symptoms (less than or equal to two weeks) was recorded from the ER of four hospitals of Delhi from March 2018 to February 2019. Daily outdoor PM2.5 concentrations and air quality index (AQI) were obtained from the Delhi Pollution Control Committee. Spatial distribution of patients with acute respiratory symptoms visiting ER, PM2.5 concentrations and AQI were mapped for three seasons of Delhi using ArcGIS software. Results: Of the 70,594 patients screened from ER, 18,063 eligible patients were enrolled in the study. Winter days had poor AQI compared to moderate and satisfactory AQI during summer and monsoon days, respectively. None of the days reported good AQI (<50). During winters, an increase in acute respiratory ER visits of patients was associated with higher PM2.5 concentrations in the highly polluted northwest region of Delhi. In contrast, a lower number of acute respiratory ER visits of patients were seen from the 'moderately polluted' south-west region of Delhi with relatively lower PM2.5 concentrations. Interpretation & conclusions: Acute respiratory ER visits of patients were related to regional PM2.5 concentrations and AQI that differed during the three seasons of Delhi. The present study provides support for identifying the hotspots and implementation of focused, intensive decentralized strategies to control ambient air pollution in worst-affected areas, in addition to the general city-wise strategies.

COVID-19 pandemic and care of transfusion-dependent patients of thalassaemia: Experience from a paediatric centre in North India.

AIM: COVID-19 has presented an unprecedented challenge to health services and has significantly affected the management of non-Covid illnesses, like thalassemia. The present study documents the impact of Covid-associated restrictions and disruptions on working of the pediatric thalassemia day care centre (TDCC), and measures taken by TDCC and blood transfusion services to adapt to and mitigate the negative impact of Covid pandemic and associated lockdown on patient care. METHODS: Pre-transfusion haemoglobin and packed cell transfusion requirement were compared across three time periods, namely pre-lockdown, lockdown and post-lockdown in paediatric transfusion-dependent thalassaemia (TDT) patients. Caregivers were interviewed to document any problems faced by them. RESULTS: The study involved 181 TDT patients. There was a significant reduction in mean pre-transfusion haemoglobin and red cells transfused during lockdown phase as compared to pre-lockdown phase. Regular care was interrupted in 45% of patients and 76% of patients getting blood from outside could not get leukoreduced red cells. Investigations, monitoring and continuity of iron chelation were also affected. Blood centre faced 30.5% reduction in blood supply during lockdown. TDCC and blood centre took several steps, including prolongation of service hours and staggering of transfusions to ensure maximum transfusions while ensuring social distancing. CONCLUSION: The COVID-19 pandemic imposed many unprecedented challenges to the routine care of thalassaemic patients; however, some of them could be dealt with by a proactive approach and micro-planning at the institution level. Other similar resource-limited settings could learn from experiences for continued quality care for chronic medical conditions during pandemic like situations.

Anti-depressant like effects of quercetin 4'-O-glucoside from Allium cepa via regulation of brain oxidative stress and monoamine levels in mice subjected to unpredictable chronic mild stress.

Objectives: Depression is a common neuropsychiatric disorder. The available pharmacotherapy is ineffective for a substantial proportion of patients and has numerous side effects. Therefore, finding safer drugs for the management of depression is of paramount importance. The present study was aimed to identify the compound responsible for anti-depressant like effects of Allium cepa outer scale extract (ACE) and to elucidate its mechanism of action. Methods:The anti-depressant compound from ACE was separated using bioactivity guided fractionation. Furthermore, mouse model of unpredictable chronic mild stress (UCMS) induced depressive behaviour was employed to investigate the anti-depressant like activity and potential mechanism of bioactive compound using behavioural tests (forced swim test (FST), sucrose preference test (SPT), open field test (OFT)) as well as by assessing brain oxidative stress, monoamine oxidase A and serotonin levels. Results:ACE and its ethylacetate fraction (EF) showed marked anti-depressant like effects in mice in the FST model. Chromatographic and spectroscopic studies of EF lead to the isolation of quercetin and quercetin 4'-O-glucoside (QG). Of these, QG (20 mg/kg) treated animals showed activity similar to that shown by fluoxetine in mice using FST. Thus, QG was tested for anti-depressant like activity against UCMS induced depressive behaviour in mice. Treatment of UCMS- exposed mice with QG (20 mg/kg) improved UCMS induced behaviour anomalies and restored brain biochemical parameters (oxidative stress, MAO-A activity and serotonin levels). Discussion:QG is responsible for anti-depressant like effects of ACE possibly via prevention of brain oxidative stress and restoring serotonin levels by inhibiting MAO-A activity.

Improvement of cognitive function in mice by Citrus reticulata var. kinnow via modulation of central cholinergic system and oxidative stress.

Memory disorders are a result of a number of factors, of which elevated brain oxidative stress and acetylcholinesterase (AChE) activity are significant hallmarks. A number of Citrus species have cognition-enhancing capacity mediated by their antioxidant and anti-cholinesterase activities. This study was designed to assess the cognitive-enhancing, antioxidant and anticholinesterase potentials of Citrus reticulata var. kinnow (CR) leaf extracts. CR extracts were examined by bioactivity guided fractionation using in-vitro DPPH and Ellman assays to determine antioxidant and AChE inhibitory capacity. The most active component was further evaluated for memory improvement effects using mouse model of scopolamine induced amnesia. Passive shock avoidance test and elevated plus maze test were employed to determine cognitive functions while brain biochemical parameters were measured to establish the neuroprotective mechanism. The methanol extract (ME) showed marked AChE inhibitory and antioxidant activities, therefore, it was fractionated. Comparative analysis of all obtained fractions revealed that ethylacetate fraction (EAF) was most active. Both ME and EAF improved cognitive dysfunction caused by scopolamine in mice by reducing TBARS levels and brain AChE activity. TLC densitometric studies showed appreciable levels of naringenin in ME (0.32 % w/w) and EAF (1.14 % w/w). The observed memory enhancement effects of ME and EAF could be attributed to their ability to inhibit AChE activity and antioxidant effects due to presence of flavonoids.

Virus-induced genetics revealed by multidimensional precision medicine transcriptional workflow applicable to COVID-19.

Precision medicine requires the translation of basic biological understanding to medical insights, mainly applied to characterization of each unique patient. In many clinical settings, this requires tools that can be broadly used to identify pathology and risks. Patients often present to the intensive care unit with broad phenotypes, including multiple organ dysfunction syndrome (MODS) resulting from infection, trauma, or other disease processes. Etiology and outcomes are unique to individuals, making it difficult to cohort patients with MODS, but presenting a prime target for testing/developing tools for precision medicine. Using multitime point whole blood (cellular/acellular) total transcriptomics in 27 patients, we highlight the promise of simultaneously mapping viral/bacterial load, cell composition, tissue damage biomarkers, balance between syndromic biology versus environmental response, and unique biological insights in each patient using a single platform measurement. Integration of a transcriptome workflow yielded unexpected insights into the complex interplay between host genetics and viral/bacterial specific mechanisms, highlighted by a unique case of virally induced genetics (VIG) within one of these 27 patients. The power of RNA-Seq to study unique patient biology while investigating environmental contributions can be a critical tool moving forward for translational sciences applied to precision medicine.

Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging: a prospective, cohort study.

BACKGROUND: Near-infrared spectroscopy (NIRS) intravascular ultrasound imaging can detect lipid-rich plaques (LRPs). LRPs are associated with acute coronary syndromes or myocardial infarction, which can result in revascularisation or cardiac death. In this study, we aimed to establish the relationship between LRPs detected by NIRS-intravascular ultrasound imaging at unstented sites and subsequent coronary events from new culprit lesions. METHODS: In this prospective, cohort study (LRP), patients from 44 medical centres were enrolled in Italy, Latvia, Netherlands, Slovakia, UK, and the USA. Patients with suspected coronary artery disease who underwent cardiac catheterisation with possible ad hoc percutaneous coronary intervention were eligible to be enrolled. Enrolled patients underwent scanning of non-culprit segments using NIRS-intravascular ultrasound imaging. The study had two hierarchal primary hypotheses, patient and plaque, each testing the association between maximum 4 mm Lipid Core Burden Index (maxLCBI4mm) and non-culprit major adverse cardiovascular events (NC-MACE). Enrolled patients with large LRPs (≥250 maxLCBI4mm) and a randomly selected half of patients with small LRPs (<250 maxLCBI4mm) were followed up for 24 months. This study is registered with ClinicalTrials.gov, NCT02033694. FINDINGS: Between Feb 21, 2014, and March 30, 2016, 1563 patients were enrolled. NIRS-intravascular ultrasound device-related events were seen in six (0·4%) patients. 1271 patients (mean age 64 years, SD 10, 883 [69%] men, 388 [31%]women) with analysable maxLCBI4mm were allocated to follow-up. The 2-year cumulative incidence of NC-MACE was 9% (n=103). Both hierarchical primary hypotheses were met. On a patient level, the unadjusted hazard ratio (HR) for NC-MACE was 1·21 (95% CI 1·09-1·35; p=0·0004) for each 100-unit increase maxLCBI4mm) and adjusted HR 1·18 (1·05-1·32; p=0·0043). In patients with a maxLCBI4mm more than 400, the unadjusted HR for NC-MACE was 2·18 (1·48-3·22; p<0·0001) and adjusted HR was 1·89 (1·26-2·83; p=0·0021). At the plaque level, the unadjusted HR was 1·45 (1·30-1·60; p<0·0001) for each 100-unit increase in maxLCBI4mm. For segments with a maxLCBI4mm more than 400, the unadjusted HR for NC-MACE was 4·22 (2·39-7·45; p<0·0001) and adjusted HR was 3·39 (1·85-6·20; p<0·0001). INTERPRETATION: NIRS imaging of non-obstructive territories in patients undergoing cardiac catheterisation and possible percutaneous coronary intervention was safe and can aid in identifying patients and segments at higher risk for subsequent NC-MACE. NIRS-intravascular ultrasound imaging adds to the armamentarium as the first diagnostic tool able to detect vulnerable patients and plaques in clinical practice. FUNDING: Infraredx.

Long-term survival in triple-vessel disease: Hybrid coronary revascularization compared to contemporary revascularization methods.

BACKGROUND: Hybrid coronary revascularization (HCR) constitutes a left internal mammary artery graft to the left anterior descending (LAD) coronary artery, coupled with percutaneous coronary intervention (PCI) for non-LAD lesions. This management strategy is not commonly offered to patients with complex multivessel disease. Our objective was to evaluate 8-year survival in patients with triple-vessel disease (TVD) treated by HCR, compared with that of concurrent matched patients managed by traditional coronary artery bypass grafting (CABG) or multivessel PCI. METHODS: A retrospective review was undertaken of 4805 patients with TVD who presented between January 2009 and December 2016. A cohort of 100 patients who underwent HCR were propensity-matched with patients treated by CABG or multivessel PCI. The primary endpoint was all-cause mortality at 8 years. RESULTS: Patients with TVD who underwent HCR had similar 8-year mortality (5.0%) as did those with CABG (4.0%) or multivessel PCI (9.0%). A composite endpoint of death, repeat revascularization, and new myocardial infarction, was not significantly different between patient groups (HCR 21.0% vs CABG 15.0%, P = .36; HCR 21.0% vs PCI 25.0%, P = .60). Despite a higher baseline synergy between percutaneous coronary intervention with taxus and cardiac surgery(SYNTAX) score, HCR was able to achieve a lower residual SYNTAX score than multivessel PCI (P = .001). CONCLUSIONS: In select patients with TVD, long-term survival and FREEDOM from major adverse cardiovascular events after HCR are similar to that seen after traditional CABG or multivessel PCI. HCR should be considered for patients with multivessel disease, presuming a low residual SYNTAX score can be achieved.

Addition of Questions on Parental Factors to the WHO (Integrated Management of Childhood Illnesses) IMCI-HIV Algorithm Improves the Utility of the Algorithm for Diagnosis of HIV Infection in Children.

The WHO Integrated Management of Childhood Illnesses-HIV (IMCI-HIV) algorithm and its regional adaptation have shown variable performance in clinically identifying HIV-infected children with lack of validation in low prevalence areas. Addition of certain 'parental factors' (proxy indicators of parental HIV) may improve its utility. In this study, children aged 2 months to 5 years were enrolled into Group A (n = 1000, 'suspected symptomatic HIV infected' children as per the IMNCI-HIV algorithm) and group B (n = 50, children newly diagnosed with HIV infection). Parental factors were asked and HIV infection was tested for in Group A. For Group B, retrospective data were collected regarding IMNCI-HIV algorithm signs and parental factors. Utility of individual and various combinations of IMNCI-HIV signs and parental factors to predict HIV status was evaluated. Results showed that incorporating parental factors to IMNCI-HIV algorithm improved its sensitivity and positive predictive value in identifying HIV-infected children while maintaining the same sensitivity.

The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review.

BACKGROUND: Traditional risk factors are insufficient to explain all cases of coronary artery disease (CAD) in patients with diabetes mellitus (DM). Advanced glycation end-products (AGEs) and their receptors may play important roles in the development and progression of CAD. BODY: Hyperglycemia is the hallmark feature of DM. An increase in the incidence of both micro-and macrovascular complications of diabetes has been observed with increased duration of hyperglycemia. This association persists even after glycemic control has been achieved, suggesting an innate mechanism of "metabolic memory." AGEs are glycated proteins that may serve as mediators of metabolic memory due to their increased production in the setting of hyperglycemia and generally slow turnover. Elevated AGE levels can lead to abnormal cross linking of extracellular and intracellular proteins disrupting their normal structure and function. Furthermore, activation of AGE receptors can induce complex signaling pathways leading to increased inflammation, oxidative stress, enhanced calcium deposition, and increased vascular smooth muscle apoptosis, contributing to the development of atherosclerosis. Through these mechanisms, AGEs may be important mediators of the development of CAD. However, clinical studies regarding the role of AGEs and their receptors in advancing CAD are limited, with contradictory results. CONCLUSION: AGEs and their receptors may be useful biomarkers for the presence and severity of CAD. Further studies are needed to evaluate the utility of circulating and tissue AGE levels in identifying asymptomatic patients at risk for CAD or to identify patients who may benefit from invasive intervention.