Age-dependent heat shock hormesis to HSF-1 deficiency suggests a compensatory mechanism mediated by the unfolded protein response and innate immunity in young Caenorhabditis elegans.

The transcription factor HSF-1 (heat shock factor 1) acts as a master regulator of heat shock response in eukaryotic cells to maintain cellular proteostasis. The protein has a protective role in preventing cells from undergoing ageing, and neurodegeneration, and also mediates tumorigenesis. Thus, modulating HSF-1 activity in humans has a promising therapeutic potential for treating these pathologies. Loss of HSF-1 function is usually associated with impaired stress tolerance. Contrary to this conventional knowledge, we show here that inactivation of HSF-1 in the nematode Caenorhabditis elegans results in increased thermotolerance at young adult stages, whereas HSF-1 deficiency in animals passing early adult stages indeed leads to decreased thermotolerance, as compared to wild-type. Furthermore, a gene expression analysis supports that in young adults, distinct cellular stress response and immunity-related signaling pathways become induced upon HSF-1 deficiency. We also demonstrate that increased tolerance to proteotoxic stress in HSF-1-depleted young worms requires the activity of the unfolded protein response of the endoplasmic reticulum and the SKN-1/Nrf2-mediated oxidative stress response pathway, as well as an innate immunity-related pathway, suggesting a mutual compensatory interaction between HSF-1 and these conserved stress response systems. A similar compensatory molecular network is likely to also operate in higher animal taxa, raising the possibility of an unexpected outcome when HSF-1 activity is manipulated in humans.

Hydrophobic C-Terminal Peptide Analog Aß31-41 Protects the Neurons from Aß-Induced Toxicity.

Spontaneous aggregation of amyloid beta (Aß) leads to the formation of neurotoxic senile plaque considered as the most crucial event in Alzheimer's disease (AD) progression. Inhibition or disruption of this deadly aggregate formation is one of the most efficient strategies for the development of potential therapeutics, and extensive research is in progress by various research groups. In this direction, the development of a peptide analogous to that of the native Aß peptide is an attractive strategy. Based on this rationale, ß-sheet breakers were developed from the Aß central hydrophobic core. These peptide derivatives will bind to the full length of the parent Aß and interfere in self-recognition, thereby preventing the folding of the Aß peptide into cross ß-sheet neurotoxic aggregates. However, this approach is effective in the inhibition of fibrillar aggregation, but this strategy is ineffective in the Aß neurotoxic oligomer formation. Therefore, an alternative and efficient approach is to use the Aß peptide analogous to the C-terminal region, which arbitrates fibrillation and oligomerization. Herein, we developed the Aß C-terminal fragment (ACT-1 to ACT-7) for inhibition of oligomerization as well as fibrillar aggregation. Screening of these seven peptides resulted in an efficient anti-Aß peptide aggregative agent (ACT-7), which was evaluated by the ThT assay peptide. The ThT assay reveals complete inhibition and showed significant neuroprotection of PC-12-derived neurons from Aß-induced toxicity and reduced cell apoptosis. Further, analysis using CD and FTIR spectroscopy reveals that the ACT-7 peptide efficiently inhibits the formation of the ß-sheet secondary structure content. HR-TEM microscopic analysis confirmed the inhibition of formation. Therefore, the inhibition of ß-sheet Aß fibrillary aggregation by the protease-stable ACT-7 peptide may provide a beneficial effect on AD treatment to control the Aß aggregates. Finally, we anticipate that our newly designed ACT peptides may also assist as a template molecular scaffold for designing potential anti-AD therapeutics.

Power of Dopamine: Multifunctional Compound Assisted Conversion of the Most Risk Factor into Therapeutics of Alzheimer's Disease.

In Alzheimer's disease (AD), reactive oxygen species (ROS) plays a crucial role, which is produced from molecular oxygen with extracellular deposited amyloid-ß (Aß) aggregates through the reduction of a Cu2+ ion. In the presence of a small amount of redox-active Cu2+ ion, ROS is produced by the Aß-Cu2+ complex as Aß peptide alone is unable to generate excess ROS. Therefore, Cu2+ ion chelators are considered promising therapeutics against AD. Here, we have designed and synthesized a series of Schiff base derivatives (SB) based on 2-hydroxy aromatic aldehyde derivatives and dopamine. These SB compounds contain one copper chelating core, which captures the Cu2+ ions from the Aß-Cu2+ complex. Thereby, it inhibits copper-induced amyloid aggregation as well as amyloid self-aggregation. It also inhibits copper-catalyzed ROS production through sequestering of Cu2+ ions. The uniqueness of our designed ligands has the dual property of dopamine, which not only acts as a ROS scavenger but also chelates the copper ion. The crystallographic analysis proves the power of the dopamine unit. Therefore, dual exploration of dopamine core can be considered as potential therapeutics for future AD treatment.

Discovery of Quinazoline and Quinoline-Based Small Molecules as Utrophin Upregulators via AhR Antagonism for the Treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease caused by the absence of a dystrophin protein. Elevating utrophin, a dystrophin paralogue, offers an alternative therapeutic strategy for treating DMD, irrespective of the mutation type. Herein, we report the design and synthesis of novel quinazoline and quinoline-based small molecules as potent utrophin modulators screened via high throughput In-Cell ELISA in C2C12 cells. Remarkably, lead molecule SG-02, identified from a library of 70 molecules, upregulates utrophin 2.7-fold at 800 nM in a dose-dependent manner, marking the highest upregulation within the nanomolar range. SG-02's efficacy was further validated through DMD patient-derived cells, demonstrating a significant 2.3-fold utrophin expression. Mechanistically, SG-02 functions as an AhR antagonist, with excellent binding affinity (Kd = 41.68 nM). SG-02 also enhances myogenesis, as indicated by an increased MyHC expression. ADME evaluation supports SG-02's oral bioavailability. Overall, SG-02 holds promise for addressing the global DMD population.

High-Affinity Fluorescent Probes for the Detection of Soluble and Insoluble Aß Deposits in Alzheimer's Disease.

The overproduction and deposition of the amyloid-ß (Aß) aggregates are accountable for the genesis and development of the neurologic disorder Alzheimer's disease (AD). Effective medications and detection agents for AD are still deficient. General challenges for the diagnosis of Aß aggregates in the AD brain are (i) crossing the blood-brain barrier (BBB) and (ii) selectivity to Aß species with (iii) emission maxima in the 500-750 nm region. Thioflavin-T (ThT) is the most used fluorescent probe for imaging Aß fibril aggregates. However, because of the poor BBB crossing (log P = -0.14) and short emission wavelength (482 nm) after binding with Aß fibrils, ThT can be limited to in vitro use only. Herein, we have developed Aß deposit-recognizing fluorescent probes (ARs) with a D-π-A architecture and a longer emission wavelength after binding with Aß species. Among the newly designed probes, AR-14 showed an admirable fluorescence emission (>600 nm) change after binding with soluble Aß oligomers (2.3-fold) and insoluble Aß fibril aggregates (4.5-fold) with high affinities Kd = 24.25 ± 4.10 nM; Ka = (4.123 ± 0.69) × 107 M-1 for fibrils; Kd = 32.58 ± 4.89 nM; and Ka = (3.069 ± 0.46) × 107 M-1 for oligomers with high quantum yield, molecular weight of <500 Da, reasonable log P = 1.77, stability in serum, and nontoxicity, and it can cross the BBB efficiently. The binding affinity of AR-14 toward Aß species is proved by fluorescence binding studies and fluorescent staining of 18-month-old triple-transgenic (3xTg) mouse brain sections. In summary, the fluorescent probe AR-14 is efficient and has an admirable quality for the detection of soluble and insoluble Aß deposits in vitro and in vivo.

Multi-Mechanistic and Therapeutic Exploration of Nephroprotective Effect of Traditional Ayurvedic Polyherbal Formulation Using In Silico, In Vitro and In Vivo Approaches.

Based on traditional therapeutic claims, NEERI KFT (a traditional Ayurvedic polyherbal preparation) has been innovatively developed in recent time on the decades of experience for treating kidney dysfunction. Due to the lack of scientific evidence, the present investigations are needed to support the rationale use of NEERI KFT. Considering the facts, the study investigated the nephroprotective effect of NEERI KFT against kidney dysfunction using in silico, in vitro and in vivo approaches. In this study, phytochemical and network pharmacology studies were performed for the developed formulation to evaluate the molecular mechanism of NEERI KFT in the amelioration of kidney disease. In vitro nephroprotective and antioxidant effect of NEERI KFT was determined on HEK 293 cells against cisplatin-induced cytotoxicity and oxidative stress. In vivo nephroprotective effect of NEERI KFT was determined against cisplatin-induced nephrotoxicity in Wistar rats, via assessing biochemical markers, antioxidant enzymes and inflammatory cytokines such as TNF-α, IL-1ß, CASP-3, etc. The results showed that the compounds such as gallic acid, caffeic acid and ferulic acid are the major constituents of NEERI KFT, while network pharmacology analysis indicated a strong interaction between polyphenols and several genes (CASPs, ILs, AGTR1, AKT, ACE2, SOD1, etc.) involved in the pathophysiology of kidney disease. In vivo studies showed a significant (p < 0.05) ameliorative effect on biochemical markers and antioxidant enzymes (SOD, CAT, GSH, etc.), and regulates inflammatory cytokine (TNF-α, IL-1ß, CASP-3) expression in kidney tissue. Hence, it can be concluded that NEERI KFT subsequently alleviates renal dysfunction mediated by cisplatin via attenuating oxidative and inflammatory stress, thus preserving the normalcy of kidney function.

Seed germination dynamics of some woody legumes: implication for restoration of arid zones ecosystems.

The seed germination dynamics of Acacia nilotica, Bauhinia rufescens, Faidherbia albida, and Piliostigma reticulatum were investigated over 28 days. Seeds were pretreated with concentrated sulfuric acid. Determined germination parameters included germination energy, germination period, germination capacity, germination inertia, and viability loss. Seeds exposed to sulfuric acid for extended periods (30, 40, 50, and 60 min) exhibited a higher germination rate (α = 0.05). For A. nilotica seeds, the 50 min acid treatment resulted in the highest germination energy of 85.5% and germination capacity of 89.5% (P = 0.001); conversely, the 60-min treatment yielded the highest germination energy and capacity, both 96.5% (P = 0.079), for P. reticulatum. In the case of B. rufescens, the 30-min treatment led to the highest germination energy of 93% and germination capacity of 88% (P = 0.001). For F. albida, all acid treatments resulted in 100% for both germination energy and germination capacity (P = 0.621). Viability losses for A. nilotica and P. reticulatum were higher (32 and 30%, respectively) than those for B. rufescens and F. albida, which were 19.5 and 6%, respectively (P = 0.000). Generally, higher germination energy resulted in lower viability loss, dependent on the species. Analyses of germination inertia and viability loss suggest that seeds of A. nilotica and P. reticulatum possess a greater ability to survive in arid land climates than those of B. rufescens and F. albida. However, due to the advantage of lower viability loss, B. rufescens and F. albida should be preferred for the natural restoration of arid land ecosystems where seed availability is a major concern.

Metabolite profiling and nephroprotective potential of Glycyrrhiza glabra L. roots against cisplatin-induced nephrotoxicity in vitro and in vivo.

Objectives: The present study was conducted to investigate the phytochemical analysis and demonstrate the nephroprotective potential of root extract of Glycyrrhiza glabra L. against cisplatin (CP) -induced nephrotoxicity in vitro and in vivo. Materials and Methods: The HPTLC analysis and UPLC-MS were carried out for standardizing and metabolite profiling of methanolic extract of roots of G. glabra (GGE). Further, in vitro studies were conducted in human embryonic kidney (HEK)-293 cells to evaluate the cytotoxicity and anti-oxidant potential of GGE with CP as a toxicant and ascorbic acid as standard. Also, in vivo nephroprotective potential at doses of 31.5, 63, and 126 mg/kg/day on CP (6 mg/kg, bw, IP) induced nephrotoxicity was evaluated on rodents. Results: Phytochemical analysis by HPTLC and UPLC-MS revealed the presence of glycyrrhizin, glabridin, and liquiritin along with other bioactive constituents. The in vitro assay of GGE showed significant (P<0.001 nephroprotective, cellular anti-oxidant potential and improvement in morphological changes induced by CP. Further, administration of CP caused significant (P<0.001) elevation in biochemical, inflammatory, oxidative stress, caspase-3, as well as histopathological changes in kidney tissue. Pre-treatment with GGE attenuated the elevated biochemical markers significantly, improved histopathological damage, and showed a comparable result to ascorbic acid and α-ketoanalogue. Conclusion: Present study concluded the nephroprotective potential of GGE which supports the traditional claim of G. glabra roots in various kidney and its related disorders. The nephroprotective activity may be attributed to its anti-oxidant, anti-inflammatory, and anti-apoptosis effects. Thus, it holds promising potential in management of nephrotoxicity.

Metabolite Profiling and Nephroprotective Potential of the Zea mays L. Silk Extract against Diclofenac-Induced Nephrotoxicity in Wistar Rats.

The lack of sufficient scientific evidence prompted the analytical investigation of nephroprotective potential of the silk extract of Zea mays L., which is traditionally and ethnomedicinally used for various disorders including kidney dysfunction. The present study was conducted to investigate the phytochemical analysis and demonstrate the nephroprotective potential of the methanolic silk extract of Z. mays L. using a rodent model. High-performance thin-layer chromatography (HPTLC) analysis was carried out to standardize the methanolic silk extract of Z. mays (ZME) using naringenin as a marker. The metabolite profiling of the ZME was carried out using ultrahigh-performance liquid chromatography mass spectrometry (UPLC-MS) on a monolithic capillary silica-based C18 column to identify bioactive compounds and for confirmation of the identified markers. Furthermore, for acute toxicity study, a single dose (2000 mg/kg bw) of the ZME was administered orally to Wistar rats. Also, nephrotoxicity was induced in Wistar rats by injecting diclofenac (DC) (50 mg/kg, bw, i.p.) at a single dose. The efficacy of the ZME as a nephroprotective agent was then evaluated at doses of 100, 200, and 400 mg/kg/day, bw, p.o. Furthermore, the kidney, liver, antioxidant, inflammatory, and apoptotic biochemical markers and histopathological and immunohistochemical alterations (caspase-3 and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-4 (NOX-4)) were evaluated. Phytochemical analysis by HPTLC and UPLC-MS revealed the presence of naringenin, vanillic acid, ferulic acid, gallic acid (GA), ellagic acid, quercetin, and morin, along with other bioactive constituents exhibiting multiple pharmacological properties. The acute toxicity study of the ZME showed no mortality or any clinical signs of toxicity through all the 14 days of the toxicity study at a dose of 2000 mg/kg. Also, administration of DC caused a significant elevation (P < 0.001) in kidney biochemical parameters and also caused oxidative, inflammatory, and apoptotic stress. Furthermore, DC also caused histopathological and immunohistochemical changes. Pretreatment with the ZME attenuated the elevated biochemical markers significantly at medium and high doses along with improvement in histopathological and immunohistochemical damages and showing comparable results to those of α-ketoanalogue. The present study verifies the traditional claims of Z. mays silk alleviating various kidney and related disorders by concluding the nephroprotective potential of the ZME. The nephroprotective activity of the ZME is attributed to the phytoconstituents present, acting as potent restoring antioxidants and preventing inflammatory and apoptotic cellular damages in rats. Thus, it holds promising potential in the management of nephrotoxicity.

Heartwood Extract of Pterocarpus marsupium Roxb. Offers Defense against Oxyradicals and Improves Glucose Uptake in HepG2 Cells.

Diabetes mellitus leads to cellular damage and causes apoptosis by oxidative stress. Heartwood extract of Pterocarpus marsupium has been used in Ayurveda to treat various diseases such as leprosy, diabetes, asthma, and bronchitis. In this study, we worked out the mechanism of the antidiabetic potential of methanolic heartwood extract of Pterocarpus marsupium (MPME). First, metabolic profiling of MPME was done using gas chromatography-mass spectrometry (GCMS), ultra-performance liquid chromatography-mass spectroscopy (UPLC-MS), and high-performance thin-layer chromatography (HPTLC) to identify phenols, flavonoids, and terpenoids in MPME. Biological studies were carried out in vitro using the HepG2 cell line. Many antidiabetic compounds were identified including Quercetin. Methanolic extract of MPME (23.43 µg/mL-93.75 µg/mL) was found to be safe and effective in reducing oxyradicals in HepG2 cells. A concentration of 93.75 µg/mL improved glucose uptake efficiently. A significant decrease in oxidative stress, cell damage, and apoptosis was found in MPME-treated HepG2 cells. The study suggests that the heartwood of Pterocarpus marsupium offers good defense in HepG2 cells against oxidative stress and improves glucose uptake. The results show the significant antidiabetic potential of MPME using a HepG2 cell model. The effect seems to occur by reducing oxidative stress and sensitizing the cells towards glucose uptake, hence lowering systemic glucose levels, as well as rescuing ROS generation.

Azanza garckeana ameliorates Bisphenol A-induced reproductive toxicities in rabbit bucks.

This study evaluated the ameliorative properties of Azanza garckeana in Bisphenol A-induced reproductive toxicities on weight, spermiogram, serum hormonal profile, sperm DNA integrity, histopathology of testes and brain tissues of rabbit bucks. Twenty-eight rabbit bucks, with live weight of 1.20-2.00 kg and aged 10-18 months. They were randomly divided into four groups of seven bucks each, group A was administered distilled water (1.5 mL) daily for 12 weeks, group B was administered Bisphenol A (100 mg/kg) for 5 consecutive days in a week for a period of 12 weeks, group C was administered Azanza garckeana (500 mg/kg) daily for 12 weeks and group D was pre-dosed with Bisphenol A (100 mg/kg) for 5 consecutive days in a week over 6 weeks period followed by Azanza garckeana (500 mg/kg) daily for another 6 weeks. Mean testicular weights differed significantly (p < 0.05) between group B (4.4 ± 0.23) when compared with groups A (8.0 ± 0.06), C (8.7 ± 0.19) and D (7.1 ± 0.18). There were significant differences (p < 0.05) in the mean reaction time, spermiogram, testosterone, follicle stimulating hormone, luteinising hormone and sperm DNA fragmentation index between Bisphenol A-exposed groups and treatment groups. On histopathology, there was testicular vacuolization, interstitial hemorrhage, reduction in spermatogenic cells following Bisphenol A exposure. There were layers of dense basophilic cells in the pineal and pituitary parenchymas. In conclusion, Bisphenol A has negative effects on reproduction but administration of Azanza garckeana may possess some therapeutic properties that can ameliorate such adverse effects.

State-of-the-Art Light to Digital Converter Circuits Applicable in Non-Invasive Health Monitoring Devices to Combat COVID-19 and Other Respiratory Illnesses: A Review.

In the past few years, a tremendous advancement in the outcome of biomedical circuits and systems has been reported. Unfortunately, at the time of the sudden outbreak of COVID-19, the electronic engineering researchers felt dearth on their side to combat the pandemic, as no such immediate cutting-edge solutions were ready to recognize the virus with some standard and smart electronic devices. Likely, in this paper, a detailed comparative and comprehensive study on circuit architectures of the biomedical devices is presented. Mostly, this study relates the industry standard circuit schemes applicable in non-invasive health monitoring to combat respiratory illnesses. The trending circuit architectural schemes casted-off to tapeout non-invasive health-care devices available in the past literature are meticulously and broadly discussed in this study. Further, the comprehensive comparison of the state of art of the device performance in terms of supply voltage, chip area, sensitivity, dynamic range, etc. is also shown in this paper. The inclusive design processes of the health monitoring devices from Lab to Industry is thoroughly discussed for the readers. The authors think, that this critical review summarising all the trending and most cited health-care devices in a single paper will alternately help the industrialists to adapt and modify the circuit architectures of the health monitoring devices more precisely and straightforwardly. Finally, the demand for health monitoring devices particularly responsible to detect respiratory illnesses, measuring blood pressure and heart-rate is growing widely in the market after the the incident of COVID-19 and other respiratory diseases.

Fiction and Facts about BCG Imparting Trained Immunity against COVID-19.

The Bacille Calmette-Guérin or BCG vaccine, the only vaccine available against Mycobacterium tuberculosis can induce a marked Th1 polarization of T-cells, characterized by the antigen-specific secretion of IFN-γ and enhanced antiviral response. A number of studies have supported the concept of protection by non-specific boosting of immunity by BCG and other microbes. BCG is a well-known example of a trained immunity inducer since it imparts 'non-specific heterologous' immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the recent pandemic. SARS-CoV-2 continues to inflict an unabated surge in morbidity and mortality around the world. There is an urgent need to devise and develop alternate strategies to bolster host immunity against the coronavirus disease of 2019 (COVID-19) and its continuously emerging variants. Several vaccines have been developed recently against COVID-19, but the data on their protective efficacy remains doubtful. Therefore, urgent strategies are required to enhance system immunity to adequately defend against newly emerging infections. The concept of trained immunity may play a cardinal role in protection against COVID-19. The ability of trained immunity-based vaccines is to promote heterologous immune responses beyond their specific antigens, which may notably help in defending against an emergency situation such as COVID-19 when the protective ability of vaccines is suspicious. A growing body of evidence points towards the beneficial non-specific boosting of immune responses by BCG or other microbes, which may protect against COVID-19. Clinical trials are underway to consider the efficacy of BCG vaccination against SARS-CoV-2 on healthcare workers and the elderly population. In this review, we will discuss the role of BCG in eliciting trained immunity and the possible limitations and challenges in controlling COVID-19 and future pandemics.

Antimicrobial activity of different plants extracts against Staphylococcus aureus and Escherichia coli.

BACKGROUND: Microbial pathogens, mainly bacteria, are a major cause of food spoilage resulting in several foodborne diseases. Food spoilage can be prevented by the application of chemical preservatives in the food industry but such process has harmful effects on human health and causes the introduction of chemicals in several food chains, leading to toxicity and long-term complications. Due to such adverse effects, the need to find natural preservatives that are safer to use, effective and less complicated is increasing. OBJECTIVES: This study is based on plant extracts that play a major role in microbicidal action (the use of natural preservatives is preferred over chemical ones). Antimicrobial action of different plant extracts was assessed using Staphylococcus aureus and Escherichia coli as experimental bacterial strains. MATERIAL AND METHODS: Ethanolic extracts of different plants like Punica granatum, Acacia catechu and Phyllanthus emblica were highly effective against the both analyzed bacterial strains at a dosage of 10 mg/mL, while the extracts of Ocimum bacilicum and Quercus infectoria were effective only against S. aureus and E. coli, respectively. RESULTS: Punica granatum and Phyllanthus emblica extracts were found to be the most effective and exhibited bacteriostatic and bactericidal activities against the highly infectious strains of pathogenic bacteria causing food spoilage, with minimum inhibitory concentration (MIC) of 2.5 mg/mL and minimum bactericidal concentration (MBC) of 5 mg/mL. CONCLUSIONS: The plant extracts used in the study were highly effective in reducing bacterial contamination and can be used as an alternative to chemical preservatives to avoid and control foodborne diseases and for preservation of food with no health-related hazards caused by chemicals.

Novel biomarkers for cholangiocarcinoma: how can it enhance diagnosis, prognostication, and investigational drugs? Part-1.

INTRODUCTION: The development of novel biomarkers for cancer has exploded over the last decade with advances in novel technologies. Cholangiocarcinoma (CCA), a cancer of the bile ducts, has a dearth of strong disease and pathophysiology biomarkers, making early detection and prognostication a difficult task. AREAS COVERED: In this comprehensive review, we discuss the spectrum of biomarkers for CCA diagnosis and prognostication. We elaborate on novel biomarker discovery through a comprehensive multi-omics approach. We also cover, how certain biomarkers may also serve as unique and potent targets for therapeutic development. EXPERT OPINION: Despite the relatively poor diagnostic and prognostic performance of existing biomarkers for CCA, there is a vast range of novel biomarkers with exquisite diagnostic and prognostic performance for CCA in the pipeline. Moreover, these biomarkers may serve as potential targets for precision medicine. Existing strategies to target unique biomolecular classes are discussed, within the context of an overall 'omics' focused profiling strategy. Omics profiling will simultaneously allow for enhanced biomarker development and identification of unique subtypes of cholangiocarcinoma and how they are influenced by an individual's unique context. In this manner, patient management strategy and clinical trial design can be optimized to the individual.

WSES/GAIS/SIS-E/WSIS/AAST global clinical pathways for patients with intra-abdominal infections.

Intra-abdominal infections (IAIs) are common surgical emergencies and have been reported as major contributors to non-trauma deaths in hospitals worldwide. The cornerstones of effective treatment of IAIs include early recognition, adequate source control, appropriate antimicrobial therapy, and prompt physiologic stabilization using a critical care environment, combined with an optimal surgical approach. Together, the World Society of Emergency Surgery (WSES), the Global Alliance for Infections in Surgery (GAIS), the Surgical Infection Society-Europe (SIS-E), the World Surgical Infection Society (WSIS), and the American Association for the Surgery of Trauma (AAST) have jointly completed an international multi-society document in order to facilitate clinical management of patients with IAIs worldwide building evidence-based clinical pathways for the most common IAIs. An extensive non-systematic review was conducted using the PubMed and MEDLINE databases, limited to the English language. The resulting information was shared by an international task force from 46 countries with different clinical backgrounds. The aim of the document is to promote global standards of care in IAIs providing guidance to clinicians by describing reasonable approaches to the management of IAIs.

Nutritional constituents of mulberry and their potential applications in food and pharmaceuticals: A review.

Mulberry is a fast growing deciduous plant found in wide variety of climatic, topographical and soil conditions, and is widely distributed from temperate to subtropical regions. Due to presence of valuable phytochemical constituents, mulberry as a whole plant has been utilized as a functional food since long time. Mulberry fruits are difficult to preserve as they have relatively high water content. Therefore for proper utilization, different value-added products like syrups, squashes, teas, pestil sand köme, pekmez (turkuish by-products), yogurts, jams, jellies, wines, vinegar, breads, biscuits, parathas, and many more are made. In overseas, these value-added products are commercially sold and easily available, though in India, this versatile medicinal plant is still missing its identity at commercial and industrial scale. Leaves of mulberry are economically viable due to their important role in the sericulture industry since ancient times. Mulberries or its extracts exhibit excellent anti-microbial, anti-hyperglycaemic, anti-hyperlipidemic, anti-inflammatory, anti-cancer effects and is used to combat different acute and chronic diseases. Different parts of Morus species like fruits, leaves, twigs, and bark exhibit strong anti-tyrosinase inhibition activity that makes it a suitable candidate in cosmetic industries as a whitening agent. The current review provides a comprehensive discussion concerning the phytochemical constituents, functionality and nutraceutical potential of mulberry and as a common ingredient in various cosmetic products.

Rare and unusual presentation of gastrocardiac syndrome.

Gastrointestinal pathology can cause cardiac symptoms and disorders. We present a case of a patient who had worsening of her palpitations with food intake. She was found to have a high burden of premature ventricular contractions in the setting of hiatal hernia and gastro-oesophageal reflux disease. After extensive investigations and ruling out cardiac causes, her arrhythmia resolved with the surgical correction of hiatal hernia.

Quality Outcomes in Appendicitis Care: Identifying Opportunities to Improve Care.

INTRODUCTION: Appendicitis is one of the most common causes of acute abdominal pain requiring surgical intervention, but the variability of diagnosis and management continue to challenge the surgeons. Aim: This study assessed patients undergoing appendectomy to identify opportunities to improve diagnostic accuracy and outcomes. METHODS: An ethically approved retrospective cohort study was undertaken between March 2016 and March 2017 at a single university hospital of all consecutive adult and paediatric patients undergoing appendectomy. Demographic data including age, gender, co-morbidities, presentation and triage timings along with investigation, imaging and operative data were analysed. Appendicitis was defined as acute based on histology coupled with intraoperative grading with the American Association for the Surgery of Trauma (AAST) grades. Complications using the Clavien-Dindo classification along with 30-day re-admission rates and the negative appendectomy rates (NAR) were recorded and categorised greater and less than 25%. The use of scoring systems was assessed, and retrospective scoring performed to compare the Alvarado, Adult Appendicitis Score (AAS) and the Appendicitis Inflammatory Response (AIR) score. Results: A total of 201 patients were studied, 115 male and 86 females, of which 136/201 (67.6%) were adults and 65/201 (32.3%) paediatric. Of the adult group, 83 were male and 53 were female, and of the paediatric group, 32 were male and 33 were female. Median age was 20 years (range: 5 years to 81 years) and no patient below the age of 5 years had an appendectomy during our study period. All patients were admitted via the emergency department and median time from triage to surgical review was 2 h and 38 min, (range: 10 min to 26 h and 10 min). Median time from emergency department review to surgical review, 55 min (range: 5 min to 6 h and 43 min). Median time to operating theatre was 21 h from admission (range: 45 min to 140 h and 30 min). Out of the total patients, 173 (86.1%) underwent laparoscopic approach, 28 (13.9%) had an open approach and 12 (6.9%) of the 173 were converted to open. Acute appendicitis occurred in 166/201 (82.6%). There was no significant association between grade of appendicitis and surgeons' categorical NAR rate (p = 0.07). Imaging was performed in 118/201 (58.7%); abdominal ultrasound (US) in 53 (26.4%), abdominal computed tomography (CT) in 59 (29.2%) and both US and CT in 6 (3%). The best cut-off point was 4 (sensitivity 84.3% and specificity of 65.7%) for AIR score, 9 (sensitivity of 74.7% and specificity of 68.6%) for AAS, and 7 (sensitivity of 77.7% and specificity of 71.4%) for the Alvarado score. Twenty-four (11.9%) were re-admitted, due to pain in 16 (58.3%), collections in 3 (25%), 1 (4.2%) wound abscess, 1 (4.2%) stump appendicitis, 1 (4.2%) small bowel obstruction and 1 (4.2%) fresh rectal bleeding. CT guided drainage was performed in 2 (8.3%). One patient had release of wound collection under general anaesthetic whereas another patient had laparoscopic drain placement. A laparotomy was undertaken in 3 (12.5%) patients with division of adhesions in 1, the appendicular stump removed in 1 and 1 had multiple collections drained. CONCLUSION: The negative appendectomy and re-admission rates were unacceptably high and need to be reduced. Minimising surgical variance with use of scoring systems and introduction of pathways may be a strategy to reduce NAR. New systems of feedback need to be introduced to improve outcomes.

HIV-Captured DCs Regulate T Cell Migration and Cell-Cell Contact Dynamics to Enhance Viral Spread.

Trafficking of cell-associated HIV-1 from the genital mucosa to lymphoid organs represents a critical first step toward systemic infection. Mature DCs capture and transmit HIV-1 to T cells, but insights into DC-to-T cell viral spread dynamics within a 3-dimensional environment is lacking. Using live-cell imaging, we show that mature DCs rapidly compartmentalize HIV-1 within surface-accessible invaginations near the uropod. HIV-1 capture did not interfere with DC migration toward lymph node homing chemo-attractants and their ability to enter lymphatic vessels. However, HIV-captured DCs engaged in prolonged contacts with autologous CD4+ T cells, which led to high T cell infection. Interestingly, we show that surface bound, virion-associated Env induced signal transduction in motile T cells that facilitated prolonged DC:T cell interactions, partially through high-affinity LFA-1 expression. Together, we describe a mechanism by which surface bound HIV-1 particles function as signaling receptors that regulate T cell motility, cell-cell contact dynamics, and productive infection.