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Background: The presence of free radicals in the human body is harmful, which may induce many diseases like cardiovascular, diabetes, cancer, inflammation, neurodegenerative disorder, atherosclerosis, cataract, etc. Antioxidants can balance the effect of free radicals. Antioxidant- rich herbs have been identified for the preparation of drugs that can be administered to neutralize the free radicals. In the present context, the selected medicinal plant is “Origanum majorana” (Family- Lamiaceae) widely known as Marwa in the Indian sub-continent. As the medical professionals show their desire towards composite or lateral treatment, the application of drugs with herbal origin has gained its importance. Objective: This review presents various in vitro and in vivo methods used in the antioxidant activity study of O. majorana and highlights its efficacy in reducing the oxidative stress. Methods: Many reliable sources like Research gate, PubMed, Science Direct, Google scholar, Wiley online library, and books have been referred to collect all information regarding the antioxidant activity of the selected plant. Results: Several methods have been used to determine the antioxidant activity of O. majorana, such as superoxide radical scavenging, ferric ion reducing antioxidant potency, thiobarbituric acid reactive substances, hydrogen peroxide scavenging, hydroxyl radical scavenging, lipid peroxidation inhibition, etc. The selected plant contains many phytoconstituents such as gallic acid, ferulic acid, apigenin, catechin, rutin, quercetin, luteolin, linolenic acid, β-sitosterol, and essential oils, which may be responsible for antioxidant activity. Conclusions: The review article provides information for investigating and developing new antioxidant methods and major phytoconstituents from O. majorana for better therapy of oxidative stress-mediated complications.

To develop a predictive model for late stillbirth among women with hypertensive disorders of pregnancy (HDP) in low- and middle-income countries. Study was part of the WHO newborn birth defect (NBBD) project and included all stillbirths occurring in the facility from November 2015 to December 2020. The age and parity matched subjects with HDP having live birth were taken as controls. All significant predictors were analyzed and a predictive model was developed. Out of 69,007 deliveries, 1691(24.5/1000) were stillborn. HDP was seen in (390/1691, 23.0%), in 265/390 (67.4%) cases it occurred at or after 28 weeks of gestation and were included as cases. On comparing the cases with controls, the significant factors were estimated fetal weight less than 2000 gms (P

Formaldehyde is extensively and commonly used in Department of Anatomy for preservation of biological specimens as well as cadavers. Formaldehyde being a noxious chemical, may cause respiratory health problems among 1st year medical students attending dissection periodically as a part of MBBS curriculum. The following study was planned to observe the effect of formaldehyde vapours on heart rate, blood pressure, percentage oxygen saturation (SpO2) and respiratory rate of 1st year medical students who are routinely exposed to formalin vapours periodically. Randomly selected fifty medical students [Mean (SD) age of 18.94 (0.65) years] were assessed within 1week of admission to college and re-examined at intervals of 1 month and 6 months. Data was entered in Microsoft Excel and was analysed using Epi Info software version 7. There was a decrease in heart rate, systolic blood pressure, SpO2 values and respiratory rate (on comparing values after 6 months with that of baseline values) but it was not statistically significant. But it may be statistically significate after 1 year of periodical exposure and it could also be due to lower quantity of formalin exposure owing to the proper ventilation of the dissection hall as per the MCI regulations. KEY WORDS: Formaldehyde, heat rate, blood pressure, SpO2, respiratory rate.

Background: To assess serum TSH and Prolactin in women with PCOS in comparison with healthy women as controls and to find correlation between TSH & Prolactin in PCOS subjects. Materials and Methods: A comparative study including 30 women diagnosed as PCOS and 30 age and BMI matched healthy women as controls was conducted. The age group for the study was 18-35 years. Fasting blood samples were drawn to measure serum thyroid stimulating hormone(TSH) and prolactin. Results: Mean TSH and prolactin were found elevated in the PCOS cases compared to controls but they were not statistically significant. No significant correlation was found between TSH and prolactin. Conclusion: We could not find any significant correlation between serum TSH and serum prolactin. Further, studies with larger number of PCOS subjects will be beneficial. However monitoring of Prolactin & TSH in PCOS should be done. Keywords: T3, T4, TSH, Depression.

Over recent years, advancements in nanomedicine have allowed new approaches to diagnose and treat tumors. Nano drug delivery systems exploit the enhanced permeability and retention (EPR) effect and enter the tumor tissue's interstitial space. However, tumor barriers play a crucial role, and cause inefficient EPR or the homing effect. Mounting evidence supports the hypothesis that the components of the tumor microenvironment, such as the extracellular matrix, and cellular and physiological components collectively or cooperatively hinder entry and distribution of drugs, and therefore, limit the theragnostic applications of cancer nanomedicine. This abnormal tumor microenvironment plays a pivotal role in cancer nanomedicine and was recently recognized as a promising target for improving nano-drug delivery and their therapeutic outcomes. Strategies like passive or active targeting, stimuli-triggered nanocarriers, and the modulation of immune components have shown promising results in achieving anticancer efficacy. The present review focuses on the tumor microenvironment and nanoparticle-based strategies (polymeric, inorganic and organic nanoparticles) for intruding the tumor barrier and improving therapeutic effects.

Background: Throughout the present medical age, laparoscopic surgery is the most effective diagnostic and therapeutic methods. But it is associated with potentially harmful neuroendocrine response. Subjects and Methods: In our study we used dexmedetomidine infusion in group D and normal saline at a rate of 0.4mcg / kg / hr as placebo in group N beginning from 10 minutes before induction before pneumoperitoneum release. Patients in both groups were alike in age, gender, BMI, grade of ASA and anaesthesia. Results: After 10 min infusion of dexmedetomidine and normal saline in group D and group N respectively, fall in HR, DBP and Mean arterial pressure was significantly increased in group D compared to group N. Difference found in both the groups was statistically significant. Group N showed significant increase in HR, SBP, DBP and MAP during laryngoscopy, intubation and at 2 min , 5 min and 10 min after creation of pneumoperitoneum. Difference found was statistically significant in both groups. Thus attenuation in HR, SBP, DBP and MAP was seen in group D as compared to group N during laryngoscopy, tracheal intubation and pneumoperitoneum which were statistically significant. Group N showed statically significant increase in HR, DBP and MAP during extubation compared to group D. Difference found in both the groups was statistically significant. Thus attenuation in HR, DBP and MAP was seen in group D as compared to group N during extubation which was statistically significant. Postoperative sedation score was more in group D compared to group N which was statistically significant. Post-extubation, rescue analgesia was required early in group N compared to group D. Adverse effect in form of bradycardia was seen in 2 patients in group D which did not require atropine administration. Conclusion: Dexmedetomidine infusion at a rate of 0.4 mcg / kg / hr apparently started 10 minutes before the induction of anesthesia before release of pneumoperitoneum without any bolus dose. Useful adjuvant anesthesia to diminish the response of haemodynamic stress to intubation, Pneumoperitoneum, and extubation in laparoscopic surgical patients.

In recent days, total hip arthroplasty (THP) become a very victorious process which relieve the pain and enhances its functioning. The main motive of the paper is to design and assess a synergic deep learning (SDL) for learning and predicting various metrics like duration of stay (DOS), discharge disposition (DD) and inpatient expenses for THA. The next motive is to develop a patient specific payment (PSP) model reporting the complexity level of the patient. By the use of 15 preoperative parameters from 78,335 THA patients for osteoarthritis from National Inpatient Sample and OME databases, the prediction of DOS, DS and inpatient expenses takes place. A set of two evaluation parameters namely accuracy and receiver operating characteristic curve is used for experimentation. In addition, a predictive uncertainty is employed. All patient refined comorbidity cohort for establishing the PSP model. The presented SDL model exhibited better learning with high trustworthiness, receptiveness, and validity in its prediction outcome. The presented model can be applied for the implementation of PSP model for tiered payments depending upon the case complexities.

Chronic use of opioids can lead to tolerance, dependence, abuse, and addiction. This in turn can result in dose escalation and opioid overdose. Opioid overdose can be fatal due to severe opioid-induced respiratory depression (OIRD). Naloxone, a nonspecific antagonist of the mu-opioid receptors, is used for the reversal of OIRD. However, one of the major challenges of using naloxone is its short elimination half-life, which is significantly shorter compared to many opioid analgesics. Thus, renarcotization and rapid return to full respiratory depression might occur, specifically in individuals who have taken large doses or long-acting opioid formulations. Additionally, because of the very low oral bioavailability of naloxone, an oral formulation is not currently available. This study examines in mice a novel oral formulation of naloxone based on polymer nanoparticles (NP-naloxone). A single dose of 1 or 5 mg/kg NP-naloxone was highly effective at inhibiting the activating effects of repeated administration of 10 mg/kg morphine for at least up to 24 h. Onset of action was approximately 5 min. Reversal of morphine-induced locomotion was already detected within 1 min and a full effect of returning to baseline activity levels was observed within 5 min. Importantly, at 1 mg/kg, NP-naloxone precipitated very minimal withdrawal behaviors. At the 5 mg/kg dose, NP-naloxone precipitated approximately 40% of the jumping withdrawal behaviors of injectable naloxone. Thus, this study demonstrates that orally administered naloxone based on polymer nanoparticles has high potential to be developed to circumvent OIRD and withdrawal symptoms.

Background Herbal plants are potent in curing various ailments of ancient times as they have comparatively lesser side effects. The demands for natural drugs, mostly from plant sources, are increasing over the past few decades. Because of their potent antioxidant activity, Acacia species are used to treat a variety of diseases. One of the species Acacia ferruginea, an endangered medicinal plant, is widely used in the traditional medicine system, and it is considered that standardization would be beneficial. The present study investigates the physicochemical parameters, preliminary phytochemical screening, trace metals by SEM–EDS, and fluorescence properties of various extracts (non-polar to polar) of leaf and bark parts. Standard spectrophotometric methods (UV–Vis, FT-IR, fluorescence spectroscopy) are employed to analyze the functional groups, and the DPPH and total antioxidant methods are used to assess antioxidant potential. Results The ethyl acetate extract of leaves and ethanol extract of the bark are found to be the highest in yield, 16.32% and 2.54%. Results reveal that the total ash percentage and moisture content are of bark and the water-soluble ash of leaves is higher (10.3 ± 0.85, 7.6 ± 0.34, 3.22 ± 0.24%). The bark polar extract contained more macro-elements such as Na, K, Mg, Ca, S, and Cl. Phytochemical analysis reveals the polar extracts of leaves and bark show saponins, flavonoids, steroids, phenolic compounds, and non-polar extracts show mild positive. The total alkaloids, phenolics, and terpenoids (1.58 ± 0.08%; 0.56 ± 0.11; 0.75 ± 0.15) are found to be higher in A. ferruginea leaves. The FT-IR result shows the presence of alkanes, alkenes, aromatic compounds, aldehydes, phenolics and does not contain any toxic substances since there is no peak observed in the region between 2220 and 2260 cm−1. The in vitro antioxidant activity of the species demonstrated that both the leaf and bark parts have prominent antioxidant properties. Conclusions The results obtained from the preliminary standardization of A. ferruginea are very helpful in the determination of the quality and purity of the crude drug. The refurbished findings of A. ferruginea are promising, and further research is important to identify the bioactive compounds, thereby developing nutritional supplements and medications through therapeutic compound isolation. Graphical Abstract

The giant cell granuloma is an identical reactive lesion which is mostly progressive in nature. The clinical behavior of these lesions varies from indolent to aggressive variant. The central form of giant cell granuloma involves the craniofacial bone, followed by long bones of hands and feet. These lesions are usually asymptomatic lesions and are discovered incidentally during routine radiographic examination. Radiograph features reveal multilocular jaw lesions, generally anterior to the first molar regions. Histologically, the lesion shows proliferating spindle-shaped stromal cells in a fibrovascular connective tissue stroma, which characteristically contains multiple multinucleated giant cells. Hemorrhage and hemosiderin pigmentations are often seen in tumor. Central giant cell granuloma is often confused with giant cell tumor of bone histologically. Here, we report a young male who was found to have large central giant cell granuloma in the anterior part of the mandible. The surgical treatment approach of central giant cell granuloma is discussed in this article.

A major challenge in drug delivery is to enhance the transport of drugs across biological barriers, such as the small intestine, the blood–brain barrier, and the blood–retinal/ocular barrier, and t...

Background The epidermal mucus of fish contains various bioactive compounds, which play a crucial role in the animal defense mechanisms. However, the mucus from giant mudskipper is not well characterized for its biochemical and pharmacological effects. This study for the first time analyzed the mucus extracts of this species for antimicrobial (against human pathogen) and hemolytic activities. Fourier-transform infrared spectrum analysis (FT-IR) and SDS-PAGE of mucus extracts were also carried out. Results The protein content in Periophthalmodon schlosseri (Gobiidae: Oxudercine) mucus extracts was 0.66 ± 0.04 mg/ml. The mucus extracts of P. schlosseri showed antibacterial activity against all eight human pathogenic bacteria and four fungal strains tested in this study. The hemolytic activities against chicken and human blood cells were observed with maximum activity for dichloromethane extracts. The FT-IR spectrum of mucus extract of P. schlosseri showed the presence of functional groups, evident protein bands of various molecular weights ranging from 14 kDa to 97 kDa. Conclusion The obtained results suggested that the mucus of this species has proteinaceous compounds responsible for antimicrobial and hemolytic activities.

Endometrial cancer (EMC) is one of the complicated gynecological cancers, affecting more than three million women worldwide. Anticancer strategies such as chemotherapy, radiation, and surgery are found to be ineffective and are associated with patient incompliances. The aim of the present study is to repurpose non-oncological drug, i.e., Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, in the treatment of endometrial cancer. The study groups consist of 50 female Swiss albino mice, out of which 40 had endometrial cancer induced with N-ethyl-N-nitrosourea (ENU) and estradiol hexadrobenzoate (EHB). The other groups received saline, EHB, paclitaxel, and different test doses of pioglitazones. Different preliminary parameters such as weekly body weight, mean survival time, percentage increase in life span, and uterine tissue weight were analyzed along with histopathological analysis. We observed a significant change in weekly body weight, improvement in percentage life span, and partial restoration of uterine tissue weight to normal compared to a standard drug, paclitaxel. In the present preliminary evaluation, we have identified that pioglitazone exhibited a significant dose-dependent anticancer activity against ENU- and EHB-induced endometrial cancer, compared to the standard paclitaxel.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication., Highlights • This consensus paper provides key recommendations on the management of epithelioid hemangioendothelioma (EHE). • Recommendations followed a consensus meeting between experts and a representative of the EHE advocacy group and SPAEN. • Authorship includes a multidisciplinary group of experts from different institutions from Europe, North America and Asia.

Drug repurposing is also termed as drug repositioning or therapeutic switching. This method is applied to identify the novel therapeutic agents from the existing FDA approved clinically used drug molecules. It is considered as an efficient approach to develop drug candidates with new pharmacological activities or therapeutic properties. As the drug discovery is a costly, time-consuming, laborious, and highly risk process, the novel approach of drug repositioning is employed to increases the success rate of drug development. This strategy is more advantageous over traditional drug discovery process in terms of reducing duration of drug development, low-cost, highly efficient and minimum risk of failure. In addition to this, World health organization declared Coronavirus disease (COVID-19) as pandemic globally on February 11, 2020. Currently, there is an urgent need to develop suitable therapeutic agents for the prevention of the outbreak of COVID-19. So, various investigations were carried out to design novel drug molecules by utilizing different approaches of drug repurposing to identify drug substances for treatment of COVID-19, which can act as significant inhibitors against viral proteins. It has been reported that COVID-19 can infect human respiratory system by entering into the alveoli of lung via respiratory tract. So, the infection occurs due to specific interaction or binding of spike protein with angiotensin converting enzyme-2 (ACE-2) receptor. Hence, drug repurposing strategy is utilized to identify suitable drugs by virtual screening of drug libraries. This approach helps to determine the binding interaction of drug candidates with target protein of coronavirus by using computational tools such as molecular similarity and homology modeling etc. For predicting the drug-receptor interactions and binding affinity, molecular docking study and binding free energy calculations are also performed. The methodologies involved in drug repurposing can be categorized into three groups such as drug-oriented, target-oriented and disease or therapy-oriented depending on the information available related to quality and quantity of the physico-chemical, biological, pharmacological, toxicological and pharmacokinetic property of drug molecules. This review focuses on drug repurposing strategy applied for existing drugs including Remdesivir, Favipiravir, Ribavirin, Baraticinib, Tocilizumab, Chloroquine, Hydroxychloroquine, Prulifloxacin, Carfilzomib, Bictegravir, Nelfinavir, Tegobuvir and Glucocorticoids etc to determine their effectiveness toward the treatment of COVID-19.

Orally delivered double-headed nanoparticle curcumin has potential to treat intraocular inflammation., Novel approaches circumventing blood-ocular barriers in systemic drug delivery are lacking. We hypothesize receptor-mediated delivery of curcumin (CUR) across intestinal and ocular barriers leads to decreased inflammation in a model of lens-induced uveitis. CUR was encapsulated in double-headed polyester nanoparticles using gambogic acid (GA)–coupled polylactide-co-glycolide (PLGA). Orally administered PLGA-GA2-CUR led to notable aqueous humor CUR levels and was dosed (10 mg/kg twice daily) to adult male beagles (n = 8 eyes) with induced ocular inflammation. Eyes were evaluated using a semiquantitative preclinical ocular toxicology scoring (SPOTS) and compared to commercial anti-inflammatory treatment (oral carprofen 2.2 mg/kg twice daily) (n = 8) and untreated controls (n = 8). PLGA-GA2-CUR offered improved protection compared with untreated controls and similar protection compared with carprofen, with reduced aqueous flare, miosis, and chemosis in the acute phase (

The non-invasive heart rate of the fetus is of great relevance for clinical measures to detect health fluctuations of the fetus during pregnancy. The electrocardiogram (ECG) is often used to detect cardiovascular malformations and heart disorders in the patient. An ECG is not able to measure fetal pulse rate because it shows a low signal-to-noise ratio due to the movement of the fetus in relation to midriff of the mother. The proposed work is based on effective removal of noise components, detection of normal sinus rhythms and arrhythmias of the fetus. Fluctuations in heart rate indicate the disease arrhythmia, i.e. either low or high heart rate. The main goal of this research is to provide an independent component analysis method for removing the maternal ECG(m-ECG) from the selected ECG signal to obtain the fetal ECG(f-ECG). Joint Approximation Diagonal Eigen Vector (JADE) is an algorithm used to discriminate the different components within the signal. The separated f-ECG is used for peak detection and feature extraction. The arrhythmia is detected from the extracted features. The proposed technique has been evaluated with 17 samples and an accuracy of 94.11% is achieved.

Orally delivered lymphatic system–specific nanoparticle cyclosporine is an effective way to treat lupus., Cyclosporine A (CsA) is a powerful immunosuppressant, but it is an ineffective stand-alone treatment for systemic lupus erythematosus (SLE) due to poor target tissue distribution and renal toxicity. We hypothesized that CD71 (transferrin receptor 1)–directed delivery of CsA to the lymphatic system would improve SLE outcomes in a murine model. We synthesized biodegradable, ligand-conjugated nanoparticles [P2Ns–gambogic acid (GA)] targeting CD71. GA conjugation substantially increased nanoparticle association with CD3+ or CD20+ lymphocytes and with intestinal lymphoid tissues. In orally dosed MRL-lpr mice, P2Ns-GA–encapsulated CsA increased lymphatic drug delivery 4- to 18-fold over the ligand-free formulation and a commercial CsA capsule, respectively. Improved lymphatic bioavailability of CsA was paralleled by normalization of anti–double-stranded DNA immunoglobulin G titer, plasma cytokines, and glomerulonephritis. Thus, this study demonstrates the translational potential of nanoparticles that enhance the targeting of lymphatic tissues, transforming CsA into a potent single therapeutic for SLE.

Chemotherapy utilizing cytotoxic drugs, such as paclitaxel (PTX), is still a commonly used therapeutic approach to treat both localized and metastasized cancers. Unlike traditional regimens in which PTX is administered at the maximum tolerated dose, alternative regimens like metronomic dosing are beneficial by administering PTX more frequently and in much lower doses exploiting antiangiogenic and immunomodulatory effects. However, PTX-induced peripheral neuropathy and lack of patient compliant dosage forms of PTX are major roadblocks for the successful implementation of metronomic regimens. Because of the success of polyester nanoparticle drug delivery, we explored the potential of nanoparticle-encapsulated paclitaxel (nPTX) in alleviating peripheral neuropathy using a rat model. Rats were injected intraperitoneally with 2 mg/kg body weight of PTX or nPTX on four alternate days, and neuropathic pain and neuronal damage were characterized using behavioral assessments, histology, and immunohistochemistry. The reduction in tactile and nociceptive pressure thresholds was significantly less in nPTX-treated rats than in PTX-treated rats over a 16-day study period. Histological analysis showed that the degree of dorsal root ganglion (DRG) degeneration and reduction in motor neurons in the spinal cord was significantly lower in the nPTX group than the PTX group. Further, immunofluorescence data reveals that nPTX-treated rats had an increased density of a neuronal marker, β-tubulin-III, reduced TUNEL positive cells, and increased high molecular weight neurofilament in the spinal cord, DRG, and sciatic nerves compared with PTX-treated rats. Therefore, this work has important implications in improving risk-benefit profile of PTX, paving the way for metronomic regimens.

We present for the first time a robust ex vivo rat eye model for investigating the transport of precision-polyester nanosystems (P2Ns) across the blood-retinal barrier, intended for systemic administration. The P2Ns-GA actively transport exploiting transferrin receptors present in the inner retinal barrier and colocalize in ganglion cells. Such delivery approaches have the potential to deliver drugs to posterior segments of the eye, which is still a major challenge in treating posterior ocular disorders.

Background: Angiosarcoma of the breast (BAS) is a rare but lethal neoplasia, either arising de novo or secondary to radiation therapy, with incidence of the latter disease increasing. We queried a database of more than 70,000 advanced cancer patients assayed with comprehensive genomic profiling (CGP) in the course of clinical care to uncover the frequency, type and associated genomic alterations (GA) in BAS and to highlight possible routes to benefit from targeted therapy. Methods: CGP was performed for 34 BAS cases using a hybrid-capture, adaptor ligation based next generation sequencing assay of up to 315 genes to a mean coverage depth of >500X. The results were analyzed for base substitutions, short insertions and deletions, selected rearrangements, and copy number changes. RNA sequencing for 265 genes was also performed for 24 cases. Limited clinical histories from submitted pathology reports were reviewed under IRB permission. Results: Clinical specimens from 34 BAS patients, all females, were assayed. The cases harbored 87 total GA for a mean of 2.59 per case, 25% of which were copy number amplifications. The most commonly altered genes were MYC (41%, 14/34), PIK3CA (26%, 9/34), and KDR (26%, 9/34). All MYC alterations were amplifications with a mean copy number of 39, and alterations in other MYC family members (MYCN and MYCL1) were not observed. KDR was recurrently altered as T771R (7/9) and T771K (1/9) and amplified in one case (1/9). MYC and KDR alterations were mutually exclusive (p Two cases harboring gene fusions were identified including CIC-MEGF8 and NTRK1-PEAR1. Two rearrangements of potential functional significance including CIC-DEDD2 and HT-ALK (exon1 HT - exon5-29 ALK including kinase domain) were also observed. The case harboring HT-ALK also had MYC amplification and known prior radiation therapy. Two other MYC amplified cases also harbored targetable kinase alterations, including FLT4 amplification (described as targetable in Ravi et al JNCCN 2016) and FGFR3 S249C, a known activating mutation. Conclusions: MYC amplification defines over 40% (14/34) of advanced BAS cases. Of MYC amplified cases, 28% (4/14) harbored targetable alterations of tyrosine kinases including a potential novel ALK fusion. FLT4 amplification only co-occurred with MYC amplification, but this result was not statistically significant in this small series. KDR and MYC alteration were mutually exclusive, and 45% of non-MYC altered cases (9/20) harbored KDR alterations, which were predominantly mutations of T771. Further clinico-pathologic correlation, particularly history of radiation therapy, will be explored in this series, as well defining BAS that harbor neither MYC nor KDR alterations. Citation Format: Ravi V, Madison R, Schrock AB, Cote G, Millis S, Alvarez R, Choy E, Katz D, Chung J, Gay L, Miller VA, Ross JS, Ali SM, Schnitt S. Comprehensive genomic profiling of 34 cases of breast angiosarcoma [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-12-01.

Here we present a "thinking-outside-the-box", tunable nanoplatform for oral delivery of proteins using insulin as a model protein. These nanosystems offer noncompetitive active transport exploiting transferrin receptors present in the intestine and permit tailored release in vivo. Such delivery approaches have the potential to individualize insulin therapy to a regimen that is compatible with the patient's glucose profile.

To explore the factors associated with hypertensive disorders of pregnancy (HDP) in women experiencing stillbirth (SB).It was an observational, analytical case-control study, done as part of the World Health Organization South-East Asian Region Office SB project. The epidemiological profile, history, clinical features, and investigations of stillborn cases having HDP were noted, an equal number of age and parity matched subjects with HDP having livebirth were taken as controls.Out of 46,816 deliveries, 1239 (26.2/1000) were stillborn. The maternal causes contributed 374/1239 (30.2%) stillbirths according to the CODAC classification, HDP was the most common maternal cause (304/1239, 24.9%). Subjects with HDP were included as cases. On comparing the cases with controls it was found that significantly more number of cases had inadequate antenatal visits (In women with HDP, adequate antenatal care would lead to the prevention of complications such as anemia, abruption, and FGR, and thus prevent SB. The high BW/PW ratio is a potential marker of risk of SB.

Herpes Simplex Virus Type 2 (HSV-2) is one of the most prevalent sexually transmitted viruses and is a known risk factor for HIV acquisition in the Female Genital Tract (FGT). Previously, we found that curcumin can block HSV-2 infection and abrogate the production of inflammatory cytokines and chemokines by genital epithelial cells in vitro. In this study, we investigated whether curcumin, encapsulated in nanoparticles and delivered by various in vivo routes, could minimize inflammation and prevent or reduce HSV-2 infection in the FGT. Female mice were pre-treated with curcumin nanoparticles through oral, intraperitoneal and intravaginal routes, and then exposed intravaginally to the tissue inflammation stimulant CpG-oligodeoxynucleotide (ODN). Local intravaginal delivery of curcumin nanoparticles, but not intraperitoneal or oral delivery, reduced CpG-mediated inflammatory histopathology and decreased production of pro-inflammatory cytokines Interleukin (IL)-6, Tumor Necrosis Factor Alpha (TNF-&alpha, ) and Monocyte Chemoattractant Protein-1 (MCP-1) in the FGT. However, curcumin nanoparticles did not demonstrate anti-viral activity nor reduce tissue pathology when administered prior to intravaginal HSV-2 infection. In an alternative approach, intravaginal pre-treatment with crude curcumin or solid dispersion formulations of curcumin demonstrated increased survival and delayed pathology following HSV-2 infection. Our results suggest that curcumin nanoparticle delivery in the vaginal tract could reduce local tissue inflammation. The anti-inflammatory properties of curcumin delivered to the vaginal tract could potentially reduce the severity of HSV-2 infection and decrease the risk of HIV acquisition in the FGT of women.

Background Synovitis is implicated in the severity and progression of pain and structural pathology of osteoarthritis (OA). Increases in inflammatory or immune cell subpopulations including macrophages and lymphocytes have been reported in OA synovium, but how the particular subpopulations influence symptomatic or structural OA disease progression is unclear. Two therapies, hyaluronan (HA) and mesenchymal stem cells (MSCs), have demonstrated efficacy in some clinical settings: HA acting as device to improve joint function and provide pain relief, while MSCs may have immunomodulatory and disease-modifying effects. We used these agents to investigate whether changes in pain sensitization or structural damage were linked to modulation of the synovial inflammatory response in post-traumatic OA. Methods Skeletally mature C57BL6 male mice underwent medial-meniscal destabilisation (DMM) surgery followed by intra-articular injection of saline, a hyaluronan hexadecylamide derivative (Hymovis), bone marrow-derived stem cells (MSCs), or MSC + Hymovis. We quantified the progression of OA-related cartilage, subchondral bone and synovial histopathology, and associated pain sensitization (tactile allodynia). Synovial lymphocytes, monocyte/macrophages and their subpopulations were quantified by fluorescent-activated cell sorting (FACS), and the expression of key inflammatory mediators and catabolic enzyme genes quantified by real-time polymerase chain reaction (PCR). Results MSC but not Hymovis significantly reduced late-stage (12-week post-DMM) cartilage proteoglycan loss and structural damage. Allodynia was initially reduced by both treatments but significantly better at 8 and 12 weeks by Hymovis. Chondroprotection by MSCs was not associated with specific changes in synovial inflammatory cell populations but rather regulation of post-injury synovial Adamts4, Adamts5, Mmp3, and Mmp9 expression. Reduced acute post-injury allodynia with all treatments coincided with decreased synovial macrophage and T cell numbers, while longer-term effect on pain sensitization with Hymovis was associated with increased M2c macrophages. Conclusions This therapeutic study in mice demonstrated a poor correlation between cartilage, bone or synovium (histo)pathology, and pain sensitization. Changes in the specific synovial inflammatory cell subpopulations may be associated with chronic OA pain sensitization, and a novel target for symptomatic treatment.

The popular anticancer drug cisplatin causes many adverse side effects, the most serious of which is acute kidney injury (AKI). Emerging evidence from laboratory and clinical studies suggests that the AKI pathogenesis involves oxidative stress pathways; therefore, regulating such pathways may offer protection. Urolithin A (UA), a gut metabolite of the dietary tannin ellagic acid, possesses antioxidant properties and has shown promise in mouse models of AKI. However, therapeutic potential of UA is constrained by poor bioavailability. We aimed to improve oral bioavailability of UA by formulating it into biodegradable nanoparticles that use a surface-conjugated ligand targeting the gut-expressed transferrin receptor. Nanoparticle encapsulation of UA led to a sevenfold enhancement in oral bioavailability compared with native UA. Treatment with nanoparticle UA also significantly attenuated the histopathological hallmarks of cisplatin-induced AKI and reduced mortality by 63% in the mouse model. Expression analyses indicated that nanoparticle UA therapy coincided with oxidative stress mitigation and downregulation of nuclear factor erythroid 2-related factor 2- and P53-inducible genes. Additionally, normalization of miRNA (miR-192-5p and miR-140-5p) implicated in AKI, poly(ADP-ribose) polymerase 1 levels, antiapoptotic signaling, intracellular NAD+, and mitochondrial oxidative phosphorylation were observed in the treatment group. Our findings suggest that nanoparticles greatly increase the oral bioavailability of UA, leading to improved survival rates in AKI mice, in part by reducing renal oxidative and apoptotic stress.

A systematic investigation has been carried out to achieve and characterize single-domain cobalt ferrite nanoparticles of high saturation magnetization with least particle size. The samples were obtained by adding different contents of chelating agent, viz., polyvinylpyrrolidone, to cobalt ferrite in the ratios 1:1–3:1 and with careful heat treatment using sol–gel technique. The ferrite samples were annealed in the temperature range 400–1100 °C in the intervals of 100 °C for achieving crystallization to the nanoscale. The prepared samples were characterized by XRD and TEM techniques to identify single-phase spinel structure and the particle size. The magnetic properties, viz., saturation magnetization (Ms), coercivity (Hc) and single-domain nature of the samples, were measured using vibrating sample magnetometer. The obtained results have been discussed in detail as a function of the content of chelating agent. The analysis indicated the developed samples are of single-domain cobalt ferrite nanoparticles with a critical size of 12.8 nm, possess high saturation magnetization (71.9 emu/g) and high coercivity (2744 Oe).

Background: Outcomes of metabolic acidosis remain unsure and needs to be explored deeply. This article presents a rational approach to diagnosis and management of metabolic acidosis. The data focusing specifically on severe metabolic acidosis (pH

Gd 3+ doped barium borophosphate glasses mixed with varying concentration of Al 2 O 3 are synthesized. Photoluminescence, thermoluminescence and other spectroscopic studies viz., IR and EPR spectral studies, have been carried out. IR spectral studies of these glasses indicated that there is a gradual increase in the degree of depolymerization of the glass network with increase in the concentration of Al 2 O 3 upto 3.0 mol%. The EPR spectral studies revealed the lowest concentration of Gd 3+ ion clusters in the glass mixed with 3.0 mol% of Al 2 O 3 . The photoluminescence emission spectra exhibited strong ultraviolet blue emission at 311 under excitation at 273 nm due to 6 P 7/2 → 8 S 7/2 transition of Gd 3+ ions. The intensity of this band is found to be enhanced four times when the glass mixed with 3.0 mol% of Al 2 O 3 with respect to that of alumina free glass. The enrichment of this emission is attributed to the declustering of Gd 3+ ions by Al 3+ ions. Thermoluminescence (TL) characteristics of these glasses have also been investigated after irradiating them with different doses of γ-rays (in the range 0–8.0 kGy). The TL emission exhibited a dosimetric peak at about 200 °C. The TL output under this glow peak is observed to increase with increase of γ-ray dose. For any fixed γ-ray dose, the TL output is increased with increasing Al 2 O 3 content up to 3.0 mol% and beyond this concentration quenching of TL is observed. The mechanisms responsible for TL emission and the variation in TL output with the concentration of Al 2 O 3 are quantitatively discussed in terms of electron and hole centers developed due to interaction of γ-rays with the glass network. The dose response of these glass samples exhibited linear behavior in the dose range 0–8.0 kGy.

To evaluate the predictive value of first trimester biomarkers and ultrasound in determining adverse fetal outcomes in a low risk Asian population.All low risk, singleton pregnancies between 11 and 14 weeks gestation underwent ultrasound with uterine artery Doppler along with PAPP-A and free β-hCG estimation, and were followed till delivery to observe the outcome. The adverse fetal outcomes detected were structural anomaly, aneuploidy, intrauterine growth restriction, preterm birth and stillbirth (SB).Out of 3500 women screened, 417 cases had adverse fetal outcome in the absence of maternal complication, 2151 had normal outcome. Major structural anomaly was detected in first trimester in 17/28 (60.7%) cases. The most important markers for adverse fetal outcome were increased uterine artery pulsatility index (UPI) (p = 0.028, OR 1.5, 95% CI: 1.05-2.38, AUC 0.56) for IUGR, nuchal translucency (p = 0.001, OR 1.7, 95% CI: 1.11-2.77, AUC 0.60) for major anomaly and low PAPP-A (p = 0.017, OR -0.075, 95% CI: 0.87-0.98, AUC 0.621) for SB.UPI, NT and PAPP-A in the first trimester are significant markers of adverse fetal outcome, although the sensitivity and specificity are not high they have a high negative predictive value.

Background: Anaemia is one of the commonest clinical problems in our country. It affects various organs including the heart. Clinical manifestations of anaemia referable to cardiovascular system may closely simulate symptoms and signs of organic heart disease. It includes some electrocardiogram (ECG) changes also. ECG changes in anaemia show correlation to haemoglobin (Hb) concentration and the changes are reversible after correction of anaemia. In this study, the main objective was to study electrocardiographic changes in patients with severe anaemia and ECG reversibility after treatment of anaemia.Methods: 50 patients admitted in medicine wards of Shri B. M. Patil Medical College, Hospital and Research Center, Vijayapura for severe anaemia (Hb concentration less than or equal to 7 gm %) were studied for ECG changes. All patients were reassessed for reversibility of changes after treatment.Results: Out of 50 patients with severe anaemia, 20 patients were having Hb % of 3 to 5 gm %. Of which 16 patients were having ECG changes (10 were females and 6 were males). All ECG changes were reverted to normal after correction of anaemia, except one patient (showed pre-treatment T wave inversion and post-treatment flat T waves).Conclusions: ECG abnormalities in patients with severe anaemia are more common in females. ECG abnormalities in patients with severe anaemia (Hb 5 gm %) can get reverted to normal after correction of anaemia.

Background & objectives: Increase in the isolation of drug resistant phenotypes of Mycobacterium tuberculosis necessitates accuracy in the testing methodology. Critical concentration defining resistance for ethionamide (ETO), needs re-evaluation in accordance with the current scenario. Thus, re-evaluation of conventional minimum inhibitory concentration (MIC) and proportion sensitivity testing (PST) methods for ETO was done to identify the ideal breakpoint concentration defining resistance. Methods: Isolates of M. tuberculosis (n=235) from new and treated patients were subjected to conventional MIC and PST methods for ETO following standard operating procedures. Results: With breakpoint concentration set at 114 and 156 µg/ml, an increase in specificity was observed whereas sensitivity was high with 80 µg/ml as breakpoint concentration. Errors due to false resistant and susceptible isolates were least at 80 µg/ml concentration. Interpretation & conclusions: Performance parameters at 80 µg/ml breakpoint concentration indicated significant association between PST and MIC methods.

Computed Tomography (CT) system with Linear Detector Array (LDA) generates a thin crosssectional image (slice) of an object where as with Flat Panel Detector (FPD) directly generates 3D volume from 2D X-ray projections. Further, CT images are free from overlying and underlying areas of the object and are highly sensitive to small density differences (

Cumulative kidney toxicity associated with cisplatin is severe and there is no clear consensus on the therapeutic management of the same. The pathogenesis involves activation of inflammatory and apoptotic pathways; therefore, regulating these pathways offers protection. Given the anti-inflammatory and antioxidant effects of urolithin A, a gut microbial metabolite of ellagic acid, our aim was to explore the potential use of urolithin A in the prevention of cisplatin-induced nephrotoxicity in an experimental rat model. For this purpose, animals received a single intraperitoneal dose of cisplatin (5 mg/kg body weight). Six hours prior to cisplatin administration, rats were orally treated with either ellagic acid or urolithin A (50 mg/kg body weight), followed by a daily dose of these compounds during the next 5 days. At the end, plasma and kidneys were collected for analysis. Cisplatin-induced kidney damage was revealed by a significant rise in the plasma creatinine levels accompanied by significant morphologic changes in tubules, T cell Ig and mucin domain-containing protein-1, ionized calcium-binding adapter molecule 1, as well as a marked increase in the number of apoptotic cells localized in tubules. Cisplatin also reduced nitric oxide synthase 3 and nuclear factor kappa-light-chain-enhancer of activated B cells resulting in regulation of various inflammatory cytokines. Urolithin A effectively attenuated cisplatin-induced kidney damage and showed significantly greater effect than its precursor ellagic acid on preserving the normal kidney architecture by downregulating the proinflammatory cytokines. In summary, urolithin A mitigates cisplatin-induced nephrotoxicity in rats by modulation of the inflammatory cascade and inhibition of the proapoptotic pathway.

To explore the role of microRNAs in osteoarthritis (OA), we conducted microRNA expression profiling on micro-dissected tibial cartilage and subchondral bone in a mouse model of OA produced by medial meniscus destabilization (DMM). DMM mice had characteristic cartilage degeneration, subchondral bone sclerosis and osteophyte formation. While subchondral bone showed no microRNA dysregulation, 139 microRNAs were differentially expressed in DMM cartilage at 1 and/or 6 weeks after OA initiation. To prioritize OA-candidates, dysregulated microRNAs with human orthologues were filtered using paired microRNA:mRNA expression analysis to identify those with corresponding changes in mRNA target transcripts in the DMM cartilage. An important cohort overlapped with microRNAs identified in human end-stage OA. Comparisons with microRNAs dysregulation in DMM mouse cartilage where aggrecan cleavage was genetically-ablated demonstrated that all were independent of aggrecan breakdown, earmarking these as important to the critical stages of OA initiation. Our comprehensive analyses identified high-priority microRNA candidates that have potential as human OA-biomarkers and therapeutic targets.SUMMARYKung et al. conducted global analysis of microRNA dysregulation in joint tissues of a well-established mouse osteoarthritis model. Stringent filtering against human microRNA orthologues, integrated mRNA target analysis and comparison with published studies on human end-stage osteoarthritis identified microRNA candidates of potential clinical relevance.