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Sidhhamantra Nighantu is one such unique lexicon which has a chapter named as Tridoshaghna Varga which enlists the drugs which pacify one, two or all the three Doshas i.e., Vata, Pitta and Kapha. Drugs pacifying all the three Doshas are unique in their Rasa Panchaka in terms of specific combination of Rasa, Guna, Virya and Vipaka. The Tridoshaghna concept and this chapter both stand unique and hence the present chapter was selected for its exploration through multiple correspondence analysis. Materials and Methods: All the relevant information about the drugs like their Botanical identity, family, Rasa, Guna, Virya and Vipaka of Tridoshaghna varga was collected with the help of previous and successive texts of Sidhhamantra Nighantu. The collected information was subjected to multiple correspondence analysis. Result: The chapter Tridoshaghna Varga enlists several substances of herbal origin, metallic/mineral origin and animal origin. MCA revealed that the combination of Sheeta Virya and Madhura Vipaka with the combination of Tikta and/or Katu Rasa can be the best properties for Tridoshaghna action in majority diseased conditions. Conclusion: The study data should be considered while clinical practice by clinicians and further studies should be carried out on the nutritional foods included in the chapter for better understanding of Aahara (nutritional herbs) as well as Aushadha (medicinal herbs) for Tridoshaghna action.

Pressing challenges in the treatment of invasive fungal infections (IFIs) include emerging and rare pathogens, resistant/refractory infections, and antifungal armamentarium limited by toxicity, drug-drug interactions, and lack of oral formulations. Development of new antifungal drugs is hampered by the limitations of the available diagnostics, clinical trial endpoints, prolonged trial duration, difficulties in patient recruitment, including subpopulations (eg, pediatrics), and heterogeneity of the IFIs. On 4 August 2020, the US Food and Drug Administration convened a workshop that included IFI experts from academia, industry, and other government agencies to discuss the IFI landscape, unmet need, and potential strategies to facilitate the development of antifungal drugs for treatment and prophylaxis. This article summarizes the key topics presented and discussed during the workshop, such as incentives and research support for drug developers, nonclinical development, clinical trial design challenges, lessons learned from industry, and potential collaborations to facilitate antifungal drug development.

Introduction: Different types of Snehapaka have been mentioned in Sarangdhar Samhita such as Mrudu Paka, Madhyama Paka, Khara Paka, Dagdha Paka, Ama Paka, and Gandha Paka. Further, different uses of sneha according to its paka had been mentioned in which Madhyama Paka and Khara Paka are stated to be used for internal (Pana) and external (Abhyang), respectively. Aim: The present study was carried out to discriminate type of paka in Katupila taila on the basis of classical and modern parameters, namely, Paka pariksha, organoleptic-physicochemical parameters, and chromatography. Results: Average 934.8 g (93.48% yield) and 845.33 g (84.53% yield) of Katupila Taila madhyama paka (KPTM) and Khara paka, respectively, was obtained from batch size of, 1 L of Tila Taila with 212 g of Kalka dravya and 4 L of Kwatha of Katupila stem. Temperature reached up to 92°C and 97°C, respectively, for completion of Madhyama Paka and Khara Paka. Heating was carried out for 3 consecutive days for both Paka. Discussion: Average duration between initiation of Madhyama Paka and end of Khara Paka was 1 h and 44 min. Here, temperature and duration of heating play a major role in the type of Paka. It showed difference in the values of physicochemical parameters of both Paka. KPTM and Khara paka were having specific gravity (0.9179 ± 0.0050 and 0.9294 ± 0.0067), refractive index (1.449 ± 0.009 and 1.474 ± 0.015), acid value (2.908 ± 0.0538 and 1.809 ± 0.0472), iodine value (108.075 ± 2.9793 and 72.875 ± 3.2548), saponification value (169.66 ± 8.9132 and 226.64 ± 6.1567), and BTTT value (19.6 ± 0.3, 28.5 ± 0.5), respectively.

Supplementary Table 1 from Mapping Genes that Contribute to Daunorubicin-Induced Cytotoxicity

Supplementary Figure Legends 1-4 from Mapping Genes that Contribute to Daunorubicin-Induced Cytotoxicity

Supplementary Figure 1 from Mapping Genes that Contribute to Daunorubicin-Induced Cytotoxicity

Supplementary Figure 2 from Mapping Genes that Contribute to Daunorubicin-Induced Cytotoxicity

Daunorubicin is an anthracycline antibiotic agent used in the treatment of hematopoietic malignancies. Toxicities associated with this agent include myelosuppression and cardiotoxicity; however, the genes or genetic determinants that contribute to these toxicities are unknown. We present an unbiased genome-wide approach that incorporates heritability, whole-genome linkage analysis, and linkage-directed association to uncover genetic variants contributing to the sensitivity to daunorubicin-induced cytotoxicity. Cell growth inhibition in 324 Centre d' Etude du Polymorphisme Humain lymphoblastoid cell lines (24 pedigrees) was evaluated following treatment with daunorubicin for 72 h. Heritability analysis showed a significant genetic component contributing to the cytotoxic phenotypes (h2 = 0.18–0.63 at 0.0125, 0.025, 0.05, 0.1, 0.2, and 1.0 μmol/L daunorubicin and at the IC50, the dose required to inhibit 50% cell growth). Whole-genome linkage scans at all drug concentrations and IC50 uncovered 11 regions with moderate peak LOD scores (>1.5), including 4q28.2 to 4q32.3 with a maximum LOD score of 3.18. The quantitative transmission disequilibrium tests were done using 31,312 high-frequency single-nucleotide polymorphisms (SNP) located in the 1 LOD confidence interval of these 11 regions. Thirty genes were identified as significantly associated with daunorubicin-induced cytotoxicity (P ≤ 2.0 × 10−4, false discovery rate ≤ 0.1). Pathway and functional gene ontology analysis showed that these genes were overrepresented in the phosphatidylinositol signaling system, axon guidance pathway, and GPI-anchored proteins family. Our findings suggest that a proportion of susceptibility to daunorubicin-induced cytotoxicity may be controlled by genetic determinants and that analysis using linkage-directed association studies with dense SNP markers can be used to identify the genetic variants contributing to cytotoxicity. [Cancer Res 2007;67(11):5425–33]

Supplementary Figure 3 from Mapping Genes that Contribute to Daunorubicin-Induced Cytotoxicity

Supplementary Figure 4 from Mapping Genes that Contribute to Daunorubicin-Induced Cytotoxicity

Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT −/− mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor β1 ( TGF β 1 ) and collagen ( COL1A1 ) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.

LaCoO3 based compounds with 5% Cr and Fe ion as impurity at Co site were prepared by standard solid state reaction method. These sample were characterized for structural confirmation via XRD technique and for microstructural and compositional studies through SEM/EDAX characterization. In addition, these materials were investigated for dielectric properties. The X-ray diffraction studies infer that the sample are pure and single phased. These samples have acquired trigonal structure. The XRD result was verified via Rietveld refinement of pristine LaCoO3 compound. FTIR technique has been used to confirm the required oxide formation. The SEM images of these samples reveals that average grain size acquired after sintering is very high however the images present the porosity in the samples. EDAX data study confirmed that all the integral elements of the samples were retained and witnesses the absence of any foreign impurity. Dielectric study of these samples witness the samples exhibit high dielectric constant (capacitance) however the loss values are comparatively high subject to the modifications in microstructure.

Anal fistula is a common disease of the anal region that can be treated using a cutting seton. The objective of this study was to investigate healing and recurrence outcomes of anal fistulas treated via cutting setons performed by a specialist colorectal surgery group at a single academic institution. This retrospective chart review study included 143 patients who underwent a cutting seton procedure at a single academic institution to treat their anal fistula between January 2013 and December 2018. The main outcomes measured in this study were healing rates, recurrences rates, incontinence rates, and infectious complication rates of anal fistulas being treated with a cutting seton. In total, 127 (88.8%) patients’ fistulas healed after treatment with a cutting seton. Fifteen (10.5%) patients had a fistula recurrence after treatment. Fourteen (9.8%) patients experienced an infectious complication after the cutting seton procedure while 8 (5.6%) patients developed some form of incontinence during the fistula healing period. Average healing time for fistulas after cutting seton treatment was 1.9 months (7–8 weeks). This study indicates that the cutting seton procedure is an effective and safe method for treating anal fistulas. Cutting setons lead to low rates of complications (like infections and incontinence) and good long-term outcomes when it comes to maintaining anal sphincter function after presence of a complicated and/or high anal fistula. This study suggests that the cutting seton remains an alternative to other procedures, which maybe more invasive and compromising.

Background The THUNDERBEAT is a multi-functional energy device which delivers both ultrasonic and bipolar energy, but there are no randomized trials which can provide more rigorous evaluation of the clinical performance of THUNDERBEAT compared to other energy-based devices in colorectal surgery. The aim of this study was to compare the clinical performance of THUNDERBEAT energy device to Maryland LigaSure in patients undergoing left laparoscopic colectomy. Methods Prospective randomized trial with two groups: Group 1 THUNDERBEAT and Group 2 LigaSure in a single university hospital. 60 Subjects, male and female, of age 18 years and above undergoing left colectomy for cancer or diverticulitis were included. The primary outcome was dissection time to specimen removal (DTSR) measured in minutes from the start of colon mobilization to specimen removal from the abdominal cavity. Versatility (composite of five variables) was measured by a score system from 1 to 5 (1 being worst and 5 the best), and adjusted/weighted by coefficient of importance with distribution of the importance as follow: hemostasis 0.275, sealing 0.275, cutting 0.2, dissection 0.15, and tissue manipulation 0.1. Other variables were: dryness of surgical field, intraoperative and postoperative complications, and mortality. Follow-up time was 30 days. Results 60 Patients completed surgery, 31 in Group 1 and 29 in Group 2. There was no difference in the DTSR between the groups, 91 min vs. 77 min (p = 0.214). THUNDERBEAT showed significantly higher score in dissecting and tissue manipulation in segment 3 (omental dissection), and in overall versatility score (p = 0.007) as well as versatility score in Segment 2 (retroperitoneal dissection p = 0.040) and Segment 3 (p = 0.040). No other differences were noted between the groups. Conclusions Both energy devices can be employed effectively and safely in dividing soft tissue and sealing mesenteric blood vessels during laparoscopic left colon surgery, with THUNDERBEAT demonstrating some advantages over LigaSure during omental dissection and tissue manipulation. ClinicalTrial.gov # NCT02628093.

The well-being and improvement of an individual’s health, is directly linked to food. Acknowledging the well-studied interrelation between health and nutritional food determines the need to cultivate, maintain and advance a novel branch of food science, known as functional foods. Research interest has extensively increased in the last three decades for the exploitation of seaweeds as functional foods or as nutraceuticals, which provide health and dietary benefits beyond their nutritional content. Additionally, seaweeds have been studied for their metabolites which exhibit biological activity, to manufacture therapeutically superior products. This chapter focuses on providing information related to omics-based seaweed metabolite identification and their applications in human health as a food ingredient

Cytokeratin and desmin expression have been associated with Sertoli cell maturity and the development of testicular germ cell cancer (TGCC). Thus, the present study aimed to characterize the expression of these intermediate filaments in normal testis development and TGCC. Cytokeratin and desmin were determined by immunohistochemistry and immunofluorescence in human fetal, and adult testis and tissue from patients with pre-invasive germ cell neoplasia in-situ (GCNIS) or invasive TGCC. Desmin was expressed in Sertoli cells of the human fetal testis, and the proportion of desmin expressing Sertoli cells was significantly reduced in the second trimester, compared with the first trimester (31.14% vs. 6.74%, p = 0.0016). Additionally, Desmin was expressed in the majority of Sertoli cells in the adult testis and TGCC samples. Cytokeratin was detected in Sertoli cells of human fetal testis but was not expressed in Sertoli cells of human adult testis. In patients with TGCC, cytokeratin was not expressed in Sertoli cells in tubules with active spermatogenesis but was detected in Sertoli cells in tubules containing GCNIS cells in patients with both pre-invasive and invasive TGCC. In conclusion, desmin was not associated with Sertoli cell maturation or progression to TGCC. However, cytokeratin appeared to be an indicator of impaired Sertoli cell maturation.

Sensory evaluation is a quantitative science in which numerical data are collected to establish lawful and specific relationships between product characteristics and human perception. Among the sensory methods available, Triangle test method was adopted. The purpose of this study was to differentiate Madhyama Paka and Khara Paka Katupila Taila with regard to smell and color. Forty pre-trained assessors were asked to identify the blindly coded sample analogous. The results were calculated using Python software and analyzed using receiver operating characteristics curve, area under curve (AUC), and d-prime (d’) with the help of sensR package in R-studio ver. 1.0.143. For both attributes, both the samples were correctly identified with a significance level of P < 0.001 and AUC of 1 and 0.999 for each set, respectively. Thus, it can be concluded that sensory analysis method efficiently discriminated the Madhyama Paka and Khara Paka Katupila Taila samples and thus can serve as a cost-effective routine quality control tool.

Background: Desmodium velutinum (Fabaceae) is one of the wild edible plants used traditionally to treat diarrhoea, haematuria, infertility and also externally used to treat scorpion bites. Though various parts of the plant have been used for therapeutic purpose, panchanga of the plant has not been studied for its Pharmacognostical and phytochemical characteristics in detail, following scientific parameters. Hence in the present study Desmodium velutinum whole plant has been studied for its pharmacognostical and phytochemical characters and compared with commonly used species Desmodium gangeticum. Methods: Whole plant of Desmodim velutinum was collected from Paikmal, Odisha and Desmodium gangeticum was collected from Junagarh, Gujarat in the month of November 2019 following good collection practices and shade dried. Pharmacognostical study and analytical study were performed following standard pharmacopoeial procedures. Results: Whole plant (Panchanga) of former is sweetish and latter is bitter. Powder microscopy of Desmodium gangeticum showed presence of rhomboidal crystals and lignified annular and spiral vessels. Desmodium velutinum showed presence of prismatic crystals and lignified pitted vessels. Physico-chemical analysis showed higher loss on drying in Desmodium gangeticum, and higher water soluble extractive values of Desmodium velutinum. Phytochemical estimation showed the presence of Proteins, tannins, and carbohydrates in both samples. HPTLC study showed similar Rf value 0.82 and 0.94 at 254 and 0.03 and 0.41 at 366nm. Conclusion: Basing upon the analytical and microscopic similarities Desmodium velutinum may be considered as substitute of Desmodium gangeticum

The accumulation of neurofibrillary tangles (NFTs), which is composed of abnormally hyperphosphorylated tau aggregates, is the classic neuropathology associated with cognitive dysfunction in tauopathies such as Alzheimer’s disease (AD). However, there is an emerging theory suggesting that dysregulation in cerebral iron may contribute to NFT formation. Iron is speculated to bind to tau and induce conformational changes of the protein, potentially leading to subsequent aggregation and cognitive decline. Deferiprone (DFP) is a clinically available iron chelator, which has demonstrated potential therapeutic advantages of chelating iron in neurodegenerative disorders, and is currently in clinical trials for AD. However, its effect on tau pathology remains unclear. Here, we report the effects of short-term DFP treatment (4 weeks, 100 mg/kg/daily, via oral gavage) in a mixed-gender cohort of the rTg((tauP301L))4510 mouse model of tauopathy. Our results revealed that DFP improved Y-maze and open field performance, accompanied by a 28% decrease in brain iron levels, measured by inductively coupled plasma mass spectrometry (ICP-MS) and reduced AT8-labeled p-tau within the hippocampus in transgenic tau mice. This data supports the notion that iron may play a neurotoxic role in tauopathies and may be a potential therapeutic target for this class of disorders that can be modulated by the clinically available metal chelator DFP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-020-00972-w.

The effects of pure ZnO and copper (Cu) dopant on the properties of ZnO thin films grown by chemical bath deposition (CBD) and dip coating method on glass substrates are investigated. For more comp...

To evaluate patterns of use and outcomes of arteriovenous fistulas and prosthetic grafts within racial categories in a large population based cohort of hemodialysis (HD) patients in the United States.A retrospective analysis of white, black, and Hispanic patients in the prospectively maintained United States Renal Database System who had an autogenous fistula or prosthetic graft placed for HD access between January 2007 and December 2014 was performed. Analysis of variance, χThis study of 359,942 patients, composed of 285,781 autogenous fistulas (79.4%) and 74,161 prosthetic grafts (20.6%) placed in 213,877 white (59.4%), 115,727 black (32.2%), and 30,338 Hispanic (8.4%) patients. There was a 11% increase in the risk-adjusted odds of HD catheter use as bridge to autogenous fistula placement in blacks (adjusted odds ratio, 1.11; 95% confidence interval [CI], 1.08-1.14; P .001) and a 9% increase in Hispanics (adjusted odds ratio, 1.09; 95% CI, 1.05-1.14; P .001) compared with whites. Fistula maturation for HD access for whites vs blacks vs Hispanics was 77.0% vs 76.3% vs 77.8% (P = .35). After adjusting for covariates, fistula maturation was higher for blacks (adjusted hazard ratio, 1.09; 95% CI, 1.06-1.13; P .001) and Hispanics (adjusted hazard ratio, 1.13; 95% CI, 1.06-1.20; P .001) compared with whites. There was no significant difference in prosthetic graft maturation for blacks and Hispanics compared with whites. Primary, primary-assisted, and secondary patency were highest for Hispanic and least for black autogenous fistula recipients. Primary, primary-assisted, and secondary patency was also highest for Hispanic patients who received prosthetic grafts. Prosthetic grafts were associated with a decrease in patency and patient survival compared with fistulas in all racial categories. Mortality was lower for blacks and Hispanics relative to white patients. Initiation of HD with a catheter and conversion to autogenous fistula was associated with decrease in patency and patient survival compared with initiation with a fistula in all racial groups.Autogenous fistulas are associated with better patency and patient survival compared with prosthetic grafts for all races studied. The use of HD catheter before fistula placement is more prevalent in Hispanic and black patients and is associated with worse patency and patient survival irrespective of race. Fistula and graft patency is highest for Hispanic patients. Patient survival is higher for Hispanic and black patients relative to whites. These associations suggest potential benefit with initiation of HD via autogenous fistula and minimizing temporizing catheter use, irrespective of race.

Background Testicular germ cell cancer (TGCC) develops from pre-malignant germ neoplasia in situ (GCNIS) cells. GCNIS originates from fetal gonocytes (POU5F1+/MAGE-A4−), which fail to differentiate to pre-spermatogonia (POU5F1−/MAGE-A4+) and undergo malignant transformation. Gankyrin is an oncogene which has been shown to prevent POU5F1 degradation and specifically interact with MAGE-A4 in hepatocellular carcinoma (HCC) cells. We aimed to investigate the role of Gankyrin in progression from gonocyte to pre-invasive GCNIS and subsequent invasive TGCC. Methods We determined Gankyrin expression in human fetal testicular tissue (gestational weeks 9–20; n = 38), human adult testicular tissue with active spermatogenesis (n = 9), human testicular tissue with germ cell maturation delay (n = 4), testicular tissue from patients with pre-invasive GCNIS (n = 6), and invasive TGCC including seminoma (n = 6) and teratoma (n = 7). Functional analysis was performed in-vitro by siRNA knock-down of Gankyrin in the NTera2 cells (derived from embryonal carcinoma). Results Germ cell expression of Gankyrin was restricted to a sub-population of prespermatogonia in human fetal testes. Nuclear Gankyrin was also expressed in GCNIS cells of childhood and adult pre-invasive TGCC patients, and in GCNIS from seminoma and non-seminoma patients. Cytoplasmic expression was observed in seminoma tumour cells and NTera2 cells. Gankyrin knock-down in NTera2 cells resulted in an increase in apoptosis mediated via the TP53 pathway, whilst POU5F1 expression was unaffected. Furthermore, Gankyrin knock-down in NTera2 cells increased cisplatin sensitivity with an increase in cell death (13%, p Conclusions These results suggest that manipulation of Gankyrin expression may reduce the cisplatin dose required for the treatment of TGCC, with benefits in reducing dose-dependent side effects of chemotherapy. Further studies are required in order to assess the effects of modulating Gankyrin on GCNIS/TGCC using in vivo models.

Background: An elevation in iron levels, together with an accumulation of α-synuclein within the oligodendrocytes, are features of the rare atypical parkinsonian disorder, Multiple System Atrophy (MSA). We have previously tested the novel compound ATH434 (formally called PBT434) in preclinical models of Parkinson’s disease and shown that it is brain-penetrant, reduces iron accumulation and iron-mediated redox activity, provides neuroprotection, inhibits alpha synuclein aggregation and lowers the tissue levels of alpha synuclein. The compound was also well-tolerated in a first-in-human oral dosing study in healthy and older volunteers with a favorable, dose-dependent pharmacokinetic profile. Objective: To evaluate the efficacy of ATH434 in a mouse MSA model. Methods: The PLP-α-syn transgenic mouse overexpresses α-synuclein, demonstrates oligodendroglial pathology, and manifests motor and non-motor aspects of MSA. Animals were provided ATH434 (3, 10, or 30 mg/kg/day spiked into their food) or control food for 4 months starting at 12 months of age and were culled at 16 months. Western blot was used to assess oligomeric and urea soluble α-synuclein levels in brain homogenates, whilst stereology was used to quantitate the number of nigral neurons and glial cell inclusions (GCIs) present in the substantia nigra pars compacta. Results: ATH434 reduced oligomeric and urea soluble α-synuclein aggregation, reduced the number of GCIs, and preserved SNpc neurons. In vitro experiments suggest that ATH434 prevents the formation of toxic oligomeric “species of synuclein”. Conclusion: ATH434 is a promising small molecule drug candidate that has potential to move forward to trial for treating MSA.