A metabolomics approach for the evaluation of Ficus benghalensis female in vivo reproductive effects relative to its metabolite fingerprint as determined via UPLC-MS and GC-MS.

ETHNOPHARMACOLOGICAL RELEVANCE: Ficus benghalensis, commonly known as Banyan Fig, is the national tree of India and its aerial roots are used traditionally to treat female reproductive disorders. However, despite this traditional use, no pharmacological evidence could be traced supporting this use. Additionally, no comprehensive metabolite profiling was reported for F. benghalensis aerial roots. AIM OF THE STUDY: This study attempts to justify biochemically the traditional use of F. benghalensis aerial roots in treatment of female reproductive disorders and in relation to its secondary metabolite profile. MATERIALS AND METHODS: Total ethanol extract (TEE) and subfractions [petroleum ether (PEF), chloroform (CHF), ethyl acetate (EAF) and n-butanol (BUF] were prepared from air-dried powdered aerial roots of F. benghalensis. Detailed in-vivo investigation of the hormonal activity and action mechanism of the total ethanol extract and subfractions was carried out through evaluation of estrogenic and gonadotropic activities. The estrogenic activity was evaluated on ovariectomized immature female rats through estimating uterine weight, vaginal cornification and serum estradiol level along with histological examination of uteri. The gonadotropic activity was measured by assay of follicle stimulating hormone (FSH) and luteinizing hormone (LH) like activities. Total follicular and corpora lutea counts in immature female rats were used to determine FSH and LH like activities, respectively in addition to histological picture of the genitalia. Comprehensive non-targeted metabolite profiling was carried out for the TEE and subfractions using UPLC-HRMS in negative and positive ionization modes. UPLC-MS fingerprint was subjected to principal component analysis (PCA) and partial least squares analyses to correlate the bioactivities to specific chemical constituents in F. benghalensis different subfractions. GC-MS was further used for non-polar silylated fractions. RESULTS: Results revealed that only the non-polar PEF and CHF displayed moderate estrogenic and FSH-like activities but with no LH-like activity. Metabolites profiling via (UPLC-HRMS) and multivariate PCA analysis enabled identification and comparison of various chemical classes in F. benghalensis extract and fractions. The active non-polar fractions revealed nearly similar metabolites profile being composed of isoflavonoids, triterpenes, sterols, fatty acids and cyclic peptides. In contrast, polar fractions were more abundant in apocarotenoids, fatty acyl amides, hydroxybenzoates and hydroxycinnamates in addition to two lignans. PLS analysis revealed strong correlation between hydroxylated fatty acids and pyranoisoflavones with estrogenic and FSH-like activities. GC-MS analysis was further employed for non-polar fractions profiling revealing for their enrichment in fatty acids/esters, terpenes, organic acids and phenolics. CONCLUSION: This is the first study to rationalize the use of F. benghalensis aerial root traditionally in treatment of gynecological disorders, revealing that the petroleum ether and chloroform non-polar subfractions of F. benghalensis showed estrogenic and FSH-like activity with absence of LH-like activity. This biological activity could possibly be attributed to its metabolites profile of isoflavonoids, fatty acids, triterpenes, sterols and cyclic peptides identified via UPLC-MS and GC-MS techniques. Consequently, F. benghalensis aerial roots should be used with caution in traditional treatment of female infertility or other reproductive disorders.

Therapeutic activity of green synthesized selenium nanoparticles from turmeric against cisplatin-induced oxido-inflammatory stress and cell death in mice kidney.

Cisplatin (CDDP) is a commonly prescribed chemotherapeutic agent; however, its associated nephrotoxicity limits its clinical efficacy and sometimes requires discontinuation of its use. The existing study was designed to explore the reno-therapeutic efficacy of turmeric (Tur) alone or conjugated with selenium nanoparticles (Tur-SeNPs) against CDDP-mediated renal impairment in mice and the mechanisms underlying this effect. Mice were orally treated with Tur extract (200 mg/kg) or Tur-SeNPs (0.5 mg/kg) for 7 days after administration of a single dose of CDDP (5 mg/kg, i.p.). N-acetyl cysteine NAC (100 mg/kg) was used as a standard antioxidant compound. The results revealed that Tur-SeNPs counteracted CDDP-mediated serious renal effects in treated mice. Compared with the controls, Tur or Tur-SeNPs therapy remarkably decreased the kidney index along with the serum levels of urea, creatinine, Kim-1, and NGAL of the CDDP-injected mice. Furthermore, Tur-SeNPs ameliorated the renal oxidant status of CDDP group demonstrated by decreased MDA and NO levels along with elevated levels of SOD, CAT, GPx, GR, GSH, and gene expression levels of HO-1. Noteworthy, lessening of renal inflammation was exerted by Tur-SeNPs via lessening of IL-6 and TNF-α besides down-regulation of NF-κB gene expression in mouse kidneys. Tur-SeNPs treatment also restored the renal histological features attained by CDDP challenge and hindered renal apoptosis through decreasing the Bax levels and increasing Bcl-2 levels. Altogether, these outcomes suggest that the administration of Tur conjugated with SeNPs is effective neoadjuvant chemotherapy to guard against the renal adverse effects that are associated with CDDP therapy.

Assessment of Ferula hermonis Boiss fertility effects in immature female rats supported by quantification of ferutinin via HPLC and molecular docking.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferula hermonis is a small shrub renowned for its aphrodisiac abilities. Middle East herbalists have utilized Ferula hermonis seed and root as an aphrodisiac folk medicine to treat women's frigidity and male erectile and sexual dysfunction. AIM OF THE STUDY: Assessment of follicle-stimulating hormone-like (FSH), luteinizing hormone-like (LH), and estrogenic activities of the methanolic extract (ME) of the roots of Ferula hermonis on female reproductive function. MATERIALS AND METHODS: The methanolic extract was prepared from the root of F. hermonis and studied at dose level 6 mg/kg in immature female rats for FSH-like, LH-like, and estrogenic activities. These activities were determined by analyzing gross anatomical features, relative organ weight, and serum level of FSH, LH, progesterone and estrogen hormones, and histopathological characteristics. Quantification of the main phytoestrogenic component ferutinin carried out by HPLC. In addition, molecular docking for the binding affinity of ferutinin inside active sites of both estrogen receptor alpha (ERα) and FSH receptor (FSHR) was performed to predict the potential role of ferutinin in regulating the female reproductive process. RESULTS: Ferula hermonis (ME) showed potent FSH-like, LH-like activities and moderate estrogenic effect at the dose of 6 mg/kg. The content of ferutinin in F. hermonis was estimated to be 92 ± 1.33 mg/g of the methanolic extract. Molecular docking of ferutinin with ERα and FSHR displayed strong interaction with target proteins. CONCLUSIONS: Based on results, it can be concluded that Ferula hermonis can be considered as a suitable female fertility improving agent.

In vitro acaricidal activity of green synthesized nickel oxide nanoparticles against the camel tick, Hyalomma dromedarii (Ixodidae), and its toxicity on Swiss albino mice.

The green synthesized nanoparticles have been determined as a novel pesticide against arthropod pests. This study was designed to evaluate the in vitro acaricidal activity of green synthesized nickel oxide nanoparticles (NiO NPs) using aqueous extract of Melia azedarach ripened fruits against different developmental stages of the camel tick Hyalomma dromedarii in addition to their toxic effect on laboratory animals. The synthesized NiO NPs were characterized by UV-visible (UV-Vis) spectroscopy, Fourier transforms infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDS). The UV-Vis spectra of the NiO NPs showed an absorption peak at 307 nm. FTIR analysis showed the possible functional groups used for capping and stabilization of NiO NPs with strong bands at 3416.2 and 1626.6 cm-1. The SEM images of the NiO NPs exhibited a size ranging from 21 to 35 nm. The immersion test was used for the in vitro application of the synthesized NiO NPs on the various tick stages (egg, nymph, larva, and adult). Mortality percentages and LC50 values of each tick stage were calculated. The oviposition and hatchability of the engorged females were monitored for the survived tick after treatment. The LC50 values for NiO NPs on embryonated eggs, larvae, and engorged nymphs were 5.00, 7.15, and 1.90 mg/mL, respectively. The egg productive index (EPI), egg number, and hatchability (%) were lower in females treated with the NiO NPs than in control ticks. The toxicity of the NiO NPs on laboratory animals was also investigated using Swiss albino mice by oral dose of 500 mg/kg/day administration for five consecutive days. The hematological, biochemical, and histopathological changes were evaluated. The hematological analysis showed significant increase in the level of white blood cells (WBC) and hemoglobin (Hb). Biochemical analysis showed non-significant decrease in alkaline phosphatase (ALP) and alanine amino transferase (ALT). We concluded that NiO NPs have a significant acaricidal activity as demonstrated on eggs, larvae, engorged nymphs, and fully fed females of H. dromedarii. From a toxicological point of view further in vivo investigations are needed to determine the mechanism of toxic effect of NiO NPs.

Identifying Outlier Hospitals in Gastric Cancer Lymph Node Yield Using the National Cancer Database.

BACKGROUND: Lymph node (LN) yield is a key quality indicator that is associated with improved staging in surgically resected gastric cancer. The National Comprehensive Cancer Network recommends a yield of ≥15 LNs for proper staging, yet most facilities in the United States fail to achieve this number. The present study aimed to identify factors that could affect LN yield on a facility level and identify outlier hospitals. METHODS: This was a retrospective review of adults (aged ≥18 y) with gastric cancer (Tumor-Node-Metastasis Stages I-III) who underwent gastrectomy. Data were analyzed from the National Cancer Database (2004-2016). Multivariate analysis identified patient and tumor characteristics, whereas an observed-to-expected ratio of identified outlier hospitals. Facility factors were compared between high and low outliers. RESULTS: A total of 26,590 patients were included in this study. Of these patients, only 50.3% had an LN yield ≥15. The multivariate model of patient and tumor characteristics demonstrated a concordance index was 0.684. A total of 1245 facilities were included. There were 198 low outlier LN yield hospitals and 135 high outlier LN yield hospitals (observed-to-expected ratio of 0.42 ± 0.24 versus 1.38 ± 0.19, P < 0.0001). There was a difference in facility type between low and high outliers (P < 0.0001). High LN yield hospitals had a larger surgical volume than low LN yield hospitals (median 8.4 [4.9, 13.5] versus 3.5 [2.4, 5.2]; P < 0.0001). CONCLUSIONS: Nearly half of the population exhibited low compliance to National Comprehensive Cancer Network recommendations. Facility-level disparities exist as high yearly surgical volume and academic facility status distinguished high-performing outlier hospitals.

Expansion of Surgical Graduate Medical Education Training Programs: A Return on Investment Analysis.

BACKGROUND: The productivity of surgical departments is limited by the staffing of attending surgeons as well as surgical residents. Despite ongoing surgeon shortages, many health care organizations have been reluctant to expand training programs because of concerns about cost. We sought to determine the return on investment for the expansion of surgical training programs within our health system. METHODS: This study was completed as a retrospective review comparing two independent surgical departments at separate hospitals within a single integrated health system, including complete fiscal information from 2012 to 2019. Hospital A is a 594-bed hospital with large growth in its graduate surgical training programs over the study's period, whereas Hospital B is a 320-bed hospital where there was no expansion in surgical education initiatives. Case volumes, the number of full-time employees (FTE), and revenue data were obtained from our health systems business office. The number of surgical trainees, including general surgery residents and vascular surgery fellows, was provided by our office of Graduate Medical Education. The average yearly net revenue per surgeon was calculated for each training program and hospital location. RESULTS: Our results indicate a positive association between the number of surgical trainees and departmental net revenue, as well as the annual revenue generated per physician FTE. Each additional ancillary provider per physician FTE resulted in a positive impact of $112,552-$264,003 (R2 of 0.69 to 0.051). CONCLUSIONS: Regardless of hospital location or surgical specialty, our results demonstrate a positive association between the average net revenue generated per surgeon and the number of surgical trainees supporting the department. These findings are novel and provide evidence of a positive return on investment when surgical training programs are expanded.

The Value of Surgical Graduate Medical Education (GME) Programs Within An Integrated Health Care System.

OBJECTIVE: Surgical graduate medical education (GME) programs add both significant cost and complexity to the mission of teaching hospitals. While expenses tied directly to surgical training programs are well tracked, overall cost-benefit accounting has not been performed. In this study, we attempt to better define the costs and benefits of maintaining surgical GME programs within a large integrated health system. DESIGN: We examined the costs, in 2018 US dollars, associated with the surgical training programs within a single health system. Total health system expenses were calculated using actual and estimated direct GME expenses (salary, benefits, supplies, overhead, and teaching expenses) as well as indirect medical education (IME) expenses. IME expenses for each training program were estimated by using both Medicare percentages and the Medicare Payment Advisor Commission study. The projected cost to replace surgical trainees with advanced practitioners or hospitalists was obtained through interviews with program directors and administrators and was validated by our system's business office. SETTING: A physician lead, integrated, rural health system consisting of 8 hospitals, a medical school and a health insurance company. PARTICIPANTS: GME surgical training programs within a single health system's department of surgery. RESULTS: Our health system's department of surgery supports 8 surgical GME programs (2 general surgery residencies along with residencies in otolaryngology, ophthalmology, oral-maxillofacial surgery, urology, pediatric dentistry, and vascular surgery), encompassing 89 trainees. Trainees work an average of 64.4 hours per week. Total health system cost per resident ranged from $249,657 to $516,783 based on specialty as well as method of calculating IME expenses. After averaging program costs and excluding IME and overhead expenses, we estimated the average annual cost per trainee to be $84,171. We projected that replacing our surgical trainees would require hiring 145 additional advanced practitioners at a cost of $166,500 each per year, or 97 hospitalists at a cost of $346,500 each per year. Excluding overhead, teaching and IME expenses, these replacements would cost the health system an estimated additional $16,651,281 or $26,119,281 per year, respectively. CONCLUSIONS: Surgical education is an integral part of our health system and ending surgical GME programs would require large expansion of human resources and significant additional fiscal capital.

A biochemometric approach for the assessment of Phyllanthus emblica female fertility effects as determined via UPLC-ESI-qTOF-MS and GC-MS.

Phyllanthus emblica L. fruits have long been used in Ayurvedic medicine for their many health benefits. In this study, we present P. emblica fruit crude extract and fractions' effects on the female reproductive system by assessing its estrogenic and gonadotropic activities. Results revealed that the non-polar petroleum ether and chloroform fractions exhibited the strongest estrogenic and follicle-stimulating hormone-like [FSH] activity, while the n-butanol fraction exhibited a significant luteinizing hormone-like [LH] activity. The ethyl acetate fraction showed neither estrogenic nor gonadotropic activities and in contrast it may impair female fertility suggesting that different metabolite classes contribute to the plant's overall effect on female fertility. To pinpoint active agents in these fractions, UPLC/ESI-qTOF-MS- was employed for secondary metabolite profiling with 100 metabolites annotated including ellagitannins, gallic acid derivatives, terpeneoids, sterols, phthalates and fatty acids. Correlation between extracts/fraction bioassays and UPLC/MS data was attempted using orthogonal partial least squares-discriminant analysis (OPLS-DA) revealing that guaiane-type sesquiterpenes, phthalates, diterpenes and oxygenated fatty acids showed positive correlation with estrogenic and gonadotropic activities. In contrast, mucic acid gallates, gallic acid derivatives and ellagitannins correlated negatively. GC/MS analysis of the non-polar bioactive fractions viz. petroleum ether and chloroform was also attempted which revealed its enrichment in fatty acids/fatty acyl esters (34%) and phenolic compounds (19.6%). This study provides the first report on the estrogenic and gonadotropic activities of P. emblica fruits in relation to their metabolite fingerprint.

Protective Effect of Ginkgo biloba and Magnetized Water on Nephropathy in Induced Type 2 Diabetes in Rat.

We aimed in our current study to explore the protective effect of Ginkgo biloba (GB) and magnetized water (MW) against nephrotoxicity associating induced type 2 diabetes mellitus in rat. Here, we induced diabetes by feeding our lab rats on a high fat-containing diet (4 weeks) and after that injecting them with streptozotocin (STZ). We randomly divided forty rats into four different groups: nontreated control (Ctrl), nontreated diabetic (Diabetic), Diabetic+GB (4-week treatment), and Diabetic+MW (4-week treatment). After the experiment was finished, serum and kidney tissue samples were gathered. Blood levels of glucose, triglycerides, cholesterol, creatinine, and urea were markedly elevated in the diabetic group than in the control group. In all animals treated with GB and MW, the levels of urea, creatinine, and glucose were significantly reduced (all P < 0.01). GB and MW attenuated glomerular and tubular injury as well as the histological score. Furthermore, they normalized the contents of glutathione reductase and SOD2. In summary, our data showed that GB and MW treatment protected type 2 diabetic rat kidneys from nephrotoxic damages by reducing the hyperlipidemia, uremia, oxidative stress, and renal dysfunction.

A study on biological control of six fresh water snails of medical and veterinary importance.

This study evaluated the molluscicidal effect of Commiphora mnolmol oil extract (Myrrh), on control of six fresh water snails (Lymnaea natalensis, Bulinus truncatus, Biomphalaria alexandrina, Physa acuta, Melania tuberculata and Cleopatra bulimoides). Also, the extract effect on the egg masses of L. natalensis, B. truncatus, B. alexandrina and Ph. acuta was evaluated. Snails and egg masses were exposed at 16-20 degrees C to various concentrations (conc.). LD50 after 24 hours expo-sure were 264/132, 283/195, 230/252, 200/224, 241/246 & 241/246 ppm for young/adult of L. natalensis, B. truncatus, B. alexandrina, Ph. acuta, M. tuberculata and C. bulimnoides respectively. LDtoo after 24 hours exposure were 400/400 for L. natalensis, B. truncatus, B. alexandrina, M. tuberculata and C. bulimoides, and 300/300 for Ph. acuta. Also, complete mortality (100%) was achieved for the egg masses of L. natalensis, B. truncatus, B. alexandrina and Ph. acuta at concentrations of 300, 200, 300 & 400 ppm respectively. Lower concentrations gave the same results after longer exposure. LD100 of C. molmol oil extract (Myrrh) had a rapid lethal effect on the six snail species and their egg masses in high conc. of 300 & 400 ppm. Commiphora molmol is a promising plant to be included with the candidate plant molluscicides. The oil extract of this plant showed a remarkable molluscicidal activity against used snail species.

Efficacy of thermotherapy to treat cutaneous leishmaniasis caused by Leishmania tropica in Kabul, Afghanistan: a randomized, controlled trial.

BACKGROUND: Pentavalent antimony is the agent recommended for treatment of cutaneous leishmaniasis (CL). Its use is problematic, because it is expensive and because of the potential for drug-associated adverse effects during a lengthy and painful treatment course. METHODS: We tested the efficacy of thermotherapy for the treatment of CL due to Leishmania tropica in a randomized, controlled trial in Kabul, Afghanistan. We enrolled 401 patients with a single CL lesion and administered thermotherapy using radio-frequency waves (1 treatment of >or=1 consecutive application at 50 degrees C for 30 s) or sodium stibogluconate (SSG), administered either intralesionally (a total of 5 injections of 2-5 mL every 5-7 days, depending on lesion size) or intramuscularly (20 mg/kg daily for 21 days). RESULTS: Cure, defined as complete reepithelialization at 100 days after treatment initiation, was observed in 75 (69.4%) of 108 patients who received thermotherapy, 70 (75.3%) of 93 patients who received intralesional SSG, and 26 (44.8%) of 58 patients who received intramuscular SSG. The OR for cure with thermotherapy was 2.80 (95% confidence interval [CI], 1.45-5.41), compared with intramuscular SSG treatment (P=.002). No statistically significant difference was observed in the odds of cure in comparison of intralesional SSG and thermotherapy treatments. The OR for cure with intralesional SSG treatment was 3.75 (95% CI, 1.86-7.54), compared with intramuscular SSG treatment (P<.001). The time to cure was significantly shorter in the thermotherapy group (median, 53 days) than in the intralesional SSG or intramuscularly SSG group (median, 75 days and >100 days, respectively; P=.003). CONCLUSIONS: Thermotherapy is an effective, comparatively well-tolerated, and rapid treatment for CL, and it should be considered as an alternative to antimony treatment.

Detection of anti-Fasciola isotypes among patients with fascioliasis before and after treatment with Mirazid.

Stool examination using modified Kato thick smear method was performed to detect Fasciola eggs and other parasites. Abdominal pain was the major presenting symptom (87.7%) followed by pallor (83.3%) and fever (16.7%). Anaemia and hepatomegaly were recorded in 77.7% of patients compared to 27.7% with splenomegaly. Abdominal ultrasonography revealed hepatomegaly and common bile duct dilatation in 77.7% of patients. Moreover, 5 cases showed diagnostic. Olympic game rings All patients had positive IgG4 levels, 55 cases were positive for specific total IgG and IgG1, whereas, only 24 cases had positive IgG2 levels (26.6%). All negative control group showed no cross reactions. On the other hand, ELISA detecting IgG4 showed the highest specificity (95%), followed by IgG2 (85%) and the least specific test was obtained with detection of IgG (70%) and IgG1 (65%). One month after treatment, 91.1% of patients (82/90) were completely cured and even after another two months follow-up. In completely cured patients none of anti-Fasciola isotypes was significantly changed. So, detection of anti-Fasciola isotypes especially IgG4 is very specific for the accurate diagnosis of human fascioliasis.

Long-term administration of vitamin A and the process of spermatogenesis.

The effect of retinoids on spermatogenesis in adult male gerbils (Gerbillus cheesemani) was studied using light and electron microscopy. Treatment with either 13-cis-retinoic acid or retinol acetate was given for 6 weeks and their effects were compared with controls. It was found that 13-cis-retinoic acid induced almost complete cessation of spermatogenesis and produced alterations in the cytoplasm of Leydig cells. No differences were seen in the testis of animals treated with retinol acetate compared with controls using light microscopy but it appeared to produce noticeable ultrastructural changes in Leydig cells. The changes observed were reversed 12 weeks after stopping treatment. Caution should be exercised regarding the use of dietary retinoids in the prevention of cancer.

Long-term administration of vitamin A and the process of spermatogenesis

The effect of retinoids on spermatogenesis in adult male gerbils [Gerbillus cheesemani] was studied using light and electron microscopy. Treatment with either 13-cis-retinoic acid or retinol acetate was given for 6 weeks and their effects were compared with controls. It was found that 13-cis-retinoic acid induced almost complete cessation of spermatogenesis and produced alterations in the cytoplasm of Leydig cells. No differences were seen in the testis of animals treated with retinol acetate compared with controls using light microscopy but it appeared to produce noticeable ultrastructural changes in Leydig cells. The changes observed were reversed 12 weeks after stopping treatment. Caution should be exercised regarding the use of dietary retinoids in the prevention of cancer