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To evaluate whether surgical start time is associated with clinical and financial outcomes of hysterectomies performed for benign indications. Retrospective cohort study. University 5-hospital healthcare system. Women who underwent benign hysterectomy between 2014 and 2019. None. We analyzed demographic, operative, and financial data to evaluate the relationships between surgical start time and perioperative outcomes including operating room time, estimated blood loss, length of stay, same-day discharge, and adverse perioperative events. Additionally, we evaluated the impact of surgical start time on total hysterectomy charges. Descriptive statistics and multivariate logistic and linear regressions were performed adjusting for confounders. Our study identified 2894 women who underwent benign hysterectomy, with 1910 hysterectomies starting prior to 12 pm (am group) and 984 hysterectomies starting after 12 pm (pm group). A pm start time was associated with higher estimated blood loss (Median 100, interquartile range 50, 200 in the am group vs Median 125, interquartile range 75, 250), increased length of stay, and decreased likelihood of same-day discharge. No significant differences were noted in the rates of adverse perioperative events between the 2 groups. Surprisingly, an afternoon start time was associated with decreased total hospital charges (median am $14 055.30 versus median pm $11 724.80). These cost differences persisted after multivariate linear regression, and when stratified by hysterectomy surgical approach, remained significant in the open and laparoscopic cohorts. Afternoon hysterectomy start time is associated with increased blood loss and length of stay with decreased rates of same-day discharge; however, there was no associated increase in perioperative adverse events or mortality. Awareness regarding surgical start time and outcomes can guide surgical scheduling and optimize same-day discharge. [ABSTRACT FROM AUTHOR]

Postoperative pain continues to be an undermanaged part of the surgical experience. Multimodal analgesia has been adopted in response to the opioid epidemic, but opioid prescribing practices remain high after minimally invasive hysterectomy. Novel adjuvant opioid-sparing analgesia to optimize acute postoperative pain control is crucial in preventing chronic pain and minimizing opioid usage. This study aimed to determine the effect of direct laparoscopic uterosacral bupivacaine administration on opioid usage and postoperative pain in patients undergoing benign minimally invasive (laparoscopic and robotic) hysterectomy. This was a single-blinded, triple-arm, randomized controlled trial at an academic medical center between March 15, 2021, and April 8, 2022. The inclusion criteria were patients aged >18 years undergoing benign laparoscopic or robotic hysterectomy. The exclusion criteria were non–English-speaking patients, patients with an allergy to bupivacaine or actively using opioid medications, patients undergoing transversus abdominis plane block, and patients undergoing supracervical hysterectomy or combination cases with other surgical services. Patients were randomized in a 1:1:1 fashion to the following uterosacral administration before colpotomy: no administration, 20 mL of normal saline, or 20 mL of 0.25% bupivacaine. All patients received incisional infiltration with 10 mL of 0.25% bupivacaine. The primary outcome was 24-hour oral morphine equivalent usage (postoperative day 0 and postoperative day 1). The secondary outcomes were total oral morphine equivalent usage in 7 days, last day of oral morphine equivalent usage, numeric pain scores from the universal pain assessment tool, and return of bowel function. Patients reported postoperative pain scores, total opioid consumption, and return of bowel function via Qualtrics surveys. Patient and surgical characteristics and primary and secondary outcomes were compared using chi-square analysis and 1-way analysis of variance. Multiple linear regression was used to identify predictors of opioid use in the first 24 hours after surgery and total opioid use in the 7 days after surgery. Of 518 hysterectomies screened, 410 (79%) were eligible, 215 (52%) agreed to participate, and 180 were ultimately included in the final analysis after accounting for dropout. Most hysterectomies (70%) were performed laparoscopically, and the remainder were performed robotically. Most hysterectomies (94%) were outpatient. Patients randomized to bupivacaine had higher rates of former and current tobacco use, and patients randomized to the no-administration group had higher rates of previous surgery. There was no difference in first 24-hour oral morphine equivalent use among the groups (P =.10). Moreover, there was no difference in numeric pain scores (although a trend toward significance in discharge pain scores in the bupivacaine group), total 7-day oral morphine equivalent use, day of last opioid use, or return of bowel function among the groups (P >.05 for all). The predictors of increased 24-hour opioid usage among all patients included only increased postanesthesia care unit oral morphine equivalent usage. The predictors of 7-day opioid usage among all patients included concurrent tobacco use and mood disorder, history of previous laparoscopy, estimated blood loss of >200 mL, and increased oral morphine equivalent usage in the postanesthesia care unit. Laparoscopic uterosacral administration of bupivacaine at the time of minimally invasive hysterectomy did not result in decreased opioid usage or change in numeric pain scores. [ABSTRACT FROM AUTHOR]

Summary Objectives In Niger, 65% of hepatocarcinoma and 75% of cirrhosis cases were due to hepatitis B virus (HBV). We studied the genotypic characteristics of HBsAg in chronically HBV-infected patients in Niamey. Methods We studied prospectively HBV genotypic patterns among hospitalized patients with HBV infection in the National Hospital of Niamey, Niger. Patients were screened for hepatitis B surface antigen (HBsAg) and HBV genotyping was performed on the HBsAg-positive patients. Results In this study, we have confirmed the predominance of the HBV genotype E (HBV-E) in Niger and have identified 2 recombinant forms including HBV-E/D and HBV-A3/E reported previously among blood donors in Niger and Ghana, respectively. Amino acid substitutions found in HBV sequences obtained here included P120T, S143L, G145A and A194T. These substitutions were characterized as being associated with modified antigenicity and, notably, with impaired serological detection of HBsAg, while the A194T variant was found to have a controversial role in reduced susceptibility to tenofovir. Conclusions We have identified two recombinant HBV forms and rare genotypic patterns in Niger that may affect hepatitis B surface antigen antigenicity, and improve current knowledge of epidemiological, clinical and virological patterns of hepatitis B in this country. [ABSTRACT FROM AUTHOR]

Ovarian torsion (OT) is the fifth most common gynecologic emergency, with one-third of cases occurring in females younger than 20 years-old. We aimed to evaluate factors associated with oophorectomy at the time of surgery for suspected OT in our pediatric population. Retrospective cohort analysis. Tertiary, academic medical center. Patients less than 18 years of age undergoing surgery for suspected ovarian torsion between 2016-2021. Evaluation of patient demographics, presentation timeline, imaging characteristics, and surgical variables associated with oophorectomy as well as perioperative outcomes. Forty-five pediatric patients underwent surgical management for suspected ovarian torsion. Five patients were excluded for planned management of antenatally diagnosed ovarian masses, of which 3 underwent oophorectomy. Of the 40 included patients, 26 (65%) were confirmed to be torsed intra-operatively. Seventeen of these patients (66%) underwent ovarian preserving surgery (OPS) while 9 (34%) underwent unilateral oophorectomy (UO). Between the UO and OPS group, there were no differences in age or race. There were no differences in ultrasound findings including absent flow, enlarged ovary, and peripheral follicles; however, the UO group had significantly larger associated ovarian masses (12.48cm vs 8.06cm, p =.015). The median time from presentation to surgical start was 480 minutes (IQR 336-800.75) in the OPS group versus 868 minutes (IQR 257.5-1353.5) in the UO group. There was no association with primary surgical service (Pediatric Surgery versus Gynecology) however time from presentation to OR was significantly faster amongst patients treated by gynecologists (p=0.018). 50% of oophorectomy patients had a minimally invasive approach compared to 78.6% in the OPS group; however, this varied significantly by surgical specialty. Given the significant sequelae associated with oophorectomy, current standards in surgical management of OT recommend conservative, ovarian-preserving techniques. Our data supports that delayed time to surgery and larger adnexal masses are associated with oophorectomy at the time of surgical management. [ABSTRACT FROM AUTHOR]

To determine the effect of laparoscopic uterosacral bupivacaine injection on post-operative pain and opioid usage in patients undergoing minimally invasive hysterectomy. Single-Blinded, Triple-Arm, Randomized Controlled Trial. Academic Hospital Center. Patients undergoing benign MIGS hysterectomy between 3/15/2021 and 4/8/2022. Exclusion criteria: conversion to laparotomy, bupivacaine allergy, concurrent procedures, supracervical hysterectomy, TAP block, preoperative opioid usage, non-English speaking. Patients were randomized in a 1:1:1 fashion to the following before colpotomy: no injection, 20cc normal saline, or 20cc of 0.25% bupivacaine. All patients received incisional infiltration with 10cc 0.25% bupivacaine. Post-operative pain scores, total opioid consumption and return of bowel function were recorded via Qualtrics surveys. Of 360 hysterectomies screened, 298 were eligible (83%), 161 (45%) agreed to participate, and 125 were ultimately included in interim analysis. The majority of hysterectomies were performed laparoscopically (91, 73%) and the remainder robotically. Most hysterectomies were discharged home POD#0 (116, 93%). Patients randomized to placebo had a lower proportion of public insurance and higher proportion of mood disorders. There was a statistical difference in the proportion of cases that required morcellation between bupivacaine and no injection (43% vs 18%, p=0.038; no difference between bupivacaine and saline, 43% and 32%, p=0.87). In regression controlling for surgical approach, administration of Toradol, and time from injection to discharge, mean pain scores on VAS at time of discharge were statistically lower in the bupivacaine group compared to placebo (-1.09, p=0.033) or no injection (-1.15, p=0.023). There was no difference between groups in PACU OME administration or post-operative OME usage, day of last use, or return of bowel function. Laparoscopic uterosacral injection of bupivacaine at the time of MIS hysterectomy results in decreased post-operative VAS pain scores, although without a difference in post-operative opioid consumption. Complete trial data to be available at the time of AAGL. [ABSTRACT FROM AUTHOR]

Ovarian torsion (OT) is a common gynecologic emergency with the potential for significant lifelong health and fertility sequelae. We aimed to evaluate surgical practice patterns in the management of patients with concern for OT, in particular factors associated with oophorectomy versus ovarian preserving surgery (OPS) and rates of minimally invasive surgery (MIS). Retrospective cohort analysis Tertiary medical center All patients presenting acutely with symptoms concerning for OT who underwent surgical management between 2016-2021. Patients with incidental torsion at the time of scheduled surgery were excluded from this analysis. Evaluation of patient demographics, background clinical context, imaging findings, and surgical variables including primary specialty, surgical approach, procedures performed, and perioperative outcomes. One hundred twenty-six-patient underwent 129 surgeries for suspected ovarian torsion. Of this, 75 cases (59.52%) were confirmed to be torsed. In total, 73 (57.9%) patients underwent OPS while 52 (41.3%) underwent oophorectomy. Patients who underwent OPS compared to oophorectomy were noted to be significantly younger (mean age 23.3 vs 29.3, p = 0.012) and have a lower BMI (mean 25.0 vs 29.7, p = 0.011). The proportion of OPS cases varied significantly by subspecialty with OPS performed in 56.9% of cases performed by Obstetrics and Gynecology generalists, 67.7% of cases by minimally invasive gynecologic surgeons (MIGS), 6% of cases by gynecologic oncologists (GO), and 79% of cases by pediatric surgeons. This data is confounded by patient age, fertility goals, and concern for malignancy. 90.28% of OPS cases were performed via a MIS approach while 69.2% of oophorectomies were MIS. MIS rates varied significantly by surgical subspecialty: 88% among generalists, 96.7% among MIGS, 60% among gynecologic oncologists, and 60% among pediatric surgeons. The surgical management of OT varies widely. Our data supports that age, BMI, and surgical subspecialty influence surgical approach and management. [ABSTRACT FROM AUTHOR]

A study was conducted to examine the performance of scheduling heuristics in a flow shop supporting multiple processors. The influence of various problem properties and the performance of heuristics was also investigated using regression analysis. Some of the problem features considered were the number of jobs, number of machine stages, and the number of parallel processors. Results indicated that heuristics significantly influenced processing times. Findings also showed that flow times were inversely proportional with the number of parallel processors.

The aim of our video is to provide fundamental knowledge regarding the use and interpretation of magnetic resonance imaging (MRI) in regard to gynecology. We will describe the mechanisms behind MRI and review clinical considerations such as indications for MRI, use of contrast, and contraindications. We will provide basic concepts in the interpretation of images and review common imaging findings the gynecologist may encounter. 6-minute educational video. N/A. Our video is targeted toward medical students, residents, fellows, and providers who practice gynecologic care. N/A. N/A. In addition to first-line diagnostic tools, MRI can serve as a helpful adjunct in the gynecologist's armamentarium. Through basic understanding of MRI and pattern recognition of common gynecologic pathologies, providers can better utilize MR images. [ABSTRACT FROM AUTHOR]

Literature from various surgical specialties has demonstrated that procedural start time is associated with operative outcomes. Herein, we sought to examine these diurnal associations in benign hysterectomy cases. Retrospective cohort analysis. Five hospital healthcare system. Women undergoing hysterectomy for benign indications from 7/1/2014 to 2/28/2019. Patients were stratified into two cohorts based on time entering the operating room: AM (before noon) and PM (after noon) groups. Demographic, clinical, and perioperative characteristics were collected. We evaluated post-operative outcomes including estimated blood loss (EBL), length of stay (LOS), and adverse perioperative events (blood transfusion, organ injury, conversion to laparotomy, cuff dehiscence, surgical site infection, readmission, reoperation, and death). Additionally, we assessed hospital costs. Statistical analysis included descriptive statistics, t-tests, and multivariate regression models. Study included 2894 patients, 1910 AM patients and 984 PM patients. EBL was significantly higher in the PM start time group (mean AM: 181 mL vs mean PM: 218 mL, p<.001) whereas same-day discharge was more prevalent in the AM start time group (24.4% vs 12.5%). Multivariate regression models were constructed to evaluate for possible confounding variables: year, age, BMI, race, comorbidities, uterine size, surgical indication, and surgeon subspecialty. These models continued to show significantly increased EBL and LOS in the PM group. There was no association with operative times or adverse perioperative events. Regarding cost, AM start time was associated with increased hospital costs (median AM: $14,055, median PM: $11,725). Multivariate regression models also demonstrated these findings. Our data suggests surgical outcomes can be associated with surgical time-of-day. While the underlying mechanism remains unclear, utilization of this information can help with surgical planning to personalize risk reduction and increase same-day discharge. Further analysis is underway to elucidate the time-of-day cost discrepancies. [ABSTRACT FROM AUTHOR]

Globally, hormone-responsive cancers afflict millions of people contributing to cancer-related morbidity and mortality. While hormone-responsive cancers overburden patients, their close families, and even health budgets at the local levels, knowledge of these cancers particularly their biology and possible avenues for therapy remains poorly exploited. Herewith, this review highlights the role of sex hormones (estrogens and androgens) in the pathophysiology of hormone-responsive cancers and the exploration of therapeutic targets. Major scientific databases including but not limited to Scopus, PubMed, Science Direct, Web of Science core collections, and Google Scholar were perused using a string of search terms: Hormone-responsive cancers, androgens and cancers, estrogens and cancer, androgen receptor signalling, estrogen receptor signalling, etc. [Display omitted] • Sex hormone receptor signaling is implicated in hormone-responsive cancers. • Andro-estrogen receptor signaling influence complexities of hormone-responsive cancers. • Upstream and downstream targets of andro-estrogen receptor signaling provide a repertoire of avenues for therapeutic strategies against hormone-responsive cancers. [ABSTRACT FROM AUTHOR]

Abstract: Cerebral aneurysms secondary to cerebral vasculitis related to systemic lupus erythematosus are rare. We report a 31-year-old woman who presented with a lupus flare associated with inaugural generalized seizures. Computed tomography angiography showed subarachnoid hemorrhage by rupture of a cerebellar artery fusiform aneurysm. Later, despite the initiation of corticosteroids and cyclophosphamide, she presented a second cerebral hemorrhage due to the rupture of a new aneurysm in lenticulostriates arteries. The outcome was fatal. We discuss the frequency and management of this severe complication of systemic lupus erythematosus. [Copyright &y& Elsevier]

Abstract There is a significant gap in our knowledge of the microbe–host relationship between urban and traditional rural populations. We conducted a large-scale study to examine the gut microbiota of different traditional rural and urban lifestyles in human populations. Using high-throughput 16S ribosomal RNA gene amplicon sequencing, we tested urban French, Saudi, Senegalese, Nigerian and Polynesian individuals as well as individuals living in traditional rural societies, including Amazonians from French Guiana, Congolese Pygmies, Saudi Bedouins and Algerian Tuaregs. The gut microbiota from individuals living in traditional rural settings clustered differently and presented significantly higher diversity than those of urban populations (p 0.01). The bacterial taxa identified by class analysis as contributing most significantly to each cluster were Phascolarctobacterium for traditional rural individuals and Bifidobacterium for urban individuals. Spirochaetae were only present in the gut microbiota of individuals from traditional rural societies, and the gut microbiota of all traditional rural populations was enriched with Treponema succinifaciens. Cross-transmission of Treponema from termites or swine to humans or the increased use of antibiotics in nontraditional populations may explain why Treponema is present only in the gut microbiota of traditional rural populations. [ABSTRACT FROM AUTHOR]

Culturomics investigates microbial diversity of the human microbiome by combining diversified culture conditions, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S rRNA gene identification. The present study allowed identification of four putative new Clostridium sensu stricto species: ‘Clostridium amazonitimonense’ strain LF2 T , ‘Clostridium massilidielmoense’ strain MT26 T , ‘Clostridium nigeriense’ strain Marseille-P2414 T and ‘Clostridium merdae’ strain Marseille-P2953 T , which we describe using the concept of taxonogenomics. We describe the main characteristics of each bacterium and present their complete genome sequence and annotation. [ABSTRACT FROM AUTHOR]

Microbial culturomics represents a completely new approach to investigate microbial diversity by using different optimized culture conditions, mass spectrometry, genome sequencing and annotation and phenotypic description that allow for an extensive characterization of new species and the study of the human microbiome. Here we present four new species within the genus Paenibacillus : ‘Paenibacillus bouchesdurhonensis’ strain Marseille-P3071 T , ‘Paenibacillus rubinfantis’ strain MT18 T , ‘Paenibacillus senegalimassiliensis’ strain SIT18 T and ‘Paenibacillus tuaregi’ strain Marseille-P2472 T , which are all facultatively aerobic and Gram-positive bacilli. [ABSTRACT FROM AUTHOR]

We report here the main characteristics of five new species, ‘ Marasmitruncus massiliensis’ strain Marseille-P3646 T (CSUR P3646), ‘ Clostridium culturomicum ’ strain Marseille-P3545 T (CSUR P3545), ‘ Blautia provencensis ’ strain Marseille-P3502 T (CSUR P3502), ‘ Bacillus caccae ’ strain Marseille-P3604 T (CSUR P3604) and ‘ Ornithinibacillus massiliensis ’ strain Marseille-P3601 T (CSUR P3601), which were isolated recently from undernourished children's stool samples from Niger using microbial culturomics. [ABSTRACT FROM AUTHOR]

The main characteristics of ‘ Khelaifiella massiliensis ’ strain Mt13 T (= CSUR P1935, = DSM100591), ‘ Niameybacter massiliensis ’ strain Mt14 T (= CSUR P1909, = DSM100592), ‘ Brachybacterium massiliense ’ strain MT5 T (= CSUR P2240, = DSM101766), ‘ Enterobacter timonensis ’ strain mt20 T (= CSUR P2201, = DSM 101775) and ‘ Massilibacillus massiliensis ’ strain Marseille-P2411 T (= CSUR P2411, = DSM102838), new species isolated from the gut of healthy African infants, are presented. [ABSTRACT FROM AUTHOR]

We report here the main characteristics of five new species ‘Urmitella timonensis’ strain Marseille-P2918 T (CSUR P2918), ‘Blautia marasmi’ strain Marseille-P2377 T (CSUR P2377), ‘Lachnoclostridium pacaense’ strain Marseille-P3100 T (CSUR P3100), ‘Bacillus marasmi’ strain Marseille-P3556 T (CSUR P3556) and ‘Anaerotruncus rubiinfantis’ strain MT15 T (CSUR P2276), which were isolated recently from stool samples taken from undernourished children in Niger and Senegal using microbial culturomics. [ABSTRACT FROM AUTHOR]

Paenibacillus phocaensis sp. nov. strain mt24 T (= CSUR P2238 = DSM 101777) is a Gram-negative, facultative anaerobic, spore-forming and motile bacilli. This strain was isolated from the stool sample of a healthy infant from Niger. Its genome was estimated to a size of 5 521 415 bp with a 53.54% GC content. It contains 4835 protein-coding genes and 89 RNAs, among which two were 16S rRNA genes. There were also 101 genes (2.09%) identified as ORFans. [ABSTRACT FROM AUTHOR]

A new Actinobacterium , designated Tessaracoccus massiliensis type strain SIT-7 T (= CSUR P1301 = DSM 29060), have been isolated from a Nigerian child with kwashiorkor. It is a facultative aerobic, Gram positive, rod shaped, non spore-forming, and non motile bacterium. Here, we describe the genomic and phenotypic characteristics of this isolate. Its 3,212,234 bp long genome (1 chromosome, no plasmid) exhibits a G+C content of 67.81% and contains 3,058 protein-coding genes and 49 RNA genes. [ABSTRACT FROM AUTHOR]

Bacillus andreraoultii strain SIT1 T (= CSUR P1162 = DSM 29078) is the type strain of B. andreraoultii sp. nov. This bacterium was isolated from the stool of a 2-year-old Nigerian boy with a severe form of kwashiorkor. Bacillus andreraoultii is an aerobic, Gram-positive rod. We describe here the features of this bacterium, together with the complete genome sequencing and annotation. The 4 092 130 bp long genome contains 3718 protein-coding and 116 RNA genes. [ABSTRACT FROM AUTHOR]

Bacillus niameyensis sp. nov. strain SIT3 T (= CSUR P1266 = DSM 29725) is the type strain of B. niameyensis sp. nov. This Gram-positive strain was isolated from the digestive flora of a child with kwashiorkor and is a facultative anaerobic rod and a member of the Bacillaceae family. This organism is hereby described alongside its complete genome sequence and annotation. The 4  286  116 bp long genome (one chromosome but no plasmid) contains 4130 protein-coding and 66 RNA genes including five rRNA genes. [ABSTRACT FROM AUTHOR]

Bacillus rubiinfantis sp. nov. strain mt2 T is the type strain of B. rubiinfantis sp. nov., isolated from the fecal flora of a child with kwashiorkor in Niger. It is Gram-positive facultative anaerobic rod belonging to the Bacillaceae family. We describe the features of this organism alongside the complete genome sequence and annotation. The 4 311 083 bp long genome (one chromosome but no plasmid) contains 4028 protein-coding gene and 121 RNA genes including nine rRNA genes. [ABSTRACT FROM AUTHOR]

Résumé Introduction La géophagie correspond à une ingestion volontaire de terre et particulièrement d’argile. Elle a surtout été rapportée chez la femme enceinte en Afrique et en Amérique du Sud. Nous rapportons 12 cas de géophagie associée à une anémie sévère chez des femmes nigériennes non gravides. Résultats/observations L’âge médian des patients était de 34,5 ans, leur niveau socio-économique était moyen. La concentration médiane d’hémoglobine était de 6,9 g/dL (3,3–8,6), le VGM médian de 78,3 fL (63–106) et la ferritinémie médiane à 9,2 ng/mL (3,6–11,2). Les raisons de la géophagie exprimées étaient l’envie (5/12) et la tradition (4/12). Conclusion La géophagie est méconnue dans les pays développés et en dehors de la grossesse. Elle peut être la cause d’une carence martiale sévère et doit être évoquée y compris en dehors de la grossesse, et aussi bien en Afrique que dans les espaces de migration où la pratique peut être exportée. Introduction Geophagy or soil eating is mostly described in pregnant women from Sub-Saharan Africa, South America. Here, we report 12 cases of geophagy associated with severe anemia in non-pregnant Nigerian women. Results/case reports The median age at diagnosis was 34.5 years. The socioeconomic level was average for all patients. The median hemoglobin level at admission was 6.9 g/dL (3.3–8.6), median corpuscular volume was 78.3 fL (63–106) and median serum ferritin was 9.2 ng/mL (3.6–11.2). The reasons of this practice were “desire” (5/12) and tradition (4/12). All patients received psychotherapy and supplementation with intravenous iron. Conclusion Geophagy is an underestimated practice in developed countries and in non-pregnant women. It can be the cause of severe iron deficiency and must be discussed in patients with anemia, including non-pregnant patients, and in Africa as well as in migration areas, where the practice can be exported. [ABSTRACT FROM AUTHOR]

[Display omitted] Human platelet 12-(S)-Lipoxygenase (12-LOX) is a fatty acid metabolizing oxygenase that plays an important role in platelet activation and cardiometabolic disease. ML355 is a specific 12-LOX inhibitor that has been shown to decrease thrombosis without prolonging hemostasis and protect human pancreatic islets from inflammatory injury. It has an amenable drug-like scaffold with nM potency and encouraging ADME and PK profiles, but its binding mode to the active site of 12-LOX remains unclear. In the current work, we combined computational modeling and experimental mutagenesis to propose a model in which ML355 conforms to the "U" shape of the 12-LOX active site, with the phenyl linker region wrapping around L407. The benzothiazole of ML355 extends into the bottom of the active site cavity, pointing towards residues A417 and V418. However, reducing the active site depth alone did not affect ML355 potency. In order to lower the potency of ML355 , the cavity needed to be reduced in both length and width. In addition, H596 appears to position ML355 in the active site through an interaction with the 2-methoxy phenol moiety of ML355. Combined, this binding model suggested that the benzothiazole of ML355 could be enlarged. Therefore, a naphthyl-benzothiazole derivative of ML355 , Lox12Slug001 , was synthesized and shown to have 7.2-fold greater potency than ML355. This greater potency is proposed to be due to additional van der Waals interactions and pi-pi stacking with F414 and F352. Lox12Slug001 was also shown to be highly selective against 12-LOX relative to the other LOX isozymes and more importantly, it showed activity in rescuing human islets exposed to inflammatory cytokines with comparable potency to ML355. Further studies are currently being pursued to derivatize ML355 in order to optimize the additional space in the active site, while maintaining acceptable drug-like properties. [ABSTRACT FROM AUTHOR]

Abrus precatorius (L.) leaves are used as folk medicine by the local communities in the western region of Ghana to treat diabetes mellitus; however, this health claim remains unverified scientifically. The study investigated glucose lowering and pancreato-protective effects of Abrus precatorius leaf extract (APLE) in normoglycemic and STZ/nicotinamide (NIC)-induced diabetic rats. Method: after preparation of APLE, it was subjected to phytochemical screening, proximate composition and elemental assessments by using standard methods. Oral glucose tolerance test (OGTT) and maltose, lactose and sucrose oral challenge were assessed in normoglycemic rats post-APLE. Morphological characteristics of glucose response curve (time of glucose peak and shape of glucose response curve) were determined. Subsequently, diabetes mellitus was experimentally established in normoglycaemic adult Sprague-Dawley rats (weighing 150–250 g) of both sexes by sequential injection of Streptozotocin (STZ, 60 mg/kg ip)-reconstituted in sodium citrate buffer and NIC (110 mg/kg ip)-reconstituted in normal saline (1:1 v/v) for 16 weeks. Except control rats (normal saline 5 ml/kg ip; baseline fasting blood glucose [FBG] of 6.48 mmol/L), rats having FBG (stable at 11.1 mmol/L or ≥ 250 mg/dL) 3 days post-STZ/NIC injection were randomly re-assigned to one of the following groups: model (STZ/NIC-induced diabetic rats), APLE (100, 200 and 400 mg/kg respectively po) and metformin (300 mg/kg po) and treated daily for 28 days. Bodyweight and FBG were measured on weekly basis. FBG was measured by using standard glucometers. On day 28, rats were sacrificed under chloroform anesthesia, blood collected via cardiac puncture; kidney, liver and pancreas surgically harvested. While the pancreas was processed, sectioned and H&E-stained for histological examination, fresh kidney and liver were homogenized for assessment of total anti-oxidant capacity. Median cross-sectional area of pancreatic islets of Langerhans was determined for each group by using Amscope. Cumulatively, APLE (100, 200 and 400 mg/kg respectively) dose-dependently decreased the initial FBG by 55.22, 76.15 and 77.77% respectively compared to model (−1.04%) and metformin (72.29%) groups. APLE treatment recovered damaged pancreatic β-cells and also increased median cross-sectional area (x106 μm2) of pancreatic islets compared to that of model group. APLE significantly (P < 0.05) increased total anti-oxidant capacity (5.21 ± 0.02 AscAE μg/mL) of plasma, kidney and liver compared to model (4.06 ± 0.04 AscAE μg/mL) and metformin (4.87 ± 0.03 AscAE μg/mL) groups. APLE has demonstrated glucose lowering and pancreato-protective effects in rats and arrested the characteristic loss in bodyweight associated with diabetes mellitus. This finding preliminarily confirms folk use of APLE as an anti-diabetic herbal medicine, whiles providing a rationale for further translational studies on APLE. Image 1 [ABSTRACT FROM AUTHOR]