Notes

Increased endemic RNA oxidative injury and also diagnostic value of RNA oxidative metabolites in the course of Shigella flexneri-induced intestinal disease.
To present a case series of primary and immunotherapy-related secondary hypophysitis.

A single-center retrospective chart review was performed at the University of British Columbia, Vancouver, Canada. Eleven cases of primary hypophysitis and 2 cases of immunotherapy-related secondary hypophysitis were included. Of the 11 primary cases, 6 were diagnosed clinically without biopsy.

In primary hypophysitis, headache was the most common presenting symptom (6/11; 55%) and stalk enlargement the prevailing radiologic sign (8/11; 73%). Central adrenal insufficiency (4/11; 36%), central hypothyroidism (4/11; 36%), and central diabetes insipidus (CDI) (4/11; 36%) were the most common pituitary deficiencies at presentation. Initial management included surgery (4/11; 36%), supraphysiologic steroids (2/11; 18%), or observation (6/11; 55%). Outcomes assessed included radiologic improvement (8/9; 89%), improvement in mass symptoms (4/7; 57%), anterior pituitary recovery (1/7; 14%), and CDI recovery (0/4; 0%). In immunotherapy-related hypophysitis either under observation or supraphysiologic steroid therapy, the inflammatory mass resolved and pituitary dysfunction persisted.

In primary hypophysitis, the inflammatory pituitary mass typically resolves and hypopituitarism persists. In the absence of severe or progressive neurologic deficits, a presumptive clinical diagnosis and conservative medical management should be attempted. In the absence of severe features, immunotherapy-related hypophysitis may be managed effectively without the use of supraphysiologic steroids.
In primary hypophysitis, the inflammatory pituitary mass typically resolves and hypopituitarism persists. In the absence of severe or progressive neurologic deficits, a presumptive clinical diagnosis and conservative medical management should be attempted. In the absence of severe features, immunotherapy-related hypophysitis may be managed effectively without the use of supraphysiologic steroids.
This study estimated the cost-effectiveness of metformin to reduce the risk of gestational diabetes mellitus (GDM) in pregnant women with polycystic ovary syndrome (PCOS) from the US health-care payer perspective.

A decision tree was developed to simulate the progression of PCOS in a hypothetical cohort of 10,000 pregnant women diagnosed with PCOS and two scenarios were tested. Normal glucose regulation without developing GDM, average cost-effectiveness ratios (ACER), and the incremental cost-effectiveness ratios (ICERs) were the outcome measures assessed through pregnancy. Evidence from randomized clinical trials and other published literature were used to assess disease progression and its associated health-care costs. Sensitivity analyses that varied key model parameters were conducted.

Management of PCOS with metformin was associated with lowest ACER ($669.78 per normal glucose regulation without GDM) as compared to 'no intervention' strategy. Metformin use is the most cost-effective strategy to manage PCOS during pregnancy with average cost savings of $7,593,372.97 and an average effect gain of 2271 of normal glucose regulation without GDM among pregnant women with PCOS. Sensitivity analyses determined that the results are robust.

Management of PCOS during pregnancy may be a cost-effective strategy to reduce GDM risk and its associated complications.
Management of PCOS during pregnancy may be a cost-effective strategy to reduce GDM risk and its associated complications.
'Prediabetes' is a condition of elevated glucose not attaining the established criteria for a diagnosis of diabetes. The United States Diabetes Prevention Program (DPP) began in 1996 and was the iconic study of prediabetes. In that study, after 3years, the risk of reaching the numerical criteria of diabetes was reduced by 58% by intensive emphasis on diet and exercise whereas treatment with metformin achieved a lesser reduction of 31%. The DPP was widely heralded as suggesting that lifestyle change was superior to pharmacologic therapy in the prediabetes population. This conclusion may be overreaching in terms of the long-term results of that study.

The author reviews the subsequent pharmacologic efforts to prevent diabetes in this population. He reviews the existing literature for pharmacologic treatment of prediabetes using Pubmed.gov using the keywords of prediabetes, impaired fasting glucose and impaired glucose tolerance.

Prediabetes is primarily related to being overweight. Obesity has health consequences going beyond glucose elevation. The approach to prediabetes should be primarily by pursuing weight loss with therapeutic agents such as GLP-1 receptor agonists and SGLT2 inhibitors.
Prediabetes is primarily related to being overweight. Obesity has health consequences going beyond glucose elevation. The approach to prediabetes should be primarily by pursuing weight loss with therapeutic agents such as GLP-1 receptor agonists and SGLT2 inhibitors.
The purpose of this study was to evaluate the individual contributions of inhalation and dermal exposures to urinary glyphosate levels following the heavy residential consumer application of a glyphosate-containing herbicide.

A pilot study was conducted in which each participant mixed and continuously spray-applied 16.3 gallons of a 0.96% glyphosate-containing solution for 100 min using a backpack sprayer. Twelve participants were divided evenly into two exposure groups, one equipped to assess dermal exposure and the other, inhalation exposure. Personal air samples (
 = 12) and dermal patch samples (
 = 24) were collected on the inhalation group participants and analyzed for glyphosate using HPLC-UV. Serial urine samples collected 30-min prior to application and 3-, 6-, 12-, 24-hr (inhalation and dermal groups) and 36-hr (dermal group only) post-application were analyzed for glyphosate and glyphosate's primary metabolite (AMPA) using HPLC-MS/MS.

The mean airborne glyphosate concentration was 0.0047 mged from the body, typically within 24 hr following application.
To investigate the safety and efficacy of high-intensity focused ultrasound (HIFU) treatment for diffuse uterine leiomyomatosis (DUL).

Eight patients with DUL were admitted to the Department of Gynecology of Shanghai First Maternity and Infant Hospital and underwent HIFU treatment. MRI was performed before and one day after HIFU treatment for the evaluation of lesion ablation. The uterine size was measured at 3-8 months after HIFU ablation. The menstrual volume score and serum levels of hemoglobin and CA-125 were measured pre-HIFU ablation and 12-36 months post-HIFU ablation.

After an average of 5.9 months of follow-up after HIFU treatment, an average uterine volume reduction of 67.6% was observed. Menstruation returned to normal in all patients, and their serum HGB and CA-125 levels also returned to normal after an average of 19.1 months of clinical follow-up. The quality of life of all patients improved significantly.

HIFU treatment is safe and effective in the treatment of patients with DUL.
HIFU treatment is safe and effective in the treatment of patients with DUL.
Patisiran and inotersen are two therapies approved for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy, a rapidly progressive disease with a substantial clinical burden. This analysis indirectly compares the efficacy of patisiran and inotersen on neuropathy and quality of life (QOL).

Published results from the NEURO-TTR study of inotersen and individual patient data from the APOLLO study of patisiran were used. Indirect comparisons were conducted for 15-month changes in neuropathy and QOL endpoints modified Neuropathy Impairment Score +7 (mNIS+7
), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire, body mass index (BMI), and Polyneuropathy Disability (PND) score. Analyses were conducted under different assumptions about the impact of missing data and to adjust for baseline differences between studies.

Patisiran showed significantly greater treatment effects than inotersen for mNIS+7
(mean difference -12.3 [95% confidence interval -21.4, -3.3]), Norfolk QOL-DN (-11.3 [-19.8, -2.9]), and BMI (1.0 [0.4, 1.7]). The proportion of patients with improvement or no change from baseline on PND score was higher for patisiran-treated patients (odds ratio 8.9 [4.6, 17.5]). Results were consistent and robust across analyses and methods.

Patisiran demonstrated greater treatment effects on neuropathy and QOL than inotersen in patients with hATTR amyloidosis with polyneuropathy.
Patisiran demonstrated greater treatment effects on neuropathy and QOL than inotersen in patients with hATTR amyloidosis with polyneuropathy.Caffeic acid phenethyl ester (CAPE), a major pharmacologically active component of poplar type propolis, is known for its proapoptotic, anti-inflammatory, antioxidant, antiviral, and enzyme inhibiting activities. The aim of this study was to perform an in vitro and in vivo safety assessment of a micellar system based on a newly synthesized copolymer, consisting of polyglycidol and poly(allyl glycidyl ether) (C12-PAGE-PG) as a drug delivery platform for CAPE. see more The in vitro studies on HepG2 and L929 cells by MTT and LDH assays after treatment with the empty and CAPE-loaded micelles showed no cytotoxic effects of the empty micelles and retained cytotoxic activity of CAPE loaded in the micelles. No hemolysis or stimulation of mouse lymphocytes or macrophages was observed in vitro. In vivo hematological, biochemical, and histological assays on rats, treated with the empty (2580 and 5160 µg/kg) or CAPE-loaded (375 and 750 µg CAPE/kg) micelles did not reveal pathological changes of any of the parameters assayed after 14-days' treatment. In conclusion, initial toxicological data characterize C12-PAGE-PG as a non-toxic and promising copolymer for development of micellar drug delivery systems, particularly for a hydrophobic active substance as CAPE.Oxidative stress is often initiated by excess reactive oxygen species (ROS) production, resulting in macromolecular damage, which is implicated in many disease states. Glutaredoxin 1 (Grx1) is an antioxidant enzyme that plays an important role in redox signaling and redox homeostasis. In the present study, we generated HeLaS3 cell lines deficient in Grx1 by the CRISPR/CAS9 system to clarify how Grx1 affects the physiological activities of HeLaS3 cells to respond to oxidative stress. First, the survival assay revealed that Grx1-deficient HeLaS3 cells were more sensitive to γ-ray irradiation, heat shock and H2O2 exposure than HeLaS3 wild-type cells. Next, the intracellular redox state was investigated using a fluorescent probe (2'-7'dichlorofluorescin diacetate), and the oxidized state of total proteins and a peroxidase Prx2 were measured by Western blot analysis. Exposure to γ-ray irradiation, heat shock and H2O2 significantly induced more accumulation of intracellular oxidants including ROS and higher levels of oxidized proteins in Grx1-deficient HeLaS3 cells. Furthermore, MitoSox Red staining demonstrated that Grx1 deficiency causes a higher level of oxidants production in mitochondria. Moreover, Grx1-deficient HeLaS3 cells had a higher cytochrome c level and higher apoptosis rate (Annexin-V/FITC and EthD-III staining assay) upon oxidative stress. These results suggested that Grx1 deficiency lead to mitochondrial redox homeostasis disruption and apoptotic cell death upon oxidative stress. In addition, the results of proliferation assay and MitoTracker staining assay (multinuclear cell formation rate) suggested that oxidative stress exposure inhibits cell proliferation maybe by affecting cytoplasmic division in Grx1-deficient HeLaS3 cells.
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