scholarly journals Neurokinin 3 receptor antagonism ameliorates key metabolic features in a hyperandrogenic PCOS mouse model

Endocrinology ◽  
2021 ◽  
Author(s):  
Irene E Sucquart ◽  
Ruchi Nagarkar ◽  
Melissa C Edwards ◽  
Valentina Rodriguez Paris ◽  
Ali Aflatounian ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Polycystic Ovary ◽  
Serum Triglyceride ◽  
Total Body Weight ◽  
Neurokinin B ◽  
Glucose Levels ◽  
Neurokinin 3 Receptor ◽  
Total Body ◽  
Novel Therapeutic Strategies

Abstract Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterised by a range of endocrine, reproductive and metabolic abnormalities. At present, management of women with PCOS is suboptimal as treatment is only symptomatic. Clinical and experimental advances in our understanding of PCOS etiology support a pivotal role for androgen neuroendocrine actions in PCOS pathogenesis. Hyperandrogenism is a key PCOS trait and androgen actions play a role in regulating the kisspeptin-/neurokinin B-/dynorphin (KNDy) system. This study aimed to investigate if targeted antagonism of neurokinin B signalling through the neurokinin 3 receptor (NK3R) would reverse PCOS traits in a dihydrotestosterone (DHT)-induced mouse model of PCOS. After 3 months, DHT exposure induced key reproductive PCOS traits of cycle irregularity and ovulatory dysfunction, and PCOS-like metabolic traits including increased body weight; white and brown fat pad weights; fasting serum triglyceride and glucose levels and blood glucose iAUC. Treatment with a NK3R antagonist (MLE4901) did not impact the observed reproductive defects. In contrast, following NK3R antagonist treatment, PCOS-like females displayed decreased total body weight, adiposity and adipocyte hypertrophy, but increased respiratory exchange ratio, suggesting NK3R antagonism altered the metabolic status of the PCOS-like females. NK3R antagonism did not improve circulating serum triglyceride or fasted glucose levels. Collectively, these findings demonstrate that NK3R antagonism may be beneficial in the treatment of adverse metabolic features associated with PCOS and support neuroendocrine targeting in the development of novel therapeutic strategies for PCOS.

scholarly journals PDE9 Inhibition By IMR-687 Improves Markers of Beta-Thalassemia in the Hbb th1/th1 Experimental Mouse Model

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 945-945
Author(s):  
Thiago Trovati Maciel ◽  
Caroline Carvalho ◽  
Rachel Rignault ◽  
Slimane Allali ◽  
Biree Andemariam ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Research Funding ◽  
Weight Ratio ◽  
Total Body Weight ◽  
Beta Thalassemia ◽  
Flow Cytometry Analysis ◽  
Publicly Traded ◽  
Once Daily ◽  
Total Body

Abstract Introduction Hbb th1/th1 mice lack functional beta-globin, leading to decreased hemoglobin (Hb) production, decreased mature red blood cells (RBCs), and ineffective erythropoiesis. The model mimics several of the pathological changes seen in beta-thalassemia. IMR-687 (tovinontrine) is a highly selective phosphodiesterase-9 (PDE9) inhibitor which increases intracellular cGMP. The aim of this study was to assess the effect of IMR-687 on markers of beta-thalassemia in the Hbb th1/th1 mouse model. Methods Eighteen Hbb th1/th1 mice were divided into three groups of six animals each and dosed once daily, by gavage, for 30 days with IMR-687 at 30 or 60 mg/kg/day or vehicle control. On day 30, blood was collected for routine hematology including measurement of Hb, reticulocytes and RBCs, and spleen tissue was dissociated to assess erythrocyte differentiation using flow cytometry analysis of immature (Ery.B: Ter119 highCD71 highFSC low) and mature (Ery.C: Ter119 highCD71 lowFSC low) erythroblast populations. Animals were observed daily for mortality and measured for total body weight (Day 0 and Day 30) and spleen to body weight ratio at necropsy (Day 30). Results After 30 days of treatment, the groups of mice treated with IMR-687 at 30 or 60 mg/kg/day showed a mean increase in Hb of 1.0 g/dL (p<0.05) and 1.5 g/dL (p<0.01), respectively, relative to vehicle controls. RBCs showed a statistically significant increase (p<0.05) following treatment with IMR-687 at 30 or 60 mg/kg/day (6.9 and 7.2 x10 6 cells/ml, respectively) relative to vehicle (6.2 x10 6 cells/ml). The number of reticulocytes decreased after treatment with IMR-687 (only in the 30 mg/kg/day group, 1.8 x10 6 cells/ml, p<0.05) relative to vehicle (2.2 x10 6 cells/ml). Flow cytometry analysis of spleens showed that both doses of IMR-687 increased (p<0.05) the percentage of Ery.C cells (24.2% and 28.5% in 30 and 60 mg/kg/day, respectively) relative to vehicle (16.6%,) and decreased (p<0.05) the percentage of Ery.B cells (38.4% and 36.9% in 30 and 60 mg/kg/day, respectively) relative to vehicle (43.5%), resulting in a maturation ratio (Ery.B/Ery.C) that favored mature RBCs. There were no deaths nor any significant differences in total body weight or spleen to body weight ratio in animals treated with IMR-687 relative to vehicle controls. Conclusions Administration of IMR-687 at 30 or 60 mg/kg/day for 30 days improved markers of disease progression in a mouse model of beta-thalassemia, as shown by a statistically significant increase in Hb and RBCs and decrease in reticulocytes as well as improved differentiation of splenic erythroblasts. Both dose levels of IMR-687 were well tolerated with no treatment-related deaths or abnormal clinical signs. These results support a role for IMR-687 in beta-thalassemia by enabling RBC maturation and improving ineffective erythropoiesis, key components in ameliorating disease pathology. Clinical testing of IMR-687 (up to 400 mg) as a once daily, oral tablet is currently ongoing in a Phase 2 study of patients with beta-thalassemia (NCT04411082). Figure 1 Figure 1. Disclosures Maciel: Imara Inc.: Research Funding. Carvalho: Imara Inc.: Research Funding. Rignault: Imara Inc.: Research Funding. Allali: Imara Inc.: Research Funding. OCain: Imara Inc.: Current Employment, Current equity holder in publicly-traded company. Ballal: Imara Inc.: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Pathogenesis of reproductive and metabolic PCOS traits in a mouse model

2021 ◽  
Author(s):  
Valentina Rodriguez Paris ◽  
Melissa C Edwards ◽  
Ali Aflatounian ◽  
Michael J Bertoldo ◽  
William L Ledger ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Hepatic Steatosis ◽  
Polycystic Ovary ◽  
Treatment Strategies ◽  
Antral Follicle ◽  
Glucose Levels ◽  
New Treatment ◽  
Early Features ◽  
Large Antral Follicle

Abstract Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder, however the etiology and pathogenesis of PCOS are poorly understood and current management is symptom based. Defining the pathogenesis of PCOS traits is important for developing early PCOS detection markers and new treatment strategies. Hyperandrogenism is a defining characteristic of PCOS and studies support a role for androgen driven actions in the development of PCOS. Therefore, we aimed to determine the temporal pattern of development of PCOS features in a well characterized dihydrotestosterone (DHT)-induced PCOS mouse model after 2, 4 and 8 weeks of DHT exposure. Following 2 weeks of treatment, DHT induced the key PCOS reproductive features of acyclicity, anovulation and multi-follicular ovaries as well as a decrease in large antral follicle health. DHT treated mice displayed the metabolic PCOS characteristics of increased body weight and exhibited increased visceral adiposity after 8 weeks of DHT treatment. DHT treatment also led to an increase in circulating cholesterol after 2 weeks exposure and had an overall effect on fasting glucose levels, but not triglycerides, aspartate transaminase (AST) and alanine transaminase (ALT) levels or hepatic steatosis. These data reveal that in this experimental PCOS mouse model, acyclicity, anovulation and increased body weight are early features of a developing PCOS phenotype whereas adiposity, impaired glucose tolerance, dyslipidemia and hepatic steatosis are later developing features of PCOS. These findings provide insights into the likely sequence of PCOS trait development and support the addition of body weight criteria to the early diagnosis of PCOS.

scholarly journals Lean body weight versus total body weight to calculate the iodinated contrast media volume in abdominal CT: a randomised controlled trial

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Moreno Zanardo ◽  
Fabio Martino Doniselli ◽  
Anastassia Esseridou ◽  
Massimiliano Agrò ◽  
Nicol Antonina Rita Panarisi ◽  
...  
Keyword(s):  
Body Weight ◽  
Contrast Media ◽  
Controlled Trial ◽  
Total Body Weight ◽  
Lean Body Weight ◽  
Iodinated Contrast Media ◽  
Abdominal Ct ◽  
Iodinated Contrast ◽  
Significant Difference ◽  
Total Body

Abstract Objectives Iodinated contrast media (ICM) could be more appropriately dosed on patient lean body weight (LBW) than on total body weight (TBW). Methods After Ethics Committee approval, trial registration NCT03384979, patients aged ≥ 18 years scheduled for multiphasic abdominal CT were randomised for ICM dose to LBW group (0.63 gI/kg of LBW) or TBW group (0.44 gI/kg of TBW). Abdominal 64-row CT was performed using 120 kVp, 100–200 mAs, rotation time 0.5 s, pitch 1, Iopamidol (370 mgI/mL), and flow rate 3 mL/s. Levene, Mann–Whitney U, and χ2 tests were used. The primary endpoint was liver contrast enhancement (LCE). Results Of 335 enrolled patients, 17 were screening failures; 44 dropped out after randomisation; 274 patients were analysed (133 LBW group, 141 TBW group). The median age of LBW group (66 years) was slightly lower than that of TBW group (70 years). Although the median ICM-injected volume was comparable between groups, its variability was larger in the former (interquartile range 27 mL versus 21 mL, p = 0.01). The same was for unenhanced liver density (IQR 10 versus 7 HU) (p = 0.02). Median LCE was 40 (35–46) HU in the LBW group and 40 (35–44) HU in the TBW group, without significant difference for median (p = 0.41) and variability (p = 0.23). Suboptimal LCE (< 40 HU) was found in 64/133 (48%) patients in the LBW group and 69/141 (49%) in the TBW group, but no examination needed repeating. Conclusions The calculation of the ICM volume to be administered for abdominal CT based on the LBW does not imply a more consistent LCE.

Increases in adipose and total body weight, but not in lean body mass, associated with subcutaneous administration of Sonic hedgehog-Ig fusion protein to mice

2002 ◽  
Vol 57 (3) ◽  
pp. 107-114 ◽  
Author(s):  
Pauline L. Martin ◽  
Joan Lane ◽  
Louise Pouliot ◽  
Malcolm Gains ◽  
Rudolph Stejskal ◽  
...  
Keyword(s):  
Body Weight ◽  
Fusion Protein ◽  
Lean Body Mass ◽  
Body Mass ◽  
Sonic Hedgehog ◽  
Subcutaneous Administration ◽  
Total Body Weight ◽  
Total Body

Effects of the teratogenic folic acid antagonist, 9-methyl pteroylglutamic acid, on hydroxyproline levels in fetal rat limbs

Development ◽  
1977 ◽  
Vol 41 (1) ◽  
pp. 289-294
Author(s):  
R. R. Schmidt ◽  
K. P. Chepenik ◽  
B. V. Paynton
Keyword(s):  
Body Weight ◽  
Folic Acid ◽  
Total Body Weight ◽  
Pregnant Rats ◽  
Skeletal Malformations ◽  
Fetal Rat ◽  
Pteroylglutamic Acid ◽  
Limb Malformations ◽  
Total Body ◽  
Rate Of Accumulation

Pregnant rats were subjected to either a folic-acid-deficient regimen that produces multiple congenital skeletal malformations, or a control folic-acid-supplemented regimen. Fetal limbs were extirpated on days 16 and 18 of gestation, pooled from each litter, homogenized, and aliquots set aside for hydroxyproline, protein and DNA determinations. We found that (1) the amount of protein recovered per treated limb was approximately half that of controls on both days, (2) the amount of protein recovered per treated or controlday-18 limb was twice that of a day-16 limb, (3) treated limbs constituted the same percentage of total body weight as in controls on day 16, but a smaller percentage than in controls on day 18, and (4) the concentration of hydroxyproline (μg/mg protein) was significantly less for treated limbs than for controls on day 18 of gestation. We noted also that: (1) lowest hydroxyproline concentrations were found in limbs from treated fetuses with gross limb malformations, (2) intermediate concentrations were found in limbs of treated fetuses not exhibiting gross limb malformations, and (3) highest concentrations were found in control limbs. We suggest that the treatment resulted in (1) a decreased rate of accumulation of protein in limbs prior to day 16, but not from day 16 to day 18, (2) a decreased rate of accumulation of some non-protein component(s) in treated limbs from day 16 to day 18, and (3) an altered collagen metabolism.

scholarly journals Growth and body weight of free-range reindeer in western Alaska

Rangifer ◽  
2000 ◽  
Vol 20 (2-3) ◽  
pp. 221 ◽  
Author(s):  
Greg L. Finstad ◽  
Alexander K. Prichard
Keyword(s):  
Body Weight ◽  
Growth Rates ◽  
Total Body Weight ◽  
Growth Patterns ◽  
Spatial And Temporal Variation ◽  
Adult Males ◽  
Body Weights ◽  
Total Body ◽  
Reproductive Females ◽  
Average Body

Total body weight of 9749 reindeer calves and 4798 adult reindeer were measured from 1984 to 1999 on the Seward Peninsula, western Alaska, USA. Growth rates of male and female calves, and annual growth patterns of adults were determined. Male calves grew faster than female calves. Reproductive females were lighter than non-reproductive females during summer but there was no effect of reproduction on average body weights the following winter. Adult males age 3-5 were heavier during summer than winter. Castrated males weighed the same as uncastrated males in summer, but were significantly heavier in winter, and did not display the large annual fluctuations in weight typical of reproductive males and females. Growth rates were higher and body weights greater in this herd than many other cir-cumpolar reindeer populations. We suggest these kinds of physiological indices should be used to monitor the possible effects of spatial and temporal variation in population density and to evaluate changes in herding practices.

scholarly journals SUN-543 Real World Evidence of Successful Weight Management for the Obese Population: Complete Reversal of Obesity Related Metabolic Co-Morbidities and Weight Loss in Patients Attending a Multidisciplinary Weight Management Clinic in Australia

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Zoe Rock ◽  
Juliana Chen ◽  
Joanna Jaques ◽  
Bernard L Champion ◽  
Reginald V Lord ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Weight Management ◽  
Exercise Physiology ◽  
Body Weight Loss ◽  
Total Body Weight ◽  
Management Interventions ◽  
Co Morbidity ◽  
Total Body ◽  
Total Body Weight Loss

Abstract Over 2.5 billion people worldwide are overweight or obese. Multidisciplinary weight management interventions have evolved to address the complexity of weight loss for those with one or more chronic diseases, and the trend of weight regain. The aim of these interventions is to encourage sustainable lifestyle changes, resulting in weight loss and weight maintenance and improvements in comorbidities. While some prospective clinical trials have demonstrated efficacy, results are often not reported by real life practices. The aim of this study was to evaluate the effectiveness of a Sydney based multidisciplinary weight management clinic with endocrinology, dietetics, exercise physiology, psychology, and bariatric surgical domains. All patients who attended the clinic for weight loss purposes between March 2017 and April 2019 were included (n=220). A retrospective chart review was conducted. Patient data on weight, BMI, waist circumference, body composition measurements, and selected blood test results and co-morbidities were analysed. All patient therapy included endocrinological input for co-morbidity identification and management, lifestyle intervention (dietetic and exercise physiology input) with optional adjunct pharmacotherapy or psychological counselling. Of the 220 cohort, 20 of the patients had sleeve gastrectomy. Patient retention in the clinic after the first consultation was 85% (n=186), a high rate within the weight management community. 59% of patients achieved a minimum of 5% total body weight loss, including 18% who achieved greater than 10% total body weight loss. Additionally, 31% of patients lost enough weight to decrease their BMI class by up to 2 or more classes. Of the gastric sleeve cohort average excess body weight loss was 32kg (21-56kg) enhanced by multidisciplinary care in the lead up to surgery. Across the cohort some patients completely reversed co-morbidities; including dyslipidaemia (n=1), hypertension (n=3), NAFLD (n=1), pre-diabetes (n=8) and type 2 diabetes (n=3), OSA (n=1). These results demonstrate that obesity is a chronic condition that can be successfully managed. We have demonstrated significant durable weight loss and improvement in metabolic co-morbidities with holistic coordinated care. Future directions include translating this model of care into standard practice in Australia and other countries where obesity to date not received the same coordinated approach as other chronic conditions.

Water Relationships of Aphis Fabae Scop. During Tethered Flight

1961 ◽  
Vol 38 (1) ◽  
pp. 175-180
Author(s):  
A. J. COCKBAIN
Keyword(s):  
Body Weight ◽  
Relative Humidity ◽  
Water Loss ◽  
Total Body Weight ◽  
Aphis Fabae ◽  
Limiting Factor ◽  
Saturation Deficit ◽  
Tethered Flight ◽  
C 23 ◽  
Total Body

1. Water content varies from 64 to 73% of the total body weight and 72-76% of the fatless body weight of 24 hr. old unflown alatae of Aphis fabae. 2. Water loss during flight may be attributed to evaporation and excretion. A mean of 0.07 mg. water is lost per aphid during a 6 hr. tethered fligh a 25-26° C. and 57-82% R.H., corresponding to c. 9% body weight; at least 66% of the loss (c. 1% body weight/hr.) is by evaporation. 3. Excretion during fligh is not affected by relative humidity differences over the range 41-75% at 25%26° C., but the relative amounts of water lost during prolonged flight are inversely related to relative humidity, because of the effect of humidity on evaporation. 4. Proportion of water in he body does no change significantly during tethered fligh. Mean percentage water to total body weight increases from c. 68-69% during 6 hr.; mean percentage water to fatless body weight decreases from c. 74 to 73%. 5. Water loss is evidently not a limiting factor to fligh in atmospheres of saturation deficit less than c. 23 mm. Hg.

Vancomycin Removal during High-Volume Peritoneal Dialysis in Acute Kidney Injury Patients

2019 ◽  
Vol 39 (2) ◽  
pp. 183-187 ◽  
Author(s):  
Daniela Ponce ◽  
Welder Zamoner ◽  
Fernanda Moreira Freitas ◽  
André Balbi ◽  
Linda Awdishu
Keyword(s):  
Acute Kidney Injury ◽  
Body Weight ◽  
Peritoneal Dialysis ◽  
Kidney Injury ◽  
High Volume ◽  
Total Body Weight ◽  
Empirical Treatment ◽  
Total Body

Studies on vancomycin pharmacokinetics in acute kidney injury (AKI) patients on high-volume peritoneal dialysis (HVPD) are lacking. We studied the pharmacokinetics of intravenous (IV) vancomycin in AKI patients treated by HVPD who received a prescribed single IV dose of vancomycin (15 - 20 mg/kg total body weight) to determine the extent of vancomycin removal and to establish vancomycin dosing guidelines for the empirical treatment of AKI patients receiving HVPD. The application of 18 mg/kg vancomycin every 48 - 72 hours in AKI patients undergoing HVPD was required to maintain therapeutic concentrations.

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