scholarly journals The rapamycin analog Everolimus reversibly impairs male germ cell differentiation and fertility in the mouse†

2020 ◽  
Vol 103 (5) ◽  
pp. 1132-1143
Author(s):  
Oleksandr Kirsanov ◽  
Randall H Renegar ◽  
Jonathan T Busada ◽  
Nicholas D Serra ◽  
Ellen V Harrington ◽  
...  
Keyword(s):  
Body Weight ◽  
Negative Impact ◽  
Transplant Rejection ◽  
Recovery Period ◽  
Mammalian Target Of Rapamycin ◽  
Organ Transplant ◽  
Testis Weight ◽  
Adult Mice ◽  
Germ Cell Differentiation ◽  
Dose Dependent

Abstract Sirolimus, also known as rapamycin, and its closely related rapamycin analog (rapalog) Everolimus inhibit “mammalian target of rapamycin complex 1” (mTORC1), whose activity is required for spermatogenesis. Everolimus is Food and Drug Administration approved for treating human patients to slow growth of aggressive cancers and preventing organ transplant rejection. Here, we test the hypothesis that rapalog inhibition of mTORC1 activity has a negative, but reversible, impact upon spermatogenesis. Juvenile (P20) or adult (P>60) mice received daily injections of sirolimus or Everolimus for 30 days, and tissues were examined at completion of treatment or following a recovery period. Rapalog treatments reduced body and testis weights, testis weight/body weight ratios, cauda epididymal sperm counts, and seminal vesicle weights in animals of both ages. Following rapalog treatment, numbers of differentiating spermatogonia were reduced, with concomitant increases in the ratio of undifferentiated spermatogonia to total number of remaining germ cells. To determine if even low doses of Everolimus can inhibit spermatogenesis, an additional group of adult mice received a dose of Everolimus ∼6-fold lower than a human clinical dose used to treat cancer. In these animals, only testis weights, testis weight/body weight ratios, and tubule diameters were reduced. Return to control values following a recovery period was variable for each of the measured parameters and was duration and dose dependent. Together, these data indicate rapalogs exerted a dose-dependent restriction on overall growth of juvenile and adult mice and negative impact upon spermatogenesis that were largely reversed; following treatment cessation, males from all treatment groups were able to sire offspring.

Maternal protein restriction in pregnancy and/or lactation affects seminiferous tubule organization in male rat offspring

2012 ◽  
Vol 3 (5) ◽  
pp. 321-326 ◽  
Author(s):  
G. L. Rodríguez-González ◽  
R. M. Vigueras-Villaseñor ◽  
S. Millán ◽  
N. Moran ◽  
R. Trejo ◽  
...  
Keyword(s):  
Body Weight ◽  
Germ Cell ◽  
Control Diet ◽  
Protein Restriction ◽  
Male Offspring ◽  
Male Rat ◽  
Testis Weight ◽  
Germ Cell Differentiation ◽  
Maternal Protein Restriction ◽  
Cell Proliferation And Differentiation

Maternal protein restriction (MPR) during pregnancy impaired the reproduction of male offspring. We investigated, during the first wave of spermatogenesis, whether MPR exerts deleterious effects on germ cell proliferation and differentiation, as well as androgen receptor (AR) protein expression, which was used as a marker for Sertoli cell (SC) maturation. At the beginning of pregnancy (day 0), dams were fed a control diet (C: 20% casein) or a restricted isocaloric diet (R: 10% casein). After birth, four groups were established: CC, RR, CR and RC (first letter diet during pregnancy and second during lactation). Male offspring were studied at postnatal days 14, 21 and 36. At birth, pup body weight was unchanged. Body weight and testis weight were reduced in RR and CR groups at all ages evaluated. MPR delayed the germinal epithelium development at all ages evaluated. On performing Western blot and immunohistochemistry, AR expression was found to be lower in the three restricted groups. The results suggest that MPR during pregnancy and/or lactation delays SC maturation and germ cell differentiation, and affects intratubular organization. These changes might be responsible for the lower fertility rate at older ages.

scholarly journals Everolimus for Compassionate Use in Multiple Basal Cell Carcinomas

2013 ◽  
Vol 2013 ◽  
pp. 1-4 ◽  
Author(s):  
Laura Eibenschutz ◽  
Delia Colombo ◽  
Caterina Catricalà
Keyword(s):  
Basal Cell ◽  
Transplant Rejection ◽  
Mammalian Target Of Rapamycin ◽  
Organ Transplant ◽  
Immunosuppressive Agent ◽  
Current Treatment ◽  
Dose Finding ◽  
Basal Cell Carcinomas ◽  
History Of ◽  
Multiple Basal Cell Carcinomas

Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and has been shown to have antineoplastic activity in addition to its use as an immunosuppressive agent for the prevention of organ transplant rejection. We report the use of everolimus for the compassionate treatment of four elderly, nontransplant patients presenting with multiple basal cell carcinomas (BCC). All patients had a long history of BCC, had refused surgery as a current treatment option, and did not respond to alternative treatments (including topical 5-fluorouracil and imiquimod). Patients were treated with oral everolimus (1.5–3.0 mg daily) for 12 months or longer: a complete and sustained response was seen in one case, and partial responses were seen in two other cases. Everolimus was well tolerated in these elderly patients. These promising preliminary data suggest that further dose-finding, controlled clinical studies are warranted to evaluate the antineoplastic effects of everolimus in patients affected by BCC who cannot or will not undergo surgery.

scholarly journals Effect of oxidized β-carotene-oxygen copolymer compound on health and performance of pre- and post-weaned pigs

2020 ◽  
Author(s):  
La Van Kinh ◽  
William W. Riley ◽  
James G. Nickerson ◽  
Doan Vinh ◽  
Nguyen Van Phu ◽  
...  
Keyword(s):  
Body Weight ◽  
Negative Impact ◽  
Body Weight Gain ◽  
Biologically Active ◽  
Control Group ◽  
Necrotic Enteritis ◽  
Feed Conversion ◽  
Potential Health ◽  
Dose Dependent ◽  
Β Carotene

AbstractThe discovery that a naturally occurring, biologically active β-carotene-oxygen copolymer compound is the main product formed in spontaneously oxidized β-carotene has stimulated interest in its potential health benefits. The copolymer, formed in nature or synthetically by the air-oxidation of β-carotene, possesses beneficial immune modulating activities that previously had been attributed to β-carotene itself. Support for these benefits is provided by previous studies showing that supplementation in feed with low parts-per-million levels of copolymer-rich, fully oxidized β-carotene (OxBC) helped reduce the negative impact of subclinical necrotic enteritis in broilers and improved growth in weaned piglets. To further assess these potential benefits, two trials were conducted in swine raised under commercial conditions in Vietnam. Trial 1, a 140-day full-grow, post-wean study with 500 28-day-old pigs, compared 2, 4 or 8 ppm OxBC against both an unsupplemented and an antibiotic control group. OxBC and antibiotics each improved growth rate, feed efficiency, and body weight compared to the control (P<0.001). Animals receiving 4 and 8 ppm OxBC performed better than did animals on antibiotics (P<0.001). In starter pigs, OxBC reduced the occurrence of diarrhea dose-dependently (4 and 8 ppm) and to a greater extent than did antibiotics (P<0.001). Trial 2, a 49-day study with 420 piglets, was conducted in two-stages. In Stage 1 (pre-wean), OxBC in the transition (creep) feed produced a dose-dependent trend toward increased body weight over 21 days, reaching significance at the highest inclusion level (16 ppm) (P<0.001). In Stage 2 (post-wean), body weight gain showed a dose-dependent trend and was significant for both 8 ppm OxBC and the antibiotics at 28 days post-wean (P<0.001). Feed conversion was better at 8 ppm OxBC and for the antibiotic group (P<0.001). These findings support the concept that β-carotene-oxygen copolymers help optimize immune function, and provide validation for the effectiveness of this strategy in enhancing animal performance in the absence of in-feed antibiotics.

The Effect of Adrenaline Infusions on Blood Coagulation in Normal and Haemophilia B Dogs

1966 ◽  
Vol 15 (03/04) ◽  
pp. 349-364 ◽  
Author(s):  
A.H Özge ◽  
H.C Rowsell ◽  
H.G Downie ◽  
J.F Mustard
Keyword(s):  
Body Weight ◽  
Factor Viii ◽  
Factor Ix ◽  
Clotting Factor ◽  
Blood Ph ◽  
Order Of Magnitude ◽  
Dose Dependent ◽  
Generation Test ◽  
Plasma Activity

SummaryThe addition of trace amounts of adrenaline to whole blood in plasma in vitro increased factor VIII, factor IX and whole plasma activity in the thromboplastin generation test. This was dose dependent.Adrenaline infusions less than 22 (μg/kg body weight in normal dogs accelerated clotting, increased factor IX, factor VIII and whole plasma activity in the thromboplastin generation test and caused a fall in blood pH. In a factor IX deficient dog, there was no increase in factor IX activity. After adrenaline infusions, however, the other changes occurred and were of the same order of magnitude as in the normal. Adrenaline in doses greater than 22 μg/kg body weight did not produce as great an effect on clotting in normal or factor IX deficient dogs. The platelet count in the peripheral blood was increased following the infusion of all doses of adrenaline. These observations suggest that the accelerating effect of adrenaline on clotting is not mediated through increase in activity of a specific clotting factor.

Evaluation of Dexmedetomidine Dosing in Obese Critically Ill Patients

2021 ◽  
pp. 089719002110215
Author(s):  
Sara A. Atyia ◽  
Keaton S. Smetana ◽  
Minh C. Tong ◽  
Molly J. Thompson ◽  
Kari M. Cape ◽  
...  
Keyword(s):  
Body Weight ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Statistical Difference ◽  
Ideal Body Weight ◽  
Weight Percentage ◽  
Before And After ◽  
Light Sedation ◽  
Icu Sedation ◽  
Dose Dependent

Background: Dexmedetomidine is a highly selective α2-adrenoreceptor agonist that produces dose-dependent sedation, anxiolysis, and analgesia without respiratory depression. Due to these ideal sedative properties, there has been increased interest in utilizing dexmedetomidine as a first-line sedative for critically ill patients requiring light sedation. Objective: To evaluate the ability to achieve goal intensive care unit (ICU) sedation before and after an institutional change of dosing from actual (ABW) to adjusted (AdjBW) body weight in obese patients on dexmedetomidine. Methods: This study included patients ≥ 18 years old, admitted to a surgical or medical ICU, required dexmedetomidine for at least 8 hours as a single continuous infusion sedative, and weighed ≥ 120% of ideal body weight. Percentage of RASS measurements within goal range (−1 to +1) during the first 48 hours after initiation of dexmedetomidine as the sole sedative agent or until discontinuation dosed on ABW compared to AdjBW was evaluated. Results: 100 patients were included in the ABW cohort and 100 in the AdjBW cohort. The median dosing weight was significantly higher in the ABW group (95.9 [78.9-119.5] vs 82.2 [72.1-89.8] kg; p = 0.001). There was no statistical difference in percent of RASS measurements in goal range (61.5% vs 69.6%, p = 0.267) in patients that received dexmedetomidine dosed based on ABW versus AdjBW. Conclusion: Dosing dexmedetomidine using AdjBW in obese critically ill patients for ongoing ICU sedation resulted in no statistical difference in the percent of RASS measurements within goal when compared to ABW dosing. Further studies are warranted.

scholarly journals Antidiabetic and antiulcerative potential of Garcinia lanceifolia Roxb. bark

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Nilutpal Sharma Bora ◽  
Partha Sarathi Bairy ◽  
Abdus Salam ◽  
Bibhuti Bhusan Kakoti
Keyword(s):  
Body Weight ◽  
Serum Levels ◽  
Northeast India ◽  
Scientific Data ◽  
Antidiabetic Activity ◽  
Histological Evaluation ◽  
Albino Rats ◽  
Antiulcer Activity ◽  
Dose Dependent

Abstract Background Garcinia lanceifolia Roxb. has been used by many ethnic communities of Northeast India to mitigate various disorders like dyspepsia, ulcers, diabetes, etc. However, a robust scientific study on its antidiabetic and antiulcer potential is unavailable till date. The aim of this present study is to scientifically validate if the antidiabetic and antiulcer effects reported by the ethnic tribes of Assam has any scientific value or not. The effects were tested in adult Wistar albino rats using approved animal models for preclinical testing of pharmacological activities. Results The hydroalcoholic extract of the bark of Garcinia lanceifolia Roxb. was prepared and its LD50 was calculated. The LD50 was determined to be greater than 5000 mg/kg body weight. The extract at doses of 250 mg/kg body weight and 500 mg/kg body weight was found to exhibit a very potent dose-dependent antidiabetic activity. The results were backed by a battery of test including analysis of serum levels of blood glucose, lipid profiles, in vivo antioxidant enzymes, and histopathological studies. Evidence of dose-dependent antiulcer activity of the extract was backed by robust scientific data. It was found that HAEGL induced a significant dose-dependent increase in the ulcer index in both alcohol-induced and acetic acid-induced ulcer models, which was evident from the macroscopic observation of the inner lining of the gastric mucosa and the histological evaluation of the extracted stomach. Conclusion The results suggested that the bark of Garcinia lanceifolia (Roxb.) has significant antidiabetic and antiulcer potential. Further studies with respect to the development herbal dosage forms and its safety evaluation are required.

Increased Urinary Excretion of Carnitine and Acylcarnitine by Mercuric Chloride Is Reversed by 2,3-Dimercapto-1-Propanesulfonic Acid in Rats

2010 ◽  
Vol 29 (3) ◽  
pp. 313-317
Author(s):  
Waleed A. Al-Madani ◽  
Nikhat J. Siddiqi ◽  
Abdullah S. Alhomida ◽  
Haseeb A. Khan ◽  
Ibrahim A. Arif ◽  
...  
Keyword(s):  
Body Weight ◽  
Urinary Excretion ◽  
Mercuric Chloride ◽  
Free Carnitine ◽  
Male Rats ◽  
Significant Protection ◽  
Total Carnitine ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Wistar Male Rats

This investigation was aimed to study the effect of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on mercuric chloride (HgCl2)-induced alterations in urinary excretion of various carnitine fractions including free carnitine (FC), acylcarnitine (AC), and total carnitine (TC). Different groups of Wistar male rats were treated with HgCl2 at the doses of 0.1, 0.5, 1.0, 2.0, and 3.0 mg/kg body weight, and the animals were sacrificed at 24 hours following HgCl2 injection. A separate batch of animals received HgCl2 (2 mg/kg) with or without DMPS (100 mg/kg) and sacrificed at 24 or 48 hours after dosing. Administration of HgCl2 resulted in statistically significant and dose-dependent increase in the urinary excretion of FC, AC, and TC in rats. However, the ratio of urinary AC:FC was significantly decreased by HgCl2. Pretreatment with DMPS offered statistically significant protection against HgCl2-induced alterations in various urinary carnitine fractions in rats.

scholarly journals Impact of Experimentally Induced Cognitive Dietary Restraint on Eating Behavior Traits, Appetite Sensations, and Markers of Stress during Energy Restriction in Overweight/Obese Women

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Isabelle Morin ◽  
Catherine Bégin ◽  
Julie Maltais-Giguère ◽  
Alexandra Bédard ◽  
André Tchernof ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Eating Behavior ◽  
Perceived Stress ◽  
Negative Impact ◽  
Dietary Restraint ◽  
Premenopausal Women ◽  
Energy Restriction ◽  
Obese Women ◽  
Experimentally Induced

Weight loss has been associated with changes in eating behaviors and appetite sensations that favor a regain in body weight. Since traditional weight loss approaches emphasize the importance of increasing cognitive dietary restraint (CDR) to achieve negative energy imbalance, it is difficult to untangle the respective contributions of energy restriction and increases in CDR on factors that can eventually lead to body weight regain. The present study aimed at comparing the effects of energy restriction alone or in combination with experimentally induced CDR on eating behavior traits, appetite sensations, and markers of stress in overweight and obese women. We hypothesized that the combination of energy restriction and induced CDR would lead to more prevalent food cravings, increased appetite sensations, and higher cortisol concentrations than when energy restriction is not coupled with induced CDR. A total of 60 premenopausal women (mean BMI: 32.0 kg/m2; mean age: 39.4 y) were provided with a low energy density diet corresponding to 85% of their energy needs during a 4-week fully controlled period. At the same time, women were randomized to either a condition inducing an increase in CDR (CDR+ group) or a condition in which CDR was not induced (CRD− group). Eating behavior traits (Three-Factor Eating Questionnaire and Food Craving Questionnaire), appetite sensations (after standardized breakfast), and markers of stress (Perceived Stress Scale; postawakening salivary cortisol) were measured before (T = 0 week) and after (T = 4 weeks) the 4-week energy restriction, as well as 3 months later. There was an increase in CDR in the CDR+ group while no such change was observed in the CDR− group (p=0.0037). No between-group differences were observed for disinhibition, hunger, cravings, appetite sensations, perceived stress, and cortisol concentrations. These results suggest that a slight increase in CDR has no negative impact on factors regulating energy balance in the context of energy restriction.

Intravenous Infusion in Dogs and Primates

1994 ◽  
Vol 13 (1) ◽  
pp. 40-47 ◽  
Author(s):  
C.J. Perkin ◽  
R. Stejskal
Keyword(s):  
Body Weight ◽  
Intravenous Infusion ◽  
Body Weight Gain ◽  
Femoral Vein ◽  
Blood Pressure Measurement ◽  
Recovery Period ◽  
Vena Cava ◽  
Test Material ◽  
Catheter Tip ◽  
Inflammatory Changes

Continuous intravenous infusion allows the intended clinical dosing regime to be better evaluated during preclinical studies. Depending on the test material and vehicle, infusion for up to 6 months in primates and 12 months in beagle dogs is possible, but 28 days is the most frequent duration. Under general anesthesia, medical grade catheters are placed in the vena cava via the femoral vein, passed subcutaneously, and exteriorized between the scapulae. A jacket and tether system are used to connect the catheter to an external pump for dosing and the animals are allowed to move freely within the cages. Dosing usually commences after a 1-week recovery period. Body weight gain, food intake, and general observations indicate that the procedure does not adversely affect the normal laboratory behavior of the animals. Test article infusion periods from a few minutes up to 24 h a day, 7 days a week are used; a low infusion rate ofsaline is used for the balance of the 24-h period. Dosage volumes up to 120 ml/kg/day can be infused for 28 days and larger volumes for shorter periods. Up to three separate catheters can be inserted to allow coadministration of compounds for assessment of potential interactions. Body weight, ophthalmoscopy, blood sampling, electrocardiography, and indirect blood pressure measurement can be performed during infusion. Histopathologic common changes in all species include thrombosis, proliferation of vascular intima, and various local inflammatory changes at the infusion site in the vicinity of the catheter tip. These generally are considered to be due to physical irritation by the catheter. Secondary changes include pulmonary microemboli or thrombosis and histiocytosis in hepatic sinusoids often with erythrophago-cytosis. The main findings associated with infusion of very large volumes are reticulocytosis and increased hematopoiesis. These spontaneous findings must be distinguished from those possibly related to administration of the test material and/or vehicle.

scholarly journals The impact of COVID-19 quarantine on dietary habits and physical activity in Saudi Arabia: a cross-sectional study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Manar Abduljalil Bakhsh ◽  
Jomana Khawandanah ◽  
Rouba Khalil Naaman ◽  
Shoug Alashmali
Keyword(s):  
Physical Activity ◽  
Body Weight ◽  
Weight Gain ◽  
Dietary Habits ◽  
Negative Impact ◽  
Adult Population ◽  
Cross Sectional Study ◽  
Future Health ◽  
Cross Sectional ◽  
The Impact

Abstract Background The COVID-19 pandemic has forced governments around the world to impose strict hygiene and national lockdown measures, which in turn has changed the dietary and lifestyle habits of the world’s population. Thus, the aim of this study is to evaluate whether dietary and physical activity behaviors of Saudi Arabia’s adult population changed during the COVID-19 quarantine. Methods An electronic questionnaire which assessed changes in body weight, dietary habits, and physical activity of Saudi Arabia’s adult population (n = 2255) during the COVID-19 quarantine was distributed on social media between June and July 2020. To test the differences between changes in dietary and physical activity behaviors in relation to changes in body weight a Chi-square test was used. Results Over 40 and 45% of participants reported eating and snacking more, respectively, which led to weight gain in around 28%. Most participants reported that they consumed home-cooked (73%) and healthy meals (47%), while only 7% reported that they consumed foods from restaurants. Feelings of boredom and emptiness (44%) and the availability of time for preparing meals (40%) were the main reasons for changing dietary habits. Honey (43%) and vitamin C (50%) were the most consumed immune-boosting food and dietary supplement, respectively. COVID-19 also had a negative impact on physical activity, lowering the practice in 52% subjects, which was associated with significant weight gain (p < 0.001). Conclusion Assessing the changes to the population’s dietary habits and physical activity during the lockdown will help predict the outcome of the population’s future health and wellbeing after the pandemic.

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