scholarly journals The fallacy of ratio correction to address confounding factors

2012 ◽  
Vol 46 (3) ◽  
pp. 245-252 ◽  
Author(s):  
Natasha A Karp ◽  
Anne Segonds-Pichon ◽  
Anna-Karin B Gerdin ◽  
Ramiro Ramírez-Solis ◽  
Jacqueline K White
Keyword(s):  
Body Weight ◽  
Gene Knockout ◽  
Weight Ratio ◽  
The Body ◽  
Analysis Of Covariance ◽  
Biological Research ◽  
Confounding Factors ◽  
Weight Changes ◽  
Ratio Correction

Scientists aspire to measure cause and effect. Unfortunately confounding variables, ones that are associated with both the probable cause and the outcome, can lead to an association that is true but potentially misleading. For example, altered body weight is often observed in a gene knockout; however, many other variables, such as lean mass, will also change as the body weight changes. This leaves the researcher asking whether the change in that variable is expected for that change in weight. Ratio correction, which is often referred to as normalization, is a method used commonly to remove the effect of a confounding variable. Although ratio correction is used widely in biological research, it is not the method recommended in the statistical literature to address confounding factors; instead regression methods such as the analysis of covariance (ANCOVA) are proposed. This method examines the difference in means after adjusting for the confounding relationship. Using real data, this manuscript demonstrates how the ratio correction approach is flawed and can result in erroneous calls of significance leading to inappropriate biological conclusions. This arises as some of the underlying assumptions are not met. The manuscript goes on to demonstrate that researchers should use ANCOVA, and discusses how graphical tools can be used readily to judge the robustness of this method. This study is therefore a clear example of why assumption testing is an important component of a study and thus why it is included in the Animal Research: Reporting of In Vivo Experiment (ARRIVE) guidelines.

scholarly journals Determining organ weight toxicity with Bayesian causal models: Improving on the analysis of relative organ weights

2019 ◽  
Author(s):  
Stanley E. Lazic ◽  
Elizaveta Semenova ◽  
Dominic P. Williams
Keyword(s):  
Body Weight ◽  
Multiple Testing ◽  
Weight Ratio ◽  
Organ Damage ◽  
Organ Weight ◽  
Analysis Of Covariance ◽  
Toxicity Tests ◽  
Weight Changes ◽  
Organ Weights ◽  
Chemically Induced

AbstractRegulatory authorities require animal toxicity tests for new chemical entities. Organ weight changes are accepted as a sensitive indicator of chemically induced organ damage, but can be difficult to interpret because changes in organ weight might reflect chemically-induced changes in overall body weight. A common solution is to calculate the relative organ weight (organ to body weight ratio), but this inadequately controls for the dependence on body weight – a point made by statisticians for decades, but which has not been widely adopted. The recommended solution is an analysis of covariance (ANCOVA), but it is rarely used, possibly because both the method of statistical correction and the interpretation of the output may be unclear to those with minimal statistical training. Using relative organ weights can easily lead to incorrect conclusions, resulting in poor decisions, wasted resources, and an ethically questionable use of animals. We propose to cast the problem into a causal modelling framework as it directly assesses questions of scientific interest, the results are easy to interpret, and the analysis is simple to perform with freely available software. Furthermore, by taking a Bayesian approach we can model unequal variances, control for multiple testing, and directly provide evidence of safety.

scholarly journals Clinical and in Vivo Response Following Surgery or Surgery Plus Adjuvant Chemotherapy or Immunotherapy for Colorectal Carcinoma in a Rat Model

1983 ◽  
Vol 76 (10) ◽  
pp. 833-840 ◽  
Author(s):  
A K House ◽  
M A L Maley
Keyword(s):  
Body Weight ◽  
Adjuvant Chemotherapy ◽  
Surgical Excision ◽  
The Body ◽  
Recurrent Tumour ◽  
Mesenteric Node ◽  
And Control ◽  
Tumour Weight

Two cohorts of rats, 240 with colon cancer and 150 controls, were assessed clinically and immunologically for their response to tumour and its management which was either by surgical excision alone or by surgical excision combined with either adjuvant chemotherapy or immunotherapy. The histology and invasion characteristics were observed for similarity with those of human lesions. Metastases were found in liver, lymph nodes, the peritoneum or lungs in 27% of animals during follow up. Significantly fewer adjuvant-treated rats had metastases than those receiving surgery alone ( P < 0.05), and less total tumour weight was found in the adjuvant-treated rats at four ( P < 0.03) and six ( P < 0.001) weeks postoperatively. Animals in the adjuvant immunotherapy group survived longer than in either other group ( P < 0.001). The crude parameters of host response to tumour, body, spleen and mesenteric lymph node weight were recorded and the latter two indexed to body weight. The body weight of tumour and control rats increased significantly with time ( P < 0.04). The spleen and mesenteric node indices were significantly ( P < 0.04) greater in tumour than control rats and were varied by recurrent tumour growth and by the adjuvant treatment administered postoperatively.

A study on the safety evaluation of buphrenorphine administered through an autoinjector compared with manual injection using haematological and biochemical variables in rats

2016 ◽  
Vol 36 (9) ◽  
pp. 901-909 ◽  
Author(s):  
D Sheela ◽  
R Vijayaraghavan ◽  
S Senthilkumar
Keyword(s):  
Body Weight ◽  
Research Work ◽  
Safety Evaluation ◽  
Weight Ratio ◽  
The Body ◽  
Control Group ◽  
Body Weight Ratio ◽  
Significant Difference ◽  
Manual Group ◽  
Significant Change

Buprenorphine drug cartridge was made for autoinjector device for use in emergency and critical situations to reduce the morbidity and mortality. Water-filled cartridges were prepared and buprenorphine was injected aseptically in the cartridge, to make 0.05 and 0.10 mg/mL. Rats were injected intraperitoneally, buprenorphine (0.3 and 0.6 mg/kg), repeatedly with the autoinjector and compared with manual injection (7 days and 14 days) using various haematological and biochemical parameters. No significant change was observed in the body weight, organ to body weight ratio and haematological variables in any of the experimental groups compared with the control group. Except serum urea and aspartate aminotransferase, no significant change was observed in glucose, cholesterol, triglycerides, bilirubin, protein, albumin, creatinine, uric acid, alanine aminotransferase, gamma glutamyltransferase and alkaline phosphatase. The autoinjectors deliver the drugs with spray effect and force for faster absorption. In the present study, the autoinjector meant for intramuscular injection was injected intraperitoneally in rats, and the drug was delivered with force on the vital organs. No significant difference was observed in the autoinjector group compared to the manual group showing tolerability and safety of the buphrenorphine autoinjector. This study shows that buprenorphine autoinjector can be considered for further research work.

Azole-resistant and -susceptible Aspergillus fumigatus isolates show comparable fitness and azole treatment outcome in immunocompetent mice

2017 ◽  
Vol 56 (6) ◽  
pp. 703-710
Author(s):  
Michaela Lackner ◽  
Günter Rambach ◽  
Emina Jukic ◽  
Bettina Sartori ◽  
Josef Fritz ◽  
...  
Keyword(s):  
Body Weight ◽  
Aspergillus Fumigatus ◽  
Severe Disease ◽  
Weight Ratio ◽  
Clinical Parameters ◽  
Fitness Advantage ◽  
Significant Difference ◽  
Immunocompetent Mice

Abstract No data are available on the in vivo impact of infections with in vitro azole-resistant Aspergillus fumigatus in immunocompetent hosts. Here, the aim was to investigate fungal fitness and treatment response in immunocompetent mice infected with A. fumigatus (parental strain [ps]) and isogenic mutants carrying either the mutation M220K or G54W (cyp51A). The efficacy of itraconazole (ITC) and posaconazole (PSC) was investigated in mice, intravenously challenged either with a single or a combination of ps and mutants (6 × 105 conidia/mouse). Organ fungal burden and clinical parameters were measured. In coinfection models, no fitness advantage was observed for the ps strain when compared to the mutants (M220K and G54W) independent of the presence or absence of azole-treatment. For G54W, M220K, and the ps, no statistically significant difference in ITC and PSC treatment was observed in respect to fungal kidney burden. However, clinical parameters suggest that in particular the azole-resistant strain carrying the mutation G54W caused a more severe disease than the ps strain. Mice infected with G54W showed a significant decline in body weight and lymphocyte counts, while spleen/body weight ratio and granulocyte counts were increased. In immunocompetent mice, in vitro azole-resistance did not translate into therapeutic failure by either ITC or PSC; the immune system appears to play the key role in clearing the infection.

Phytochemical Screening and Anti-Diabetic Efficacy of O. Sanctum Seed Extract on Streptozotocin Induced Diabetic Rats

2017 ◽  
Vol 54 (3) ◽  
pp. 336
Author(s):  
Kavitha K. ◽  
Ponne S.
Keyword(s):  
Body Weight ◽  
Digestive Enzymes ◽  
Fasting Blood Glucose ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Seed Extract ◽  
Phytochemical Screening ◽  
Weight Changes

The present study was designed to assess the in vitro and in vivo anti-diabetic efficacy of <em>O. sanctum</em> seed and its phytochemical screening. In vitro inhibitory effect on carbohydrate digestive enzymes like α-amylase and α-glucosidase and in vivo parameters such as fasting blood glucose and body weight changes were studied, a potent inhibitory effect was observed on activities of digestive enzymes and a marked decrease in the glucose level in the <em>O. sanctum</em> seed extract treated streptozotocin induced diabetic rats was noted. Further a marked reduction in body weight was also observed.

scholarly journals Carboxylated branched poly(β-amino ester) nanoparticles enable robust cytosolic protein delivery and CRISPR-Cas9 gene editing

2019 ◽  
Vol 5 (12) ◽  
pp. eaay3255 ◽  
Author(s):  
Yuan Rui ◽  
David R. Wilson ◽  
John Choi ◽  
Mahita Varanasi ◽  
Katie Sanders ◽  
...  
Keyword(s):  
Protein Delivery ◽  
Gene Editing ◽  
Gene Knockout ◽  
Cell Types ◽  
Endosomal Escape ◽  
Biological Research ◽  
Amino Ester ◽  
Cytosolic Protein

Efficient cytosolic protein delivery is necessary to fully realize the potential of protein therapeutics. Current methods of protein delivery often suffer from low serum tolerance and limited in vivo efficacy. Here, we report the synthesis and validation of a previously unreported class of carboxylated branched poly(β-amino ester)s that can self-assemble into nanoparticles for efficient intracellular delivery of a variety of different proteins. In vitro, nanoparticles enabled rapid cellular uptake, efficient endosomal escape, and functional cytosolic protein release into cells in media containing 10% serum. Moreover, nanoparticles encapsulating CRISPR-Cas9 ribonucleoproteins (RNPs) induced robust levels of gene knock-in (4%) and gene knockout (>75%) in several cell types. A single intracranial administration of nanoparticles delivering a low RNP dose (3.5 pmol) induced robust gene editing in mice bearing engineered orthotopic murine glioma tumors. This self-assembled polymeric nanocarrier system enables a versatile protein delivery and gene editing platform for biological research and therapeutic applications.

Effects of altitude acclimatization on rat myoglobin. Changes in myoglobin content of skeletal and cardiac muscle

1959 ◽  
Vol 196 (3) ◽  
pp. 512-516 ◽  
Author(s):  
Adam Anthony ◽  
Eugene Ackerman ◽  
G. K. Strother
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Cardiac Muscle ◽  
Water Content ◽  
Skeletal Muscles ◽  
The Body ◽  
Continuous Exposure ◽  
Weight Changes ◽  
Body Weight Changes ◽  
Muscle Weight

Analyses were made of myoglobin content of rat skeletal and cardiac muscle following continuous exposure to simulated altitudes of 18,000 feet for a 2–10-week period. About five dozen rats were used. Acclimatization was associated with an increase in the myoglobin concentration of thigh, diaphragm, gastrocnemius and heart muscles. Total myoglobin content, however, increased during acclimatization in cardiac muscle but not in the three skeletal muscles. This finding together with the body weight changes and muscle weight changes suggested that the increases in myoglobin concentration of skeletal muscle may be merely a reflection of a decreased water content of muscles.

scholarly journals Allylmethylsulfide, a Sulfur Compound Derived from Garlic, Attenuates Isoproterenol-Induced Cardiac Hypertrophy in Rats

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Soheb Anwar Mohammed ◽  
Bugga Paramesha ◽  
Yashwant Kumar ◽  
Ubaid Tariq ◽  
Sudheer Kumar Arava ◽  
...  
Keyword(s):  
Body Weight ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Chronic Administration ◽  
The Body ◽  
Heart Weight ◽  
Serum Biochemical ◽  
Enalapril Treatment ◽  
Histopathological Investigation

Allylmethylsulfide (AMS) is a novel sulfur metabolite found in the garlic-fed serum of humans and animals. In the present study, we have observed that AMS is safe on chronic administration and has a potential antihypertrophic effect. Chronic administration of AMS for 30 days did not cause any significant differences in the body weight, electrocardiogram, food intake, serum biochemical parameters, and histopathology of vital organs. Single-dose pharmacokinetics of AMS suggests that AMS is rapidly metabolized into Allylmethylsulfoxide (AMSO) and Allylmethylsulfone (AMSO2). To evaluate the efficacy of AMS, cardiac hypertrophy was induced by subcutaneous implantation of ALZET® osmotic minipump containing isoproterenol (~5 mg/kg/day), cotreated with AMS (25 and 50 mg/kg/day) and enalapril (10 mg/kg/day) for 2 weeks. AMS and enalapril significantly reduced cardiac hypertrophy as studied by the heart weight to body weight ratio and mRNA expression of fetal genes (ANP and β-MHC). We have observed that TBARS, a parameter of lipid peroxidation, was reduced and the antioxidant enzymes (glutathione, catalase, and superoxide dismutase) were improved in the AMS and enalapril-cotreated hypertrophic hearts. The extracellular matrix (ECM) components such as matrix metalloproteinases (MMP2 and MMP9) were significantly upregulated in the diseased hearts; however, with the AMS and enalapril, it was preserved. Similarly, caspases 3, 7, and 9 were upregulated in hypertrophic hearts, and with the AMS and enalapril treatment, they were reduced. Further to corroborate this finding with in vitro data, we have checked the nuclear expression of caspase 3/7 in the H9c2 cells treated with isoproterenol and observed that AMS cotreatment reduced it significantly. Histopathological investigation of myocardium suggests AMS and enalapril treatment reduced fibrosis in hypertrophied hearts. Based on our experimental results, we conclude that AMS, an active metabolite of garlic, could reduce isoproterenol-induced cardiac hypertrophy by reducing oxidative stress, apoptosis, and stabilizing ECM components.

scholarly journals FURTHER STUDIES ON EFFECTS OF TISSUE EXTRACTS ON STAPHYLOCOCCUS AUREUS

1946 ◽  
Vol 84 (3) ◽  
pp. 247-261 ◽  
Author(s):  
Leo G. Nutini ◽  
Sister Eva Maria Lynch
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
The Body ◽  
Brain Extract ◽  
Toxicity Tests ◽  
Control Series ◽  
Experimental Animals ◽  
Tissue Extracts

1. The ability of alcoholic-precipitated extracts of beef tissue—brain, spleen, heart, and kidney—to stimulate the growth of Staphylococcus aureus, in vitro, and to convert the yellow S form to a white R variant with altered biochemical characteristics conforming to those of an avirulent organism, has been confirmed. 2. The avirulence of the white R variant has been established by tests in vivo on mice. 3. Staphylococcus aureus infections induced subcutaneously, intraperitoneally, and intravenously in mice responded favorably to brain extract following subcutaneous or oral administration. The mortality was 2 per cent in 444 experimental animals and 81 per cent in 448 control animals. 4. The extracts appeared equally efficient when used therapeutically (mortality 2 per cent of 162 experimental animals and 90 per cent in the control series) or prophylactically (mortality 2 per cent of 282 experimental animals and 76 per cent in 286 control mice). Extracts of brain and spleen were more effective than those of either heart or kidney. 5. Studies concerning the mechanism of action of the tissue extracts indicate that they prevented the formation of toxin by Staphylococcus aureus, and had but little effect on toxin actions. 6. Toxicity tests revealed that the brain and spleen extracts were relatively non-toxic, dosages equivalent to 2 per cent of the body weight being well tolerated. Kidney and heart extracts were much more toxic, producing mortality in dosages as low as 0.3 per cent of the body weight.

Effective Induction of Apoptosis by Mistletoe Plant Extracts in an Acute Lymphoblastic Leukemia Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1880-1880
Author(s):  
Georg Seifert ◽  
Patrick Jesse ◽  
Aram Prokop ◽  
Tobias Reindl ◽  
Stephan Lobitz ◽  
...  
Keyword(s):  
Cell Death ◽  
Body Weight ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
The Body ◽  
Induction Of Apoptosis ◽  
First Time ◽  
Over Time

Abstract Mistletoe (Viscum album) is one of the most used alternative cancer therapies applied as monotherapy or in combination with conventional therapies. Anti-tumor effects of mistletoe (MT) extracts were related to cytostatic and immunomodulatory effects observed in vitro. Aqueous MT extracts contain the three mistletoe lectins I, II and III as one predominant group of biologically active agents. The MT lectins inhibit protein biosynthesis by inactivating the 60S ribosomal subunit. Mistletoe lectin-I (ML-I) is one important apoptosis inducing compound. It is a heterodimer that consists of a cytotoxic A-chain (ribosome inactivating protein, RIP type 1) linked by a carbohydrate binding B-chain for cellular lectin uptake. However, although MT is widely used, there is a lack of scientific preclinical and clinical data. Here, we describe for the first time efficacy and mechanism of MT extracts against lymphoblastic leukemia in vitro and in vivo. For this purpose, we first investigated both the cytotoxic effect and mechanism of action of two standardized aqueous MT extracts (MT obtained from fir trees (MT-A); MT obtained from pine trees (MT-P)) and isolated ML-I, in three human acute lymphoblastic leukemia (ALL) cell lines (NALM-6, sup-B-15 and REH). MT-A, MT-P and ML-I clearly inhibited cell proliferation as determined by LDH reslease assays at very low concentrations (ML-I LD50 from 0,05 ng/ml to 10 ng/ml depending on the host tree) with MT-P being the most cytotoxic extract. The mechanism of cell death was determined by DNA-fragmentation assays. These indicated dose dependent induction of apoptosis as the main mechanism of cell death. Finally, we evaluated the efficacy of MT-A and MT-P in an in vivo SCID-model of pre-B ALL (NALM-6). For this purpose, mice (n=8/group) were injected i.v. with 1 × 106NALM6 cells and treated by intraperitoneal injections four times per week for 3 weeks (day 1–4; 7–11; 14–18) at varying doses (1, 5 and 50 mg/Kg (plant weight/body weight)). Mice (n=8) treated with PBS and cyclophosphamide (100 mg/kg, once on day 1) were used as negative and positive controls, respectively. Toxicity, peripheral blood counts, bodyweight and survival was determined over time. Interestingly, both MT extracts in all tested concentrations significantly improved survival (up to 55,4 days) in contrast to controls (34,6 days). Furthermore, no hematologic side effects were observed from this treatment as indicated by completely stable blood counts. Also the body weight of treated animals remained stable over time indicating a complete absence of systemic toxicity in the selected dose range. In summary, we demonstrate for the first time efficacy and mechanism of MT extracts against ALL in vitro and in vivo and hereby provide an important base line for the design of clinical trials with these compounds.

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