Introduction: Krabbe disease (KD) is an autosomal recessive disorder caused by mutations in the galactocerebrosidase (GALC) gene resulting in neuro-inflammation and defective myelination in the central and peripheral nervous systems. Most infantile patients present with clinical features before six months of age and die before two years of age. The only treatment available for presymptomatic or mildly affected individuals is hematopoietic stem cell transplantation (HSCT). In the animal models, combining bone marrow transplantation (BMT) with gene therapy has shown the best results in disease outcome. In this study, we examine the outcome of gene therapy alone. Methods: Twitcher (twi) mice used in the study, have a W339X mutation in the GALC gene. Genotype identification of the mice was performed shortly after birth or post-natal day 1 (PND1), using polymerase chain reaction on the toe clips followed by restriction enzyme digestion and electrophoresis. Eight or nine-day-old affected mice were used for gene therapy treatment alone or combined with BMT. While iv injection of 4 × 1013 gc/kg of body weight of viral vector was used originally, different viral titers were also used without BMT to evaluate their outcomes. Results: When the standard viral dose was increased four-and ten-fold (4X and 10X) without BMT, the lifespans were increased significantly. Without BMT the affected mice were fertile, had the same weight and appearance as wild type mice and had normal strength and gait. The brains showed no staining for CD68, a marker for activated microglia/macrophages, and less astrogliosis than untreated twi mice. Conclusion: Our results demonstrate that, it may be possible to treat human KD patients with high dose AAVrh10 without blood stem cell transplantation which would eliminate the side effects of HSCT.

Introduction: Krabbe disease (KD) is an autosomal recessive lysosomal disorder caused by mutations in the galactocerebrosidase (GALC) gene. This results in defective myelination in the peripheral and central nervous systems due to low GALC activity. Treatment at this time is limited to hematopoietic stem cell transplantation (HSCT) in pre-symptomatic individuals. While this treatment extends the lives of treated individuals, most have difficulty walking by the end of the first decade due to peripheral neuropathy. Studies in the murine model of KD, Twitcher (twi) combining bone marrow transplantation (BMT) with AAVrh10-mGALC showed a great extension of life from 40 days to about 400 days, with some living a full life time. Methods: In order to find the optimum conditions for dosing and timing of this combined treatment, twi mice were injected with five doses of AAVrh10-mGALC at different times after BMT. Survival, as well as GALC expression were monitored along with studies of sciatic nerve myelination and possible liver pathology. Results: Dosing had a pronounced effect on survival and measured GALC activity. There was window of time after BMT to inject the viral vector and see similar results, however delaying both the BMT and the viral injection shortened the lifespans of the treated mice. Lowering the viral dose too much decreased the correction of the sciatic nerve myelination. There was no evidence for hepatic neoplasia. Conclusion: These studies provide the conditions optimum for successfully treating the murine model of KD. There is some flexibility in dosing and timing to obtain a satisfactory outcome. These studies are critical to the planning of a human trial combining the “ standard of care” , HSCT, with a single iv injection of AAVrh10-GALC.

Introduction: Cefixime is an antimicrobial agent which is prescribed by many physicians. This drug has widespread reaction against various pathogens, especially gram-negative organisms. Regarding the side effects of some of these antibiotics on rat reproductive system, the aim of this study is to determine the effects of Cefixime on pituitary-gonadal hormones, gonadotropins and the morphology of adult male mice.Materials and Methods: Eighteen male mice (ages: 12-16 weeks; weight: 35±5 grms). were divided to three groups, including control, sham and experience. The experience group received Cefixime (0.5 grm/kg) during 10 days while the sham group received Solvent Dimethyl Solfoxide (DMSO) (7 c.c/kg). At the end of the study, titre of hormones was measured by ratio using Immuno Assay (RIA) methods. The morphological criteria of testis (volume, length, weight) were measured, too.Results: The difference of FSH hormones between the control and experience groups was significant (P<0.05). Also, DHEA hormone differences between sham & experience groups was significant (P<0.05). No significant differences were found between the groups of study in testis morphological assays and testostron.Conclusion: Regarding physiological role of sertoli cells during spermatogenesis, reduction of FSH hormone may effect on sperm production and reproductive potentials of male mice. Significant reduction of DHEA hormone between sham and experience groups may be due to probable mistakes or the effects of Solvent drugs, DMSO.

Requiring accurate, complete and reliable data is the first step in climate studies. Incomplete data challenges climate analysis. Missing (incomplete) data is often found in meteorology. Therefore, completing the data (imputation) is the primary need for analysis. There are several ways to imputation missing data that vary depending on the data type and climatic characteristics of each region. Precipitation and temperature are the most important variables of meteorology and climatology. The length of the statistical period plays a pivotal role in the accurate analysis of these variables. The monthly temperature of three cities in Iran, including Mashhad, Bushehr and Jask, has been available in a book called World Weather Records since about 1890. This information contains missing data, especially during World War II (1941-1949). This missing data is more visible. The purpose of this study is to increase the accuracy of estimating these missing data by introducing the applied mice method and providing a complete series of monthly temperatures over 130 years. Stations from neighboring countries were selected as independent (predictor) stations in the patterns. First, the missing monthly temperature data of these three stations were estimated by fitting regression patterns (RMSE of 0. 71 to 0. 94 ο, C). The classical regression method requires the study of basic hypotheses and pattern pathology. These patterns were also estimated by the mice method (RMSE of 0. 39 to 0. 82 ο, C). The results of the study and implementation of this package in Rstudio show the superiority of this method. This method is designed for missing data, does not have regression problems, and has many capabilities. Therefore, it is recommended to estimate missing meteorological data.

Aim:  Physical activity is one of the most effective ways to improve cardiovascular function. The present study was performed to evaluate cardiovascular responses following high-intensity interval exercise (HIIE) and moderate-intensity continuous exercise (mice) in inactive obese men. Methods:  In the present semi-experimental study, eight inactive obese men (age: 22.5 2 2.5 years, body mass index: 31.5 ± 1.5 kg / m2) using a randomized crossover design, participated in three HIIE, mice and control interventions.  Blood samples were taken before, immediately and one hour after exercise to measure nitric oxide (NO) concentration. Also, heart rate and blood pressure were measured before, immediately and every 15 minutes for one hour after exercises.  Results:  No significant changes in hemodynamic factors and NO were observed in the control group. However, after HIIE and mice protocols, a significant decrease (p <0.05) in systolic blood pressure (SBP) was observed compared to baseline conditions, which this phenomenon has persisted for a long time following HIIE. Heart rate and NO increased significantly after both protocols (p <0.05), with the increase in NO following HIIE persisting for longer. Conclusion: It seems that training intensity can be an influential factor in the development of PEH. Also, due to the longer increase in NO caused by HIIE compared to mice, it can be considered that longer PEH after HIIE is probably related to the mechanism of NO-induced vasodilation.

Objectives: This study was designed to investigate the correlation between thermodynamic parameters, ideal solubility and some pharmacokinetic parameters of the compounds.Methods: For thermodynamics analysis, 5 mg of pure drug was weighed in a aluminum pan. Thermodynamic parameters were used for determination of ideal solubility. Correlation between ideal solubility and physicochemical and pharmacokinetic parameters was investigated.Results: The results indicated that there is a linear correlation between ideal solubility and permeability with R=0.8. There are also meaningful correlation between ideal solubility and other physicochemical and pharmacokinetic parameters.Conclusion: This investigation revealed that the ideal solubility could be an appropriate parameter for prediction of drugs pharmacokinetics.