Interferon-ß Decreases the Hypermetabolic State of Red Blood Cells from Patients with Multiple Sclerosis.

Multiple sclerosis (MS) is an inflammatory disease characterized by damage to the myelin sheath surrounding axons in the central nervous system. While the exact mechanism of this destruction is unknown, excess nitric oxide (NO) and adenosine triphosphate (ATP) have been measured in tissues and fluids obtained from people with MS. Here, incubation of interferon-beta (IFN-ß), an MS drug with an unknown mechanism of action, with red blood cells (RBCs) obtained from people with MS provide evidence of a potential hypermetabolic state in the MS RBC that is decreased with IFN-ß intervention. Specifically, binding of all three components of an albumin/C-peptide/Zn2+ complex to MS RBCs was significantly increased in comparison to control RBCs. For example, the binding of C-peptide to MS RBCs was significantly increased (3.4 ± 0.1 nM) compared to control RBCs (1.6 ± 0.2 nM). However, C-peptide binding to MS RBCs was reduced to a value (1.6 ± 0.3 nM) statistically equal to that of control RBCs in the presence of 2 nM IFN-ß. Similar trends were measured for albumin and Zn2+ binding to RBCs when in the presence of IFN-ß. RBC function was also affected by incubation of cells with IFN-ß. Specifically, RBC-derived ATP and measurable membrane GLUT1 were both significantly decreased (56 and 24%, respectively) in the presence of IFN-ß. Collectively, our results suggest that IFN-ß inhibits albumin binding to the RBC, thereby reducing its ability to deliver ligands such as C-peptide and Zn2+ to the cell and normalizing the basal hypermetabolic state.

A C-peptide complex with albumin and Zn2+ increases measurable GLUT1 levels in membranes of human red blood cells.

People with type 1 diabetes (T1D) require exogenous administration of insulin, which stimulates the translocation of the GLUT4 glucose transporter to cell membranes. However, most bloodstream cells contain GLUT1 and are not directly affected by insulin. Here, we report that C-peptide, the 31-amino acid peptide secreted in equal amounts with insulin in vivo, is part of a 3-component complex that affects red blood cell (RBC) membranes. Multiple techniques were used to demonstrate saturable and specific C-peptide binding to RBCs when delivered as part of a complex with albumin. Importantly, when the complex also included Zn2+, a significant increase in cell membrane GLUT1 was measured, thus providing a cellular effect similar to insulin, but on a transporter on which insulin has no effect.

Technologies for Measuring Pharmacokinetic Profiles.

The creation of a pharmacokinetic (PK) curve, which follows the plasma concentration of an administered drug as a function of time, is a critical aspect of the drug development process and includes such information as the drug's bioavailability, clearance, and elimination half-life. Prior to a drug of interest gaining clearance for use in human clinical trials, research is performed during the preclinical stages to establish drug safety and dosing metrics from data obtained from the PK studies. Both in vivo animal models and in vitro platforms have limitations in predicting human reaction to a drug due to differences in species and associated simplifications, respectively. As a result, in silico experiments using computer simulation have been implemented to accurately predict PK parameters in human studies. This review assesses these three approaches (in vitro, in vivo, and in silico) when establishing PK parameters and evaluates the potential for in silico studies to be the future gold standard of PK preclinical studies.

Flexitempo e psicanálise em tempos virtuais / Flexitime and Psychoanalysis in Virtual Time

A vida é urgente no século XXI. As avançadas tecnologias da comunicação são uma realidade contundente. Freud tem paixão pela verdade e fé inabalável na razão. O homem pode se tornar aquilo o que é em sua verdade, em sua potencialidade. O homem tanto pode conhecer sua realidade externa, o mundo atual, quanto compreender sua realidade interna com intuito de vir a ser completamente humano. Na consciência o simbólico é expresso como linguagem, brotando da necessidade, da exigência do intercâmbio com outros homens. A psicanálise é um percurso que se debruça no tempo, que expõe bem as mudanças trazidas na modernidade. A tomada de consciência é uma possibilidade nova, que se repete em cada ato humano e ciência. Na contramão do tempo tudo ficou mais flexível: flexitempo e acting out. Como está o tempo das pessoas?(AU)

Life is urgent. The advanced technologies of communication are an overwhelming reality. Freud has passion for the truth an unwavering faith on reasoning. People can become what they are in their effectiveness, in their potential. They can both know their external reality, today’s world, and understand their inner reality with the purpose of becoming completely human. In the consciousness, what is symbolic expresses itself as language, coming from the necessity and the demanding of exchange with other people. Psychoanalysis is a journey that looks over the time, which shows very well the changes brought from modernity. Becoming conscious is a new possibility, repeated in each human act or science. In the wrong direction of the time, everything became more flexible: flexitime and acting out. How is people’s time?(AU)

Temperature and precipitation projections over Bangladesh and the upstream Ganges, Brahmaputra and Meghna systems.

South Asia is a region of complex atmospheric dynamics and therefore changes resulting from increasing greenhouse gas concentrations, combined with existing vulnerability to extreme weather events such as flooding, could put the region at particular risk from climate change. However, current climate projections for the region show a range of uncertainty, particularly in terms of changes in the variability and extremes of precipitation. Focusing on Bangladesh and the region encompassing parts of the Ganges, Brahmaputra and Meghna river basins, we aim to explore and quantify climate model uncertainty in climate change projections for the 21(st) century. We use results from a 17-member perturbed physics ensemble of projections from a global climate model which have been used to drive a higher resolution (25 km) regional climate model over the south Asia region from 1971 to 2099. The range of temperature and precipitation responses across the ensemble are assessed including representation of the annual cycle, trends, and changes in precipitation extremes. The 17 ensemble members consistently simulate increasing annual mean temperatures by 2100 compared with present day, ranging between 2.6 °C and 4.8 °C. Additionally, all ensemble members indicate increasing annual precipitation by 2100 of between around 8% and 28%, though with interdecadal variability which results in one ensemble member showing a slight decrease in precipitation in the mid-century period. The frequency of light precipitation events is projected to decrease in the future, but with an increase in the frequency of heavy events. Three members of the climate model ensemble, representing a range of projected climate outcomes, have been selected for use in further impacts modelling for the region.

Physiologically Based Pharmacokinetic (PBPK) Modeling of Metabolic Pathways of Bromochloromethane in Rats.

Bromochloromethane (BCM) is a volatile compound and a by-product of disinfection of water by chlorination. Physiologically based pharmacokinetic (PBPK) models are used in risk assessment applications. An updated PBPK model for BCM is generated and applied to hypotheses testing calibrated using vapor uptake data. The two different metabolic hypotheses examined are (1) a two-pathway model using both CYP2E1 and glutathione transferase enzymes and (2) a two-binding site model where metabolism can occur on one enzyme, CYP2E1. Our computer simulations show that both hypotheses describe the experimental data in a similar manner. The two pathway results were comparable to previously reported values (V(max⁡) = 3.8 mg/hour, K(m) = 0.35 mg/liter, and k(GST) = 4.7 /hour). The two binding site results were V(max⁡(1) ) = 3.7 mg/hour, K(m⁡(1) ) = 0.3 mg/hour, CL(2) = 0.047 liter/hour. In addition, we explore the sensitivity of different parameters for each model using our obtained optimized values.

Evaluation of the therapeutic and protective efficacy of doramectin against psoroptic scabies in cattle.

Three studies were conducted to evaluate the therapeutic and protective efficacy of doramectin when given by injection at a dose of 200 micrograms/kg against induced Psoroptes otis infestations of cattle. The first study investigated therapeutic efficacy. Mite infestations were established on 15 test animals held in stanchions by transfer of material from infested donor calves. Test animals were then allotted on the basis of mite counts to a treatment group (10 animals) which received doramectin and a control group (5 animals) which received saline. Skin scrapings were collected for mite counts on the day before treatment and on days 7, 14, 21 and 28 after treatment. Efficacy assessed on the basis of the proportion of animals cured by day 28 was 100%. The second study was designed to determine the duration of protective efficacy. Forty-eight scabies-free heifers were allotted to a treated group of 32 which received doramectin, and a control group of 16 which remained untreated. These treatment groups were each divided into eight subgroups. Commencing on treatment day and continuing at weekly intervals for 7 weeks, a subgroup of animals from each treatment was placed in stanchions and challenged by transfer of material from infested donor calves. Skin scrapings for mite counts were collected 7 and 14 days later. Infestations were successfully established on all untreated control calves. Doramectin prevented the establishment of infestation for three weeks and significantly (P < 0.05) reduced infestation levels for an additional two weeks. The third study established the duration of residual protection conferred by doramectin and ivermectin under contact transmission. Ninety-six scabies-free heifers were divided into two equal treatment groups. Animals in one group received doramectin and animals in the other group received ivermectin at its recommended dose of 200 micrograms/kg by subcutaneous injection. Each treatment group was then divided into eight subgroups of six animals. Commencing on treatment day and continuing at weekly intervals for 7 weeks a subgroup of animals from each treatment was exposed to purposely infested seeder animals for one week. Three animals from each treatment subgroup were then placed in individual stanchions in which grooming was prevented and the other three were placed together in a pen where normal grooming behavior was permitted. Skin scrapings for mite counts were collected at weekly intervals for up to 4 weeks. Doramectin provided complete protection against infestation for five weeks compared to four weeks for ivermectin. These periods were not influenced by grooming behavior.