New Therapeutic Interventions (new + therapeutic_intervention)

Distribution by Scientific Domains

Selected Abstracts

A review of current large-scale mouse knockout efforts

Chunmei Guan
Abstract After the successful completion of the human genome project (HGP), biological research in the postgenome era urgently needs an efficient approach for functional analysis of genes. Utilization of knockout mouse models has been powerful for elucidating the function of genes as well as finding new therapeutic interventions for human diseases. Gene trapping and gene targeting are two independent techniques for making knockout mice from embryonic stem (ES) cells. Gene trapping is high-throughput, random, and sequence-tagged while gene targeting enables the knockout of specific genes. It has been about 20 years since the first gene targeting and gene trapping mice were generated. In recent years, new tools have emerged for both gene targeting and gene trapping, and organizations have been formed to knock out genes in the mouse genome using either of the two methods. The knockout mouse project (KOMP) and the international gene trap consortium (IGTC) were initiated to create convenient resources for scientific research worldwide and knock out all the mouse genes. Organizers of KOMP regard it as important as the HGP. Gene targeting methods have changed from conventional gene targeting to high-throughput conditional gene targeting. The combined advantages of trapping and targeting elements are improving the gene trapping spectrum and gene targeting efficiency. As a newly-developed insertional mutation system, transposons have some advantages over retrovirus in trapping genes. Emergence of the international knockout mouse consortium (IKMP) is the beginning of a global collaboration to systematically knock out all the genes in the mouse genome for functional genomic research. genesis 48:73,85, 2010. 2010 Wiley-Liss, Inc. [source]

Optimal treatment of hypertension in the elderly: A Korean perspective

Kwang-Il Kim
With the progression of the aging population, common diseases of the elderly have become the center of attention in most developed countries. Hypertension is one of the most common morbid conditions in the elderly and has a great impact on their health status because it is the main risk factor of cardiovascular and cerebrovascular diseases. However, a considerable amount of uncertainty remains regarding hypertension in the elderly, such as the benefits of hypertension control in oldest-old populations, the optimal level of blood pressure control, and the efficacy of antihypertensive drugs for the prevention of cognitive dysfunction. While there are many controversial issues concerning the optimal management of hypertension in the elderly, the number of elderly hypertensive patients that require treatment is expected to increase due to the aging population. As a result, knowledge regarding the mechanisms of hypertension in the elderly and specific consideration in managing hypertensive elderly patients are needed to improve the clinical outcome. Furthermore, new therapeutic interventions that are aimed at attenuating age-related vascular changes should be investigated, because hypertension in the elderly, especially isolated systolic hypertension has specific characteristics of increased arterial stiffness in most cases. [source]

Antiretroviral effects on HIV-1 RNA, CD4 cell count and progression to AIDS or death: a meta-regression analysis

HIV MEDICINE, Issue 10 2008
EJ Mills
Objective Governments, clinicians and drug-licensing bodies have adopted changes in CD4 cell counts and HIV-1 RNA levels as evidence of effectiveness for new therapeutic interventions. We aimed to determine the strength of the association between the magnitude of the effect of changes in CD4 cell count and HIV-1 RNA and progression to AIDS or death in the highly active antiretroviral therapy (HAART) era. Methods We identified all randomized clinical trials (RCTs) evaluating the effect of HAART on both clinical and surrogate endpoints (1994 to September 2006). We performed a meta-regression and weighted linear regression. We additionally estimated potential RCT sample sizes that would be required to assess the effectiveness of new interventions in terms of clinical endpoints. Results We included data from 178 RCTs. We were unable to demonstrate a strong relationship at any time-point. Specifically, this was the case when CD4 T-cell change and clinical outcomes were examined at week 24 [coefficient ,0.01, 95% confidence interval (CI) ,0.03 to 0.001, P=0.54], week 48 (coefficient ,0.01, 95% CI ,0.02 to 0.001, P=0.83) and week 96 (coefficient 0.00, 95% CI ,0.03 to 0.04, P=0.76). This was also the case when viral load was examined as a surrogate marker. Given the small number of clinical events occurring in new interventional RCTs, any RCT aiming to evaluate clinical endpoints within these time-points would require an exceptionally large sample size. Conclusions Our findings indicate that, within short-term clinical trial settings, it is not possible to estimate the proportion of treatment effect associated with surrogate endpoints. [source]

QTL Analysis of Trabecular Bone in BXD F2 and RI Mice,

Abbey L Bower
Abstract A sample of 693 mice was used to identify regions of the mouse genome associated with trabecular bone architecture as measured using ,CT. QTLs for bone in the proximal tibial metaphysis were identified on several chromosomes indicating regions containing genes that regulate properties of trabecular bone. Introduction: Age-related osteoporosis is a condition of major concern because of the morbidity and mortality associated with osteoporotic fractures in humans. Osteoporosis is characterized by reduced bone density, strength, and altered trabecular architecture, all of which are quantitative traits resulting from the actions of many genes working in concert with each other and the environment over the lifespan. ,CT gives accurate measures of trabecular bone architecture providing phenotypic data related to bone volume and trabecular morphology. The primary objective of this research was to identify chromosomal regions called quantitative trait loci (QTLs) that contain genes influencing trabecular architecture as measured by ,CT. Materials and Methods: The study used crosses between C57BL/6J (B6) and DBA/2J (D2) as progenitor strains of a second filial (F2) generation (n = 141 males and 148 females) and 23 BXD recombinant inbred (RI) strains (n , 9 of each sex per strain). The proximal tibial metaphyses of the 200-day-old mice were analyzed by ,CT to assess phenotypic traits characterizing trabecular bone, including bone volume fraction, trabecular connectivity, and quantitative measures of trabecular orientation and anisotropy. Heritabilities were calculated and QTLs were identified using composite interval mapping. Results: A number of phenotypes were found to be highly heritable. Heritability values for measured phenotypes using RI strains ranged from 0.15 for degree of anisotropy in females to 0.51 for connectivity density in females and total volume in males. Significant and confirmed QTLs, with LOD scores ,4.3 in the F2 cohort and ,1.5 in the corresponding RI cohort were found on chromosomes 1 (43 cM), 5 (44 cM), 6 (20 cM), and 8 (49 cM). Other QTLs with LOD scores ranging from 2.8 to 6.9 in the F2 analyses were found on chromosomes 1, 5, 6, 8, 9, and 12. QTLs were identified using data sets comprised of both male and female quantitative traits, suggesting similar genetic action in both sexes, whereas others seemed to be associated exclusively with one sex or the other, suggesting the possibility of sex-dependent effects. Conclusions: Identification of the genes underlying these QTLs may lead to improvements in recognizing individuals most at risk for developing osteoporosis and in the design of new therapeutic interventions. [source]

Modulation of peroxisome proliferator-activated receptor-, activity by N -acetyl cysteine attenuates inhibition of oligodendrocyte development in lipopolysaccharide stimulated mixed glial cultures

Manjeet K. Paintlia
Abstract Glial cells secrete proinflammatory mediators in the brain in response to exogenous stimuli such as infection and injury. Previously, we documented that systemic maternal lipopolysaccharide (LPS)-exposure at embryonic gestation day 18 causes oligodendrocyte (OL)-injury/hypomyelination in the developing brain which can be attenuated by N -acetyl cysteine (NAC; precursor of glutathione). The present study delineates the underlying mechanism of NAC-mediated attenuation of inhibition of OL development in LPS-stimulated mixed glial cultures. Factors released by LPS-stimulated mixed glial cultures inhibited OL development as shown by decrease in both proliferation 3bromo-deoxyuridine+/chondroitin sulfate proteoglycan,NG2+, hereafter BrdU+/NG+ and differentiation (O4+ and myelin basic protein+) of OL-progenitors. Correspondingly, an impairment of peroxisomal proliferation was shown by a decrease in the level of peroxisomal proteins in the developing OLs following exposure to LPS-conditioned media (LCM). Both NAC and WY14643, a peroxisome proliferator-activated receptor (PPAR)-, agonist attenuated these LCM-induced effects in OL-progenitors. Similar to WY14643, NAC attenuated LCM-induced inhibition of PPAR-, activity in developing OLs. Studies conducted with cytokines and diamide (a thiol-depleting agent) confirmed that cytokines are active agents in LCM which may be responsible for inhibition of OL development via peroxisomal dysfunction and induction of oxidative stress. These findings were further corroborated by similar treatment of developing OLs generated from PPAR-,(,/,) and wild-type mice or B12 oligodendroglial cells co-transfected with PPAR-, small interfering RNAs/pTK-PPREx3-Luc plasmids. Collectively, these data provide evidence that the modulation of PPAR-, activity, thus peroxisomal function by NAC attenuates LPS-induced glial factors-mediated inhibition of OL development suggesting new therapeutic interventions to prevent the devastating effects of maternal infections. [source]

Resource use and costs in a Swedish cohort of patients with Parkinson's disease

Peter Hagell RN
Abstract We estimated resource use and costs in patients with Parkinson's disease (PD), thereby providing baseline data for future economic evaluations of therapeutic interventions. Data were collected from medical records of a South Swedish cohort of 127 PD patients during 1 year (1996) and a mailed questionnaire inquiring about cost-related consequences and resource use in 1996 and in 2000. Annual costs were calculated based on prevalence and expressed in SEK (monetary value of the year 2000). Direct health care costs averaged approximately SEK 29,000 (,USD 2,900; EUR 3,200) per patient per year, of which drugs were the most costly component. Nonmedical direct costs were higher than direct health care costs, averaging approximately SEK 43,000 (,USD 4,300; EUR 4,800) per patient per year, and costs due to lost production were approximately SEK 52,000 (,USD 5,200; EUR 5,800) per patient per year. The mean total annual cost for PD in our sample approximated SEK 124,000 (,USD 12,400; EUR 13,800) per patient. These findings are roughly within the same range as estimates from other countries and show that PD causes a considerable societal burden. In addition to other outcomes, evaluations of the economic implications of new therapeutic interventions are highly warranted. In this perspective, the present study provides valuable baseline data. 2002 Movement Disorder Society [source]

Prognostic implications of admission inflammatory profile in acute ischemic neurological events

T. Anuk
Anuk T, Assayag EB, Rotstein R, Fusman R, Zeltser D, Berliner S, Avitzour D, Shapira I, Arber N, Bornstein NM. Prognostic implications of admission inflammatory profile in acute ischemic neurological events. Acta Neurol Scand 2002: 106: 196,199. Blackwell Munksgaard 2002. Objective, To reveal the potential prognostic implications of admission inflammatory markers in patients with acute ischemic neurological events. Patients and methods, Sixty patients with an acute ischemic neurological event who were examined within 24 h from the appearance of symptomatology. We determined the high-sensitive C-reactive protein (hs-CRP) concentrations, erythrocyte sedimentation rate (ESR), fibrinogen concentrations and degree of erythrocyte adhesiveness/aggregation. Results, A significant correlation was noted between baseline hs-CRP concentrations, ESR as well as adhesiveness/aggregation and the outcome of the ischemic neurological event as determined by the modified Rankin scale 8,12 months following the insult. Conclusion, Admission inflammatory markers have long-term prognostic implications in patients with acute ischemic neurological events. These findings are relevant in view of the new therapeutic interventions now available for reducing the inflammatory response. [source]

Mycobacterium vaccae administration during allergen sensitization or challenge suppresses asthmatic features

J. J. Smit
Summary Background and objective The hygiene hypothesis suggests that a lack of bacterial infections would favour the development of allergic disease. For this reason, bacteria or their components can be used as potential treatment for allergic asthma. We investigated whether heat-killed Mycobacterium vaccae is either able to suppress the induction of allergic asthma or able to suppress already established allergic asthma. Methods Mice were sensitized with ovalbumin (OVA)/alum on days 0 and 14. Thereafter, mice were challenged on days 35, 39 and 42 by inhalation of either OVA or saline aerosols. M. vaccae -treated mice received an injection with 106, 107 or 108 CFU heat-killed M. vaccae on days 0 and 14 or 107 CFU on days 35 and 39. On day 43, the airway responsiveness of the mice to increasing concentrations of methacholine was assessed, blood was withdrawn to measure serum parameters, and lung lavage was performed to detect cytokines and inflammatory cell number. Results Treatment of OVA-sensitized mice with 107 CFU M. vaccae either during sensitization or challenge suppresses airway hyper-responsiveness, airway eosinophilia and IL-5 production after OVA challenge. The increases in OVA-specific serum IgE and in IL-4 by respiratory challenges with OVA were only diminished after M. vaccae treatment (107 CFU) during sensitization. Conclusions Heat-killed M. vaccae prevents allergic and asthmatic manifestations in a mouse model and, more importantly, M. vaccae treatment during challenge suppresses features of asthma, which opens up possibilities for new therapeutic interventions. [source]