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Devastating Disease (devastating + disease)
Selected AbstractsTherapy of HIV infectionDERMATOLOGIC THERAPY, Issue 6 2004Yuchi C. Chang ABSTRACT:, HIV is a devastating disease caused by the human immunodeficiency virus. Symptoms of illness can manifest in every organ system, including the skin. Although there is no definitive cure, the creation of antiretroviral drugs and aggressive treatment regimens have dramatically altered disease morbidity and mortality. However, the precise drug selection is often difficult and intimidating given the sheer abundance of drug therapies available. In this article, the HIV disease course is reviewed and different classes of antiretroviral medications are presented with emphasis on initial drug regimens, potential adverse effects, particularly those of dermatologic nature, possible drug interactions, patient compliance, and the emergence of drug resistance. [source] ,-Amyloid immunization approaches for Alzheimer's diseaseDRUG DEVELOPMENT RESEARCH, Issue 2 2002Bruno P. Imbimbo Abstract Alzheimer's disease (AD) represents the third leading cause of death in the U.S. and the leading cause of dementia in the elderly population. Until recently, there was little hope of efficiently combating this devastating disease. The deposition of ,-amyloid (A,) is the major pathological hallmark of AD brains. Genetic, biochemical, and pharmacological evidence support the hypothesis that A, plays a key role in the development of the disease. Thus, in the last 5 years a number of pharmacological strategies have been developed to interfere with the A, cascade. The most revolutionary of these approaches was proposed in 1999 by scientists at Elan Pharmaceuticals, which immunized against A, transgenic mice with spontaneously developing A, pathology. The immunization was achieved by subcutaneous injections of a preaggregated form of the synthetic human 42-amino acid A, emulsified with Freund's adjuvant, an immune stimulant. The vaccination caused a near complete inhibition of A, plaque formation in younger animals and a marked reduction of the A, burden in older animals. The effects on A, plaques were accompanied by a reduction of A,-associated astrogliosis and neuritic dystrophy. These results were later confirmed by other groups with similar vaccination protocols, which also demonstrated that the A, immunization of transgenic animals normalize or reduce the cognitive impairment associated with A, pathology. Interestingly, effective removal of brain A, plaques was also obtained by peripherally administering A, antibodies. The mechanism with which the vaccine increases A, clearance is not fully understood. Centrally, the vaccine appears to activate A, phagocytosis by microglial monocytes. Peripherally, serum A, antibodies bind and sequester A,, thus altering its equilibrium between CNS and plasma. The dramatic results obtained in animal models of AD raised unprecedented hopes for both a preventive and a curative intervention for this devastating disorder. A vaccine preparation for human use (AN-1792) composed of preaggregated human A,42 peptide and a highly purified saponin derivative (QS-21) was developed by Elan Pharmaceuticals and Wyeth Ayerst and tested in AD patients. Unfortunately, a Phase IIa study aimed at evaluating the safety and immunological activity of AN-1792 in 360 AD patients was discontinued because 15 subjects receiving the vaccine developed serious signs of CNS inflammation. Both central activation of cytotoxic T cells and autoimmune reactions were proposed as potential mechanisms of toxicity. Other therapeutic A, vaccination strategies are being pursued, including immuno-conjugates and monoclonal antibodies. The future of these and other A, immunization approaches depend on a clear understanding of the mechanism of A, clearance and additional insight into the role of inflammation in the AD brain. Drug Dev. Res. 56:150,162, 2002. © 2002 Wiley-Liss, Inc. [source] NAALADase (GCP II) inhibitors protect in models of amyotrophic lateral sclerosis (ALS)JOURNAL OF NEUROCHEMISTRY, Issue 2002A. G. Thomas Chronic glutamate toxicity is implicated in the pathogenesis of ALS. The neuropeptide N-acetyl-aspartyl glutamate (NAAG) appears to function both as a storage form for glutamate and as a neuromodulator at glutamatergic synapses. Catabolism of NAAG by N-acetylated-,-linked acidic dipeptidase (NAALADase; also termed glutamate carboxypeptidase II), yields N-acetyl aspartate (NAA) and glutamate. Since prior studies demonstrate an up-regulation of NAALADase in motor cortex and increased levels of NAA and glutamate in the CSF of ALS patients, we hypothesized that inhibition of NAALADase could protect against neuronal degeneration in ALS. Neuroprotective effects of two NAALADase inhibitors were assessed. 2-(Phosphonomethyl)pentanedioic acid (2-PMPA) decreased motor neuron loss and prevented loss of choline acetyltransferase (ChAT) activity in an in vitro model of ALS wherein chronic glutamate toxicity was induced by blocking glutamate transport. Gross morphology was preserved in 2-PMPA-treated cultures. In a SOD-1 transgenic mouse model of ALS, oral administration of a structurally different NAALADase inhibitor (GPI 5693) increased survival by 29 days and delayed onset of clinical symptoms by 17 days. Preliminary analysis of spinal cord pathology revealed severe neuronal depletion and astrocytosis with white matter changes in control mice. In mice treated with GPI 5693, normal neuronal populations with modest vacuolar changes were observed. These data suggest that NAALADase inhibition may provide an exciting therapeutic approach to the devastating disease, ALS. [source] Recurrent pregnancy loss: A disease of inflammation and coagulationJOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 4 2009Joanne Kwak-Kim Abstract Recurrent pregnancy loss (RPL) is one of the most common obstetrical complications. Multiple etiologies, such as endocrine, anatomic, genetic, hematological and immunological causes have been reported for this devastating disease. However, over half of the cases remain unexplained. Thrombotic/inflammatory processes are often observed at the maternal-fetal interface as the final pathological assault in many cases of RPL, including those of unexplained etiologies. In the present paper, cellular immune responses (T, natural killer [NK], natural killer-T [NKT], regulatory T [Treg] cells and their cytokines) and autoimmune abnormalities of women with RPL are reviewed. In addition, metabolic diseases and hematological conditions which often lead to thrombotic/inflammatory conditions are discussed in association with RPL. Finally, current therapeutic options for RPL are reviewed. [source] The case for routine use of adjuvant therapy in pancreatic cancerJOURNAL OF SURGICAL ONCOLOGY, Issue 7 2007Eugene P. Kennedy MD Abstract Pancreatic cancer is a devastating disease with a poor prognosis for most patients. Surgical resection remains the cornerstone of treatment, providing the only realistic hope of long-term survival. Even with optimal surgical management, 5-year survival averages 15% to 20% for resectable disease. Progress is being made, however. Currently, the benefits of postoperative therapy for resected pancreatic ductal adenocarcinoma appear clear, and recommendations for such therapy appear to us to be well justified. Additional benefit to patients awaits the development of new agents, molecular targeted drugs, and novel approaches such as immunotherapy. J. Surg. Oncol. 2007;95:597,603. © 2007 Wiley-Liss, Inc. [source] Clinical review of Crohn's diseaseJOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS, Issue 8 2007APRN-BC, Brenda Ruthruff MSN, CWOCN (Adult Nurse Practitioner, Continence Nurse), Ostomy, Wound Abstract Purpose: This clinical review presents proposed theories regarding the etiology of Crohn's disease (CD), the pathophysiology of the disorder, and current diagnostic methods. Data sources: Pertinent publications in the literature, the Crohn's and Colitis Foundation web page, and relevant texts regarding pathophysiology of the gastrointestinal system. Conclusions: CD can be a devastating disease and difficult to diagnose. The advanced practice nurse (APRN) should be aware of the etiology, pathophysiology, diagnostic methods, and current treatment options of this disorder. Implications for practice: In collaboration with a gastroenterologist, APRNs can provide much needed information to the patient with CD. Practice recommendations include patient education, pain management, and support for quality of life issues. [source] Resistance to cassava mosaic disease in transgenic cassava expressing antisense RNAs targeting virus replication genesPLANT BIOTECHNOLOGY JOURNAL, Issue 4 2005Peng Zhang Summary African cassava mosaic virus (ACMV) is a major contributor to cassava mosaic disease (CMD), the economically most important and devastating disease of cassava in Africa. We have developed transgenic cassava plants with increased ACMV resistance using improved antisense RNA technology by targeting the viral mRNAs of Rep (AC1), TrAP (AC2) and REn (AC3). Viral DNA replication assays in detached leaves demonstrated that replication of two ACMV isolates was strongly reduced or inhibited in most transgenic lines. After ACMV infection of plants using biolistic inoculation, several lines remained symptomless at lower infection pressure (100 ng viral DNA/plant). Symptom development was reduced and attenuated even at higher DNA doses. Transgenic ACMV-resistant plants had significantly reduced viral DNA accumulation in their infected leaves. Short sense and antisense RNAs specific to AC1 were identified in transgenic lines expressing AC1 antisense RNA, suggesting that the short RNAs mediate interference by post-transcriptional gene silencing. Our results demonstrate that resistance to ACMV infection of cassava can be achieved with high efficacy by expressing antisense RNAs against viral mRNAs encoding essential non-structural proteins, providing a new tool to combat CMD in Africa. [source] QTL analysis of crown rust resistance in perennial ryegrass under conditions of natural and artificial infectionPLANT BREEDING, Issue 4 2007B. Schejbel Abstract Crown rust is an economically devastating disease of perennial ryegrass. Both artificial crown rust inoculations, with the possibility of several selection cycles in one year, as well as marker-assisted selection can be used for more efficient breeding of new resistant cultivars. The objective of this study was to map quantitative trait loci (QTL) for response to crown rust infection in perennial ryegrass. In order to identify relevant markers for response to crown rust infection, QTL mapping was performed on a ryegrass mapping population which was evaluated for resistance in the field for two years as well as by artificial pathogen inoculations using a detached leaf assessment. The broad sense heritability values for the field, detached leaf and combined assays were 0.42, 0.56, and 0.64, respectively, indicating a good potential for selection for crown rust resistance. A total of six QTLs were identified and mapped to linkage groups (LG) LG1, LG4 and LG5, explaining between 6.8% and 16.4% of the total phenotypic variation. [source] Mapping polygenes for tuber resistance to late blight in a diploid Solanum phureja × S. stenotomum hybrid populationPLANT BREEDING, Issue 4 2006I. Simko Abstract Potato tuber blight is a disease caused by the oomycete Phytophthora infestans (Mont.) de Bary. Due to the significant economic impact of this disease, introgression of durable resistance into the cultivated potato is one of the top priorities of breeding programmes worldwide. Though numerous resistance loci against this devastating disease have already been mapped, most of the detected loci are contributing towards foliar resistance while specific information on tuber resistance is limited. To identify the genetic components of tuber resistance and its relationship to foliar resistance and plant maturity we have investigated the host-pathogen interaction in a segregating diploid hybrid Solanum phureja × S. stenotomum family. Mature tubers from this mapping family were inoculated with a sporangial suspension of P. infestans (US-8 clonal lineage) and evaluated for lesion expansion. No significant correlation was detected between late blight resistance in foliage and tubers, and between plant maturity and tuber resistance. Four chromosomal regions were significantly associated with tuber resistance to the disease. The largest effect was detected near the marker locus PSC (LOD 10.7) located on chromosome 10. This locus explained about 63% of the total phenotypic variation of the trait. The other three resistance-related loci were mapped on chromosomes 8 (GP1282, LOD 4.4), 6 (CP18, LOD 4.0) and 2 (CP157, LOD 3.8). None of the four tuber resistance loci coincides with the foliage resistance loci detected in this same family. Tuber blight resistance quantitative trait loci (QTL) on chromosomes 2, 8 and 10 are distinct from the maturity QTLs and have an additive effect on tuber resistance. These results indicate that different genes are involved in foliar and tuber resistance to P. infestans in the present family and that some of the resistance genes might be associated with late maturity. [source] QTL analysis of resistance to Fusarium head blight in wheat using a ,Wangshuibai'-derived populationPLANT BREEDING, Issue 4 2005M. Mardi Abstract Fusarium head blight (FHB) is a devastating disease that reduces the yield, quality and economic value of wheat. For quantitative trait loci (QTL) analysis of resistance to FHB, F3 plants and F3:5 lines, derived from a ,Wangshuibai' (resistant)/,Seri82'(susceptible) cross, were spray inoculated during 2001 and 2002, respectively. Artificial inoculation was carried out under field conditions. Of 420 markers, 258 amplified fragment length polymorphism and 39 simple sequence repeat (SSR) markers were mapped and yielded 44 linkage groups covering a total genetic distance of 2554 cM. QTL analysis was based on the constructed linkage map and area under the disease progress curve. The analyses revealed a QTL in the map interval Xgwm533-Xs18/m12 on chromosome 3BS accounting for up to 17% of the phenotypic variation. In addition, a QTL was detected in the map interval Xgwm539-Xs15/m24 on chromosome 2DL explaining up to 11% of the phenotypic variation. The QTL alleles originated from ,Wangshuibai' and were tagged with SSR markers. Using these SSR markers would facilitate marker-assisted selection to improve FHB resistance in wheat. [source] Overexpression of synuclein-, in pancreatic adenocarcinomaCANCER, Issue 1 2004Zhongkui Li Ph.D. Abstract BACKGROUND Currently, pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Despite the advances in pancreatic carcinoma research, patients with this devastating disease have a very poor prognosis. To identify the gene expression profile of pancreatic carcinoma, an important step in the process of developing new diagnostic and therapeutic strategies, the authors investigated the alteration of gene expression in this disease. METHODS The authors analyzed a public serial analysis of gene expression (SAGE) database and examined in greater detail the expression of synuclein-, mRNA in several pancreatic carcinoma cell lines and tumor tissue samples by reverse transcriptase,polymerase chain reaction (RT-PCR) analysis and Northern blot analysis. The expression of synuclein-, protein was investigated further by immunohistochemical and Western blot analyses using tumor cell lines, tumor tissue, and serum samples. RESULTS Synuclein-, mRNA was overexpressed in 11 of 12 pancreatic carcinoma cell lines, including AsPc-1, MDAPanc28, Capan-1, Capan-2, PANC-1, HS766T, MDAPanc3, MDAPanc48, Colo357FG, MiaPaCa2, CFPac1, and BxPc3. The expression of synuclein-, protein was detectable in 8 of 12 pancreatic carcinoma cell lines (67%) and in 22 of 32 pancreatic tumor tissue samples (69%) by Western blot analysis. On immunohistochemical staining, synuclein-, protein was present in 61% of the tumor tissue samples examined from patients with Stage I and II pancreatic carcinoma. The overexpression of synuclein-, is correlated with perineural and lymph node invasion. Synuclein-, protein also was detectable by Western blot in serum samples from 21 of 56 patients (38%) with pancreatic carcinoma. CONCLUSIONS Synuclein-,, which initially was described as a breast carcinoma,specific gene involved in invasion, metastasis, and chemotherapy resistance, was frequently overexpressed in pancreatic carcinoma. Overexpression of synuclein-, may play a role in pancreatic carcinoma invasion. Further studies will be necessary to determine the role of synuclein-, in pancreatic carcinoma. Cancer 2004. © 2004 American Cancer Society. [source] Cholesterol at the crossroads: Alzheimer's disease and lipid metabolismCLINICAL GENETICS, Issue 1 2004CL Wellington Alzheimer's Disease (AD) is a devastating disease that affects millions of elderly persons. Despite years of intense investigations, genetic risk factors that affect the majority of AD cases have yet to be determined. Recent studies suggest that cholesterol metabolism has integral part in AD pathogenesis, suggesting that genes that regulate lipid metabolism may also play roles in AD. This review will first describe emerging evidence that links cholesterol to the mechanisms thought to underlie AD. Based on this rationale, candidate genes located in regions implicated in AD that have roles in lipid metabolism will then be discussed. [source] Parallel protein folding with STAPLCONCURRENCY AND COMPUTATION: PRACTICE & EXPERIENCE, Issue 14 2005Shawna Thomas Abstract The protein-folding problem is a study of how a protein dynamically folds to its so-called native state,an energetically stable, three-dimensional conformation. Understanding this process is of great practical importance since some devastating diseases such as Alzheimer's and bovine spongiform encephalopathy (Mad Cow) are associated with the misfolding of proteins. We have developed a new computational technique for studying protein folding that is based on probabilistic roadmap methods for motion planning. Our technique yields an approximate map of a protein's potential energy landscape that contains thousands of feasible folding pathways. We have validated our method against known experimental results. Other simulation techniques, such as molecular dynamics or Monte Carlo methods, require many orders of magnitude more time to produce a single, partial trajectory. In this paper we report on our experiences parallelizing our method using STAPL (Standard Template Adaptive Parallel Library) that is being developed in the Parasol Lab at Texas A&M. An efficient parallel version will enable us to study larger proteins with increased accuracy. We demonstrate how STAPL enables portable efficiency across multiple platforms, ranging from small Linux clusters to massively parallel machines such as IBM's BlueGene/L, without user code modification. Copyright © 2005 John Wiley & Sons, Ltd. [source] Environmental epigenomics in human health and diseaseENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 1 2008Dana C. Dolinoy Abstract The epigenome consists of the DNA methylation marks and histone modifications involved in controlling gene expression. It is accurately reproduced during mitosis and can be inherited transgenerationally. The innate plasticity of the epigenome also enables it to be reprogrammed by nutritional, chemical, and physical factors. Imprinted genes and metastable epialleles represent two classes of genes that are particularly susceptible to environmental factors because their regulation is tightly linked to epigenetic mechanisms. To fully understand the etiology of the most devastating diseases that plague humans, the full complexity of the human epigenome will ultimately need to be characterized. Moreover, the elucidation of the interaction of the environment with the epigenome should allow for the development of novel epigenetic-based diagnostic, prevention, and therapeutic strategies for human diseases. Herein, we introduce the emerging field of environmental epigenomics, discuss the importance of imprinted genes and metastable epialleles as epigenetically labile genomic targets, and endorse the genome-wide identification of the full suite of epigenetically labile targets in both the mouse and human genomes. Environ. Mol. Mutagen., 2008. © 2008 Wiley-Liss, Inc. [source] EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relativesEUROPEAN JOURNAL OF NEUROLOGY, Issue 12 2005An evidence-based review with good practice points Despite being one of the most devastating diseases known, there is little evidence for diagnosing and managing patients with amyotrophic lateral sclerosis (ALS). Although specific therapy is lacking, correct early diagnosis and introduction of symptomatic and specific therapy can have a profound influence on the care and quality of life of the patient and may increase survival time. This document addresses the optimal clinical approach to ALS. The final literature search was performed in the spring of 2005. Consensus recommendations are given graded according to the EFNS guidance regulations. Where there was lack of evidence but consensus was clear we have stated our opinion as good practice points. People affected with possible ALS should be examined as soon as possible by an experienced neurologist. Early diagnosis should be pursued and a number of investigations should be performed with high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. PEG is associated with improved nutrition and should be inserted early. The operation is hazardous in patients with vital capacity <50%. Non-invasive positive pressure ventilation improves survival and quality of life but is underused. Maintaining the patients ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end of life care are important and should be fully discussed early with the patient and relatives respecting the patients social and cultural background. [source] Use of quantitative real-time polymerase chain reaction to estimate the size of the house-fly Musca domestica genomeINSECT MOLECULAR BIOLOGY, Issue 6 2006J. Gao Abstract House-flies, Musca domestica, are carriers of more than 100 devastating diseases that have severe consequences for human and animal health. A key bottleneck to progress in controlling the devastating human diseases transmitted by house-flies is lack of knowledge of the basic molecular biology of this species. However, before sequencing of the house-fly genome can be seriously considered it is important to know the size of the genome. In this paper, we used quantitative real-time polymerase chain reaction to calculate genome size of the house-fly in side-by-side experiments with Drosophila melanogaster (known genome size of 180 Mb). Our results indicate the size of the house-fly genome is 295 ± 10 Mb and that of D. melanogaster is 184 Mb. Thus, the house-fly genome is only about 1.6-fold larger than the genome of D. melanogaster. This indicates that the size of the house-fly genome makes it an excellent candidate for whole genome sequencing and that quantitative real-time polymerase chain reaction is an accurate method for the estimation of the size of insect genomes. [source] Review article: nuclear receptors and liver disease , current understanding and new therapeutic implicationsALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2009D. A. H. ELFAKI Aliment Pharmacol Ther,30, 816,825 Summary Background, The important role of nuclear receptors and their contribution to liver function in both physiological and pathological conditions has come to attention in recent years and has advanced our understanding of several liver diseases. These findings led to the introduction of targeting nuclear receptors as treatment strategies for various liver diseases. Aims, To review the new insights brought by the study of nuclear receptors to our understanding of the molecular basis of various liver diseases, and to summarize some of the recent studies that evaluated the efficacy of targeting nuclear receptor as a new approach in treating liver diseases. Methods, Review of articles, using PubMed and article references. Results, Nuclear receptor ligands in patients with liver diseases have been associated with a variety of toxicities. Some clinical results have not met the expectations predicted from animal experiments. Mechanistic explanations at the molecular level are needed for preventing toxicity and improving outcomes from nuclear receptor ligands. Conclusion, The use of various nuclear receptor ligands in liver diseases is a promising approach that can benefit many patients suffering from these devastating diseases. However, we are far from a full understanding of the molecular mechanisms by which these receptors work. [source] Restricted transgene persistence after lentiviral vector-mediated fetal gene transfer in the pregnant rabbit modelTHE JOURNAL OF GENE MEDICINE, Issue 9 2008Rafael Moreno Abstract Background Prenatal gene transfer may enable early causal intervention for the treatment or prevention of many devastating diseases. Nevertheless, permanent correction of most inherited disorders requires a sustained level of expression from the therapeutic transgene, which could theoretically be achieved with integrating vectors. Methods Rabbit fetuses received 8.5 × 106 HIV-based recombinant lentivirus particles containing the enhanced green fluorescent protein (EGFP) transgene by intrahepatic, intra-amniotic or intraperitoneal injection at 22 days of gestation. Provirus presence and transgene expression in rabbit tissues were evaluated at both 1.5 and 16 weeks post- in utero intervention by polymerase chain reaction (PCR) and reverse transcriptase-PCR, respectively. Moreover, we assessed persistence of EGFP by immunohistochemistry. Enzyme-linked immunosorbent assays confirmed the development of antibodies specific against both the viral vector and the reporter protein. Results Regardless of the route of administration employed, lentiviral vector-based in utero gene transfer was safe and reached 85% of the intervened fetuses at birth. However, the integrated provirus frequency was significantly reduced to 50% of that in young rabbits at 16 weeks post-treatment. In these animals, EGFP expression was evident in many tissues, including cytokeratin 5-rich basal cells from stratified and pseudostratified epithelia, suggesting that the lentiviral vector might have reached progenitor cells. Conversely, we identified the presence of immune-inflammatory infiltrates in several EGFP-expressing tissues. Moreover, almost 70% of the lentiviral vector-treated rabbits elicited a humoral immune response against the viral envelope and/or the EGFP. Conclusions At two-thirds gestational age, the adaptive immune system of the rabbit appears a relevant factor limiting transgene persistence and expression following lentiviral vector-mediated in utero gene transfer. Copyright © 2008 John Wiley & Sons, Ltd. [source] | |||||||||||||