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991.
992.
Modifier genes are defined as inherited genetic variation that leads to a qualitative or quantitative difference in disease phenotype. This has made the prediction of the phenotype based upon the genotype more difficult. Beta-thalassemia phenotype is modified by co-existent other genetic alterations. Changes alpha/beta-globin ratio can either ameliorate the disease phenotype or increase the severity of the disease in beta-thalassemia. Primary modifiers primarily affecting the clinical presentation include alpha gene changes, XmnI polymorphism and hereditary persistence of fetal hemoglobin (HPFH) variants. 'Thalassemia intermedia' is a heterogenous group with interplay of several genetic factors. The nature of the beta-genotype as well as the knowledge of the presence or absence of alleviating factors help the physician to decide on commencement of a regular transfusion regime or other lines of management including hydroxyurea therapy. The secondary modifiers affect the severity of jaundice, bone disease, cardiac and thrombotic complications. The present review gives a concise discussion of various modifying genes and the influence on the phenotype of beta-thalassemia. 相似文献
993.
Meg Jardine Zien Zhou Hiddo J. Lambers Heerspink Carinna Hockham Qiang Li Rajiv Agarwal George L. Bakris Christopher P. Cannon David M. Charytan Tom Greene Adeera Levin Jing-Wei Li Brendon L. Neuen Bruce Neal Richard Oh Megumi Oshima Carol Pollock David C. Wheeler Dick de Zeeuw Hong Zhang Bernard Zinman Kenneth W. Mahaffey Vlado Perkovic 《Clinical journal of the American Society of Nephrology》2021,16(3):384
994.
995.
Comparison of acute elastic recoil between the SAPIEN‐XT and SAPIEN valves in transfemoral–transcatheter aortic valve replacement 下载免费PDF全文
Shikhar Agarwal MD MPH Olcay Aksoy MD Muhammad Hammadah MD Kanhaiya Lal Poddar MD Rishi Puri MD Lars G. Svensson MD PhD Amar Krishnaswamy MD E. Murat Tuzcu MD FACC Samir R. Kapadia MD FACC 《Catheterization and cardiovascular interventions》2015,85(3):490-496
- Complex arch anatomy (type 2, type 3) and bovine configuration were identified in 34.4% and 20.5% of carotid stent patients, respectively.
- Catheter manipulation time (CMT), rather than arch complexity per se, was the only independent predictor of adverse events after carotid stenting.
- Careful attention to patient selection, preprocedural planning, and stent technique are important to ensure success.
996.
Background:
Diabetic neuropathy is a common and often debilitating condition for which available treatments are limited. Because a low-fat plant-based diet has been shown to improve glycemic control in individuals with type 2 diabetes, we hypothesized that such a diet would reduce painful symptoms of diabetic neuropathy.Methods:
In this 20-week pilot study, individuals with type 2 diabetes and painful diabetic neuropathy were randomly assigned to two groups. The intervention group was asked to follow a low-fat, plant-based diet, with weekly classes for support in following the prescribed diet, and to take a vitamin B12 supplement. The control group was asked to take the same vitamin B12 supplement, but received no other intervention. At baseline, midpoint and 20 weeks, clinical, laboratory and questionnaire data were collected. Questionnaires included an analog ‘worst pain'' scale, Michigan Neuropathy Screening Instrument, global impression scale, Short Form McGill Pain Questionnaire, Neuropathy Total Symptom Score, a weekly pain diary and Norfolk Quality of Life Questionnaire.Results:
After 20 weeks, body weight change with the intervention was −6.4 kg (95% confidence interval (CI) −9.4 to −3.4, P<0.001) in an effect size analysis. Electrochemical skin conductance in the foot improved by an average of 12.4 microseimens (95% CI 1.2–23.6, P=0.03) with the intervention in an effect size analysis. The between-group difference in change in pain, as measured by the McGill pain questionnaire, was −8.2 points (95% CI −16.1 to −0.3, P=0.04). Michigan Neuropathy Screening Instrument questionnaire score change was −1.6 points (95% CI −3.0 to −0.2, P=0.03).Conclusions:
Improvements were seen in some clinical and pain measures. This pilot study suggests the potential value of a plant-based diet intervention, including weekly support classes, for treating painful diabetic neuropathy. 相似文献997.
998.
Ashok Agarwal Gulfam Ahmad Rakesh Sharma 《Journal of assisted reproduction and genetics》2015,32(12):1721-1729
PurposeA physiological balance exists between seminal reactive oxygen species (ROS) and antioxidant capacity. An overproduction of ROS which exceeds the seminal plasma antioxidant capacity results in oxidative stress (OS). The aim of the present study was to describe a detailed protocol to measure ROS in a diagnostic laboratory and revise our previous cutoff value of ROS in seminal ejaculates in a larger cohort of infertile men and controls with proven and unproven fertility.MethodsA total of 258 infertile men and 92 controls were enrolled in the study. Following initial semen analysis, ROS measurement in whole ejaculates was carried out using luminol-based chemiluminescence assay. Chemiluminescence was measured for 15 min with a Berthold luminometer. Results were expressed as relative light units (RLU/s/106 sperm). The test’s specificity, sensitivity, and cutoff values were calculated using the receiver operating characteristic (ROC) curve.ResultsSignificantly higher ROS levels were seen in infertile men compared to controls (p < 0.001). The optimal cutoff value to differentiate between controls and infertile men was 102.2 RLU/s/106 sperm. At this cutoff value, the test was 76.4% sensitive and 53.3% specific. The positive and negative predictive values of the test were 82.1% and 44.5%, respectively. A total of 76.4% infertile population was above this cutoff value compared to 46.7% of controls.ConclusionsThe luminol-based chemiluminescence assay can be used in routine diagnostic screening to test for male infertility diagnosis in a clinical setting. The current ROS cutoff value substantially distinguishes infertile from normal controls. Patients with elevated ROS must be evaluated for the underlying cause of ROS production. 相似文献
999.
P.C. Rath Sundar Chidambaram Pallavi Rath Byomakesh Dikshit Sudhir Naik Prashant K. Sahoo Brajraj Das Mohanshankar Mahalingam Lakshmipathi Khandrika Jugnu Jain 《Indian heart journal》2015,67(2):114-121
Background
A thorough understanding of the patient''s genotype and their functional response to a medication is necessary for improving event free survival. Several outcome studies support this view particularly if the patient is to be started on clopidogrel due to the prevalence of clopidogrel resistance. Such guided therapy has reduced the incidence of Major Adverse Cardiac Events (MACE) after stent implantation.Methods
Between August 2013 and August 2014, 200 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) were prescribed any one of the anti-platelet medications such as clopidogrel, prasugrel or ticagrelor and offered testing to detect CYP2C19 gene mutations along with a platelet reactivity assay (PRA). Intended outcome was modification of anti-platelet therapy defined as either dose escalation of clopidogrel or replacement of clopidogrel with prasugrel or ticagrelor for the patients in clopidogrel arm, and replacement of ticagrelor or prasugrel with clopidogrel if those patients were non-carrier of mutant genes and also if they demonstrated bleeding tendencies in the ticagrelor and prasugrel arms.Conclusion
Clopidogrel resistance was observed to be 16.5% in our study population. PRA was useful in monitoring the efficacy of thienopyridines. By having this test, one can be safely maintained on clopidogrel in non-carriers, or with increased dose of clopidogrel in intermediate metabolizers or with newer drugs such as ticagrelor or prasugrel in poor metabolizers. Patients on ticagrelor and prasugrel identified as non-carriers of gene mutations for clopidogrel metabolism could be offered clopidogrel resulting in economic benefits to the patients. Patients at high risk of bleeding were also identified by the PRA. 相似文献1000.
Roberto A. Maldonado Robert A. LaMothe Joseph D. Ferrari Ai-Hong Zhang Robert J. Rossi Pallavi N. Kolte Aaron P. Griset Conlin O’Neil David H. Altreuter Erica Browning Lloyd Johnston Omid C. Farokhzad Robert Langer David W. Scott Ulrich H. von Andrian Takashi Kei Kishimoto 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(2):E156-E165
Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.Undesired immunogenicity can have a profound impact on human health. Allergies, including allergic asthma and severe food allergies, affect ∼20% of the population, and the prevalence has been steadily increasing over the past several decades (1). The prevalence of autoimmune diseases, including multiple sclerosis and type 1 diabetes, is ∼4.5% (2). Unwanted immunogenicity can also affect both efficacy and safety of biologic drugs (3), particularly in the case of protein replacement therapies for the treatment of genetic deficiencies, such as hemophilia A (4) and Pompe Disease (5). Immunomodulatory agents commonly used to control immunogenicity are often broadly immunosuppressive and typically require chronic administration that can lead to reactivation of latent pathogens, development of tumors, and opportunistic infections (6, 7). Therefore, antigen-specific, durable tolerogenic therapy would be highly desirable from an efficacy and safety perspective.Multiple techniques for antigen-specific immunotherapy have been described, although only allergen immunotherapy, wherein low doses of antigen are delivered in the absence of immunomodulating agents, is currently used in the clinic (1). Experimental approaches have included oral administration of antigen, high dose tolerance, and the use of altered peptide ligands (8). Although these methods have been successful in preclinical models, translation to human clinical trials has been largely disappointing (8). Alternative strategies to leverage tolerogenic programming associated with apoptotic cells include conjugating antigen to splenocytes (9–12) or synthetic microparticles (13, 14) or targeting antigen to the surface of red blood cells (15). Other approaches include loading particles with MHC complexes that present relevant peptides in the absence of costimulation (16, 17), liposomal copresentation of antigen with a ligand specific for the negative signaling receptor CD22 on B cells (18), codelivery of peptide antigen with an aryl hydrocarbon receptor agonist (19), and cotreatment with pharmacological agents, such as methotrexate (20). A major concern for antigen immunotherapy is the ability to induce and maintain tolerance in the presence of proinflammatory stimuli caused by tissue stress, injury, or concurrent infections. We sought to develop an antigen-specific tolerogenic technology that could control both T-cell– and B-cell–mediated immunity and that was durable over time and to multiple challenges with the antigen, even in the presence of strong innate immune stimulants.Dendritic cells (DCs) are an attractive target for immunotherapies due to their central role in antigen presentation to T cells and their ability to induce and control regulatory responses to secure self-tolerance (21–25). Thomson and colleagues (26, 27) demonstrated that treating DCs with rapamycin, an inhibitor of the mTOR pathway, induces a tolerogenic DC phenotype capable of inducing Treg differentiation and antigen-specific immune tolerance that is resistant to the proinflammatory cascade triggered by TLR signaling. However, conventional therapy with free rapamycin requires chronic systemic administration, resulting in broad immunosuppression due to its direct effect on lymphocytes (28), whereas low doses of rapamycin may paradoxically augment effector T-cell memory (29). Thus, it would be desirable to transiently target rapamycin’s effects to DCs and other antigen-presenting cells (APCs) at the time of antigen encounter. Nanoparticles (NPs) are an ideal mechanism to deliver antigen (16, 30, 31) and drugs (32) to APCs, as these cells are keyed to capture and internalize nanoparticulates such as viruses.Here we describe the development of tolerogenic NPs (tNPs) using materials and compounds that have been well validated in the clinic. These self-assembling, biodegradable poly(lactide-coglycolide) (PLGA) tNPs containing either protein or peptide antigens and rapamycin are capable of inducing durable antigen-specific tolerance that control adaptive immune responses and withstand multiple immunogenic challenges with antigen. We demonstrate that either s.c. or i.v. administration of tNPs inhibits the activation of antigen-specific CD4+ and CD8+ T cells and B cells while inducing antigen-specific Tregs and Bregs. Swiss Jack Lambert (SJL) mice immunized with the myelin proteolipid protein 139–151 peptide in complete Freud’s adjuvant (PLP139–151/CFA) and treated therapeutically with a single dose of tNPs at the peak of disease are completely protected from developing relapsing paralysis. In hemophilia A animals, administration of tNP before or after the establishment of an anti-factor VIII (FVIII) antibody response led to a significant reduction of the neutralizing antibody response against FVIII. Treatment of mice with tNP prevents both cellular and humoral immunity even in the presence of potent TLR agonists. These effects are dependent on the presence of the encapsulated rapamycin (not free in solution). 相似文献