The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh ...insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes is still unidentified as only a single gene has been isolated for each opioid receptor. In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. The upregulation of DOR expression and DOR activation increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and antioxidative capacity. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this article is to review the recent work done on opioids and their receptor functions. It shall provide an informative reference for better understanding the opioid system and further elucidation of the opioid receptor function from a physiological and pharmacological point of view.
Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2011, ...significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid disease in women during pregnancy, preconception, and the postpartum period.
The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations. The guideline task force had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members.
The revised guidelines for the management of thyroid disease in pregnancy include recommendations regarding the interpretation of thyroid function tests in pregnancy, iodine nutrition, thyroid autoantibodies and pregnancy complications, thyroid considerations in infertile women, hypothyroidism in pregnancy, thyrotoxicosis in pregnancy, thyroid nodules and cancer in pregnant women, fetal and neonatal considerations, thyroid disease and lactation, screening for thyroid dysfunction in pregnancy, and directions for future research.
We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid disease in pregnant and postpartum women. While all care must be individualized, such recommendations provide, in our opinion, optimal care paradigms for patients with these disorders.
Thyroid function in pregnancy LAZARUS, John H
British medical bulletin,
03/2011, Letnik:
97, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Advances in understanding the physiology of thyroid function in normal pregnancy have highlighted the importance of the consequences of abnormal function on obstetric outcome and foetal well-being. ...Pubmed search was done using the terms thyroid and pregnancy. Areas of agreement are the following: gestational normative reference ranges for thyroid function tests are required for proper interpretation of any abnormalities. Measurement of thyroid-stimulating antibodies and antithyroid peroxidase antibodies is useful for diagnosis of thyroid disease in pregnancy. Treatment of Graves' hyperthyroidism should be done with propylthiouracil for first trimester only, then carbimazole or methimazole. Patients on levothyroxine require an increase in dosage during gestation. Areas of controversy are the following: total thyroxine (TT4) versus Free T4 (FT4) assays in pregnancy. Screening for thyroid function in early gestation: should it be routinely performed on everyone? What tests are appropriate? Growing points are the following: physiology of thyroxine delivery to the foetus. Establishment of gestational thyroid hormone reference ranges. Evaluation of strategies to screen thyroid function in early pregnancy. Areas timely for developing research are the following: placental thyroid hormone physiology, thyroid hormone therapy and screening thyroid function.
Objective:
The aim was to update the guidelines for the management of thyroid dysfunction during pregnancy and postpartum published previously in 2007. A summary of changes between the 2007 and 2012 ...version is identified in the Supplemental Data (published on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org).
Evidence:
This evidence-based guideline was developed according to the U.S. Preventive Service Task Force, grading items level A, B, C, D, or I, on the basis of the strength of evidence and magnitude of net benefit (benefits minus harms) as well as the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence.
Consensus Process:
The guideline was developed through a series of e-mails, conference calls, and one face-to-face meeting. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society, Asia and Oceania Thyroid Association, and the Latin American Thyroid Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes.
Conclusions:
Practice guidelines are presented for diagnosis and treatment of patients with thyroid-related medical issues just before and during pregnancy and in the postpartum interval. These include evidence-based approaches to assessing the cause of the condition, treating it, and managing hypothyroidism, hyperthyroidism, gestational hyperthyroidism, thyroid autoimmunity, thyroid tumors, iodine nutrition, postpartum thyroiditis, and screening for thyroid disease. Indications and side effects of therapeutic agents used in treatment are also presented.
AML treatment presents significant challenges in the elderly, who more often have poor risk cytogenetic and molecular markers, comorbidities and compromised performance status. Although ...population-based studies indicate that treated patients' survival is better than those who are not treated, there is an understandable reluctance of physicians to choose aggressive therapy. Even in this older population 40-60% CR rates are achievable. Several scoring systems and web-based programs help to predict TRM and CR rates. These sources can assist physicians in the difficult decision-making process of aggressive therapy in an individual patient. Clofarabine and hypomethylating agents are reasonable options and can induce CR in patients who cannot receive standard induction with anthracyclines and cytarabine. Despite encouraging CR rates, median survival remains short (<12 months) in elderly AML patients. Even those patients achieving CR have limited long-term survival (∼20% at 3 years) without allogeneic hematopoietic cell transplantation (alloHCT). AlloHCT is feasible and can provide approximately 40% survival at 2 years in appropriately selected patients. Although increased age is associated with poorer survival, higher comorbidities and poor performance status have more negative impact than age per se. The short duration of CR demands that leukemia and transplant physicians collaborate immediately after diagnosis to move quickly toward alloHCT. This collaboration is also essential to choosing the right individuals to transplant and to bridging post-remission therapy (intermediate-dose cytarabine, a hypomethylating agent or FLT-3 inhibitor) in this sometimes frail population. Future studies should be designed not only to address who should receive alloHCT, but also to improve our understanding of AML biology and the process of its cure.
Failure to undergo activation-induced cell death due to global dysregulation of apoptosis is the pathogenic hallmark of large granular lymphocyte (LGL) leukemia. Consequently, immunosuppressive ...agents are rational choices for treatment. This first prospective trial in LGL leukemia was a multicenter, phase 2 clinical trial evaluating methotrexate (MTX) at 10 mg/m(2) orally weekly as initial therapy (step 1). Patients failing MTX were eligible for treatment with cyclophosphamide at 100 mg orally daily (step 2). The overall response in step 1 was 38% with 95% confidence interval (CI): 26 and 53%. The overall response in step 2 was 64% with 95% CI: 35 and 87%. The median overall survival for patients with anemia was 69 months with a 95% CI lower bound of 46 months and an upper bound not yet reached. The median overall survival for patients with neutropenia has not been reached 13 years from study activation. Serum biomarker studies confirmed the inflammatory milieu of LGL but were not a priori predictive of response. We identify a gene expression signature that correlates with response and may be STAT3 mutation driven. Immunosuppressive therapies have efficacy in LGL leukemia. Gene signature and mutational profiling may be an effective tool in determining whether MTX is an appropriate therapy.
Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to ...allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning.
Transplantation-associated thrombotic microangiopathy (TA-TMA) is an infrequent but devastating syndrome that occurs in allogeneic hematopoietic stem cell transplant recipients, and is associated ...with a variety of transplantation-related factors, including conditioning regimens, immunosuppressive agents, GVHD and opportunistic infections. Progress in managing this condition has been hampered by lack of a consensus definition and poor understanding of the pathophysiology of the disorder. Two different groups recently have proposed consensus definitions, yet they fail to distinguish the primary syndrome from the secondary causes, such as a variety of infections, medication exposure or other conditions. Increasing evidence suggests that TA-TMA is a multifactorial disorder that is distinct from thrombotic thrombocytopenic purpura (TTP), and likely represents the final common pathway of a number of endothelial cell insults. TA-TMA responds poorly to conventional treatment for TTP, including plasma exchange, but newer agents, including daclizumab and defibrotide show promise. In addition, other agents known to modify endothelial responses to injury, including statins, prostacyclin analogues, endothelin-receptor antagonists and free radical scavengers, may lead to improved outcomes for patients affected by this disorder.
PURPOSE Surgery is curative therapy for pediatric low-grade gliomas (LGGs) in areas of the brain amenable to complete resection. However, LGGs located in areas where complete resection is not ...possible can threaten both function and life. The purpose of this study was to compare two chemotherapy regimens for LGGs in children younger than age 10 years for whom radiotherapy was felt by the practitioner to pose a high risk of neurodevelopmental injury. PATIENTS AND METHODS Previously untreated children younger than age 10 years with progressive or residual LGGs were eligible. Children were randomly assigned to receive carboplatin and vincristine (CV) or thioguanine, procarbazine, lomustine, and vincristine (TPCV). Children with neurofibromatosis are reported separately. Results Of 274 randomly assigned patients who met eligibility requirements, 137 received CV and 137 received TPCV. The 5-year event-free survival (EFS) and overall survival (OS) rates for all eligible patients were 45% ± 3.2% and 86% ± 2.2%, respectively. The 5-year EFS rates were 39% ± 4% for CV and 52% ± 5% for TPCV (stratified log-rank test P = .10; cure model analysis P = .007). On multivariate analysis, factors independently predictive of worse EFS and OS were younger age and tumor size greater than 3 cm(2). Tumor location in the thalamus was also associated with poor OS. CONCLUSION The difference in EFS between the regimens did not reach significance on the basis of the stratified log-rank test. The 5-year EFS was higher for TPCV on the basis of the cure model analysis. Differences in toxicity may influence physician choice of regimens.
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