Trypanosoma cruzi antigen that interacts with the beta1-adrenergic receptor and modifies myocardial contractile activity

Previously, we have demonstrated that plasma membranes from the parasite Trypanosoma cruzi (T. cruzi) recognize and adhere to host cells through parasite surface attachment molecules that have affinity for beta(1)-adrenergic receptors (beta(1)-ARs) on target organs. In this report we identify a parasite protein that not only interacts with beta(1)-ARs, but also displays beta-agonist-like activity. We demonstrate that a recombinant maltose binding protein fusion of Tc13 Tul (MBP-Tc13 Tul), a member of the T. cruzi antigen 13 family of surface antigen proteins, competes for binding sites with the beta-adrenergic receptor antagonist [125I]-CYP on membranes purified both from CHO cells expressing human beta(1)-ARs and from rat atria. The competition is prevented by pre-treating MBP-Tc13 Tul with antibodies directed against the EPKSA repeat domain of Tc13 Tul, implicating this portion of the molecule in binding to the beta(1)-AR. Furthermore, MBP-Tc13 Tul activates rat myocardial beta(1)-ARs, resulting in synthesis of cyclic adenosine monophosphate (cAMP) and an increase in cardiac contractility. These biological effects are selectively suppressed by the beta(1)-AR antagonist atenolol, by a synthetic peptide corresponding to the second extracellular loop of the human beta(1)-AR, and by the anti-EPKSA repeat antibodies. These results imply that the Tc13 Tul cell-surface antigen of T. cruzi plays a central role in misregulating the beta(1)-AR following parasite infection, and may be a causative factor of dysautonomic syndrome described in Chagas' disease.     

Understanding laboratory testing in diagnostic uncertainty: a qualitative study in general practice.

BACKGROUND: Better knowledge of the professional's motives for ordering laboratory tests in the case of diagnostic uncertainty may lead to interventions directed at reducing unnecessary testing. AIM: To gain insight into the general practitioner's (GP's) motives for ordering laboratory tests for patients presenting with unexplained complaints. DESIGN OF STUDY: Semi-structured interviews based on surgery observations. SETTING: Twenty-one general practices in rural and urban areas of The Netherlands. METHOD: Investigation of the GP's perception of determinants of test-ordering behaviour in the situation of diagnostic uncertainty. The interviews were structured by evaluating the consultations and test-ordering performance of that day. RESULTS: Dutch GPs vary considerably in their motives for ordering tests. Numerous motives emerged from the data. Some examples of important themes include: personal routines; tolerance of diagnostic uncertainty; time pressure; and tactical motives for test ordering. Complying with the perceived needs of the patient for reassurance through testing is seen as an easy, cost- and time-effective strategy. A clear hierarchy in the determinants was not found. CONCLUSION: The decision to request laboratory testing is the result of a complex interaction of considerations that are often conflicting. Designers of interventions meant to improve the ordering of tests should be aware of the numerous determinants, and take contextual variables into account.     

Fludarabine-based conditioning secures engraftment of second hematopoietic stem cell allografts (HSCT) in the treatment of initial graft failure.

Graft failure is associated with a high mortality rate. To date, regimens invoked for second transplants have resulted in inconsistent engraftment with high transplant-related mortality (TRM). We here report 16 consecutive patients, aged 4-59 years, who received second HSCT (HSCT-2) at a median of 45 days following primary or secondary failure of an initial unmodified (N = 3) or T cell-depleted (TCD) (N = 13) HSCT (HSCT-1). HSCT-1 was administered after myeloablative total body irradiation (TBI)- or alkylator-based conditioning for acute leukemias (N = 7), MDS (N = 6), CML (N = 2), and Fanconi anemia (N = 1). All patients experienced 1 or more infectious complications between HSCT-1 and HSCT-2, and 10 patients had active infections at the time of HSCT-2. Cytoreduction regimens used for HSCT-2 included fludarabine (Flu) in combination with cyclophosphamide (CTX) (N = 9), or thiotepa (Thio) (N = 5). In addition, 1 patient received Flu alone and 1 patient Thio combined with CTX. Antithymocyte globulin (ATG) (N = 11) or Alemtuzumab (N = 3) was added pretransplant to prevent rejection. For HSCT-2, donors included HLA-matched (N = 3) or mismatched (N = 8) related, or matched (N = 2) or mismatched (N = 3) unrelated donors. The primary graft donor was used in 6 of 16 cases. The grafts administered were unmodified peripheral blood stem cell transplantation (PBSCT) (N = 5) or bone marrow transplantation (BMT) (N = 3), TCD PBSCT (N = 8). All patients achieved engraftment at a median of 12 days and evaluable patients achieved complete donor chimerism. Six patients are alive with a median follow-up of 49 months, including 4/9 conditioned with Flu/CTX. In this series, outcome was statistically superior for younger patients (相似文献   

Controversies in plastic surgery: Suction-assisted lipectomy (SAL) and the hCG (human chorionic gonadotropin) protocol for obesity treatment

The advent of SAL (suction-assisted lipectomy) has dramatically increased the number of obese patients coming to our consultation offices. Despite several articles suggesting a conservative approach to fat suction, some reports insinuate that SAL might be a useful tool for obesity treatment. This hypothesis is refuted by a vast body of evidence that concludes that the adipose tissue may regenerate in adult humans. Therefore, surgical procedures are not advised as the method of choice to manage the disease. On the other hand, the terms obesity and being overweight may not be interchangeable. Obesity may be a disease whereas being overweight is asign of the disease. Consequently, proper preoperative selection of candidates for SAL becomes mandatory. The hCG (human chorionic gonadotropin) method for obesity treatment appears to be a complete program for the management of obesity. It contains pharmacologic, dietetic, and behavior modification aspects in a 40-day course of treatment. Some data suggest hCG to be lipolytic, thus explaining former clinical observations regarding body fat redistribution in treated patients. hCG commercial preparations contain -endorphin, an opioid peptide linked to mood behavior. This article speculates on the possible actions of the complex hCG -endorphin in the neuromodulation of mood and energy metabolism. The method comprises a behavior modification that helps in handling the patient better. There are some correlations between a current behavior modification program and the basic guidelines contained in the hCG protocol. Thus, the hCG method appears to be a reasonable alternative in the management of a long-standing, unsolved problem of human metabolism.     

Evaluating and Strengthening the Evidence for Nutritional Bone Research: Ready to Break New Ground?

A healthy diet is essential to attain genetically determined peak bone mass and maintain optimal skeletal health across the adult lifespan. Despite the importance of nutrition for bone health, many of the nutritional requirements of the skeleton across the lifespan remain underexplored, poorly understood, or controversial. With increasingly aging populations, combined with rapidly changing diets and lifestyles globally, one anticipates large increases in the prevalence of osteoporosis and incidence of osteoporotic fractures. Robust, transparent, and reproducible nutrition research is a cornerstone for developing reliable public health recommendations to prevent osteoporosis and osteoporotic fractures. However, nutrition research is often criticized or ignored by healthcare professionals due to the overemphasis of weak science, conflicting, confusing or implausible findings, industry interests, common misconceptions, and strong opinions. Conversely, spurious research findings are often overemphasized or misconstrued by the media or prominent figures especially via social media, potentially leading to confusion and a lack of trust by the general public. Recently, reforms of the broader discipline of nutrition science have been suggested and promoted, leading to new tools and recommendations to attempt to address these issues. In this perspective, we provide a brief overview of what has been achieved in the field on nutrition and bone health, focusing on osteoporosis and osteoporotic fractures. We discuss what we view as some of the challenges, including inherent difficulties in assessing diet and its change, disentangling complex interactions between dietary components and between diet and other factors, selection of bone-related outcomes for nutrition studies, obtaining evidence with more unbiased designs, and perhaps most importantly, ensuring the trust of the public and healthcare professionals. This perspective also provides specific recommendations and highlights new developments and future opportunities for scientists studying nutrition and bone health. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Genome-Wide Association Analysis of Longitudinal Bone Mineral Content Data From the Iowa Bone Development Study

The foundation for osteoporosis risk is, in part, established during childhood, adolescence, and young adulthood, all periods of development when bone mass is acquired rapidly. The relative quantity of bone mass accrued is influenced by both lifestyle and genetic factors, although the genetic component is not yet well understood. The purpose of this study was to use a genome-wide association (GWA) analysis to discover single nucleotide polymorphisms (SNPs) associated with: (1) the sex-specific hip bone mineral content at approximately the age of 19 when the amount of bone accrued is near its peak; and (2) the sex-specific rate of hip bone mineral content accrual during the adolescent growth spurt. The Iowa Bone Development Study, a longitudinal cohort study exploring bone health in children, adolescents, and young adults was the source of data. From this cohort, n = 364 (190 females, 174 males) participants were included in GWA analyses to address (1) and n = 258 participants (125 females and 133 males) were included in GWA analyses to address (2). Twenty SNPS were detected having p < 1.0 × 10^?5. Of most biologic relevance were 2 suggestive SNPs (rs2051756 and rs2866908) detected in an intron of the DKK2 gene through the GWA analysis that explored peak bone mass in females.     

Limited sensitivity of iodine-123-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl ] benzamide whole-body scintigraphy in patients with malignant melanoma: a comparison with thallium-201 imaging

The aim of this prospective study was to assess the diagnostic value of iodine-123-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl] benzamide (IBZM) whole-body imaging in comparison to thallium-201 scintigraphy in patients with metastatic malignant melanoma. Ten patients with suspected or proven locoregional metastases of malignant melanoma underwent whole-body scintigraphy both with 201Tl and 123I-IBZM prior to scheduled surgery. Whole-body scans and planar scintigrams were acquired at 5 min and 30 min after injection of 100 MBq 201Tl and at 10 min, 2 h, 4 h and 24 h after injection of 185 MBq 123I-IBZM. Ten out of 12 melanoma metastases, both melanotic and amelanotic as proven histologically, were detected by 201Tl with a sensitivity of 83%. 123I-IBZM showed tracer uptake only in 3 melanotic metastases (sensitivity: 25%) with a maximum tumor-to-background ratio within 4 h, while none of the amelanotic metastases was IBZM-positive. All lesions localized by 123I-IBZM showed tracer uptake of 201Tl as well, while 201Tl-negative lesions were also negative with IBZM. Because of the poor results of IBZM, the study was terminated after an interim evaluation of 10 patients. 123I-IBZM is a tracer with only moderate sensitivity in melanotic melanoma lesions, suggesting that this method has no clinical value as a routine investigation in melanoma patients. In comparison, our previous results with 201Tl whole-body scintigraphy yielded a significantly higher sensitivity of about 80% in patients with locoregional melanoma metastases and may thus offer considerable potential in non-PET melanoma imaging.     

Correlation between Extreme Drug Resistance Assay and Response to Primary Paclitaxel and Cisplatin in Patients with Epithelial Ovarian Cancer

Objective.The extreme drug resistance (EDR) assay has been correlated with failure of response to chemotherapy in greater than 99% of patients. The goal of this study is to correlate the results of the EDR assay to response to first-line paclitaxel/cisplatin among patients with epithelial ovarian cancer.Methods.Seventy-five of 100 patients with epithelial ovarian cancer for whom EDR assay was performed were treated with weekly induction cisplatin (1 mg/kg body wt) × 4, followed by monthly paclitaxel (135 mg/m²) and cisplatin (75 mg/m²) × 6 and were evaluable for correlation of response to chemotherapy and EDR assay. Specimens for EDR assay were obtained at primary surgery and the EDR assay was performed by Oncotech, Inc. Response to chemotherapy was correlated to EDR assay results regarding paclitaxel and cisplatin.Results.Among 75 evaluable patients, the prevalence of EDR to paclitaxel was 20.0% (n= 15) and to cisplatin it was 2.7% (n= 2). Only 1 patient (1.3%) exhibited EDR to both paclitaxel and cisplatin. Surgical assessment of response was performed in 42 patients; 33 patients were clinically evaluable. The overall response rate was 85.3%. The overall response rate for patients whose tumors demonstrated no EDR to either paclitaxel or cisplatin did not differ significantly from that for patients whose tumors demonstrated EDR to at least one of these two drugs (86.4% versus 81.3%, respectively,P= 0.692). Similarly, the complete surgical response rate for both groups did not differ significantly (25.4% versus 12.5%, respectively,P= 0.34). A single patient whose tumor exhibited EDR to both paclitaxel and cisplatin had tumor progression. The sensitivity, specificity, positive predictive value, and negative predictive value of the EDR assay were 79.6, 27.0, 86.0, and 19.0%, respectively.Conclusions.EDR to paclitaxel does not preclude response to the combination of paclitaxel and cisplatin as primary therapy for patients with epithelial ovarian cancer. The role of the EDR assay in the primary management of patients with epithelial ovarian cancer remains to be determined.