The role of plasma biomarkers in acute heart failure. Serial changes and independent prognostic value of NT-proBNP and cardiac troponin-T

AIMS: Brain natriuretic peptide (BNP), NT-proBNP and troponins are useful for the assessment of patients with heart failure. Few data exist about their serial changes and their prognostic value in patients with acute heart failure (AHF). METHODS AND RESULTS: NT-proBNP and troponin-T plasma levels were measured at baseline, after 6, 12, 24, 48 h and at discharge in 116 consecutive patients with AHF and no evidence of acute coronary syndrome. NT-proBNP levels were 4421 pg/mL at baseline, declined after 24 h and reached their nadir at 48 h (2703 pg/mL). Troponin-T was detectable in 48% of patients. During a median follow-up of 184 days, 52 patients died or had a non-fatal cardiovascular hospitalisation. At a multivariable analysis including clinical and echo-Doppler variables, NT-proBNP plasma levels at discharge, detectable troponin-T plasma levels, and NYHA class at discharge were the only independent prognostic factors. CONCLUSION: In patients with AHF, NT-proBNP levels decline 24 h after the initiation of intravenous therapy and troponin-T is detectable in 48% of cases. NT-proBNP levels at discharge, detectable troponin-T levels, NYHA class and serum sodium have independent prognostic value.     

Functional BSND variants in essential hypertension

BACKGROUND: Defects in the handling of renal salt reabsorption may contribute to interindividual differences in blood-pressure regulation and susceptibility to hypertension. Sodium chloride reabsorption in the thick ascending limb (TAL) is dependent in part on the chloride channel, ClC-Kb (encoded by CLCNKB), and its accessory subunit, barttin (encoded by BSND). METHODS: We investigated genetic variations in BSND in a screening population, and genotyped a homogenous cohort of normotensive and hypertensive Ghanaian subjects, in addition to four ethnically defined control populations. Functional consequences of the identified BSND variants were examined using a heterologous expression system. RESULTS: Three novel, nonsynonymous coding-sequence single-nucleotide polymorphisms were identified (V43I, E255Q, and G284D) in the screening population. BSND-V43I was identified in African American, Asian, and Hispanic subjects, with minor allele frequencies of 0.14, 0.18, and 0.01, respectively, but it was absent in the Caucasian population. BSND-E225Q and BSND-G284D were rare variants. Two of these variants (V43I and G284D) exhibited partial loss-of-function phenotypes when heterologously expressed with ClC-Kb chloride channels in cultured cells. In logistic regression analyses, we observed no association between hypertension and BSND-I43 in our study population. However, we did observe significant deviation from Hardy-Weinberg equilibrium in the normotensive population. CONCLUSIONS: We conclude that BSND-V43I, a common variant conferring partial loss of function, exhibits significant deviation from Hardy-Weinberg equilibrium in the Ghanaian normotensive control population. However, it does not independently confer protection against hypertension.     

Roles of Neutrophil Gelatinase-Associated Lipocalin in Continuous Ambulatory Peritoneal Dialysis-Related Peritonitis

Introduction  We measured the neutrophil gelatinase-associated lipocalin (NGAL) concentration in peritoneal dialysate effluent (PDE) collected following an acute episode of continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis. Results  NGAL concentration in PDE increased in the first 3 days after developing peritonitis and correlated well with the neutrophil count. In patients with culture-negative peritonitis, the NGAL in PDE was lower than that in patients with gram-positive or gram-negative peritonitis. Apart from providing additional diagnostic support to bacterial-induced peritonitis, measurement of NGAL in PDE may be useful to differentiate the neutrophil-dependent culture-negative peritonitis from that associated with non-bacterial or non-cellular etiologies. Conclusion  Human peritoneal mesothelial cell (HPMC) is another source of NGAL during peritonitis. NGAL was specifically induced in HPMC by IL-1β. Incubation of HPMC with recombinant NGAL reversed the transforming growth factor-β-induced up-regulation of Snail and vimentin but rescued the down-regulation of E-cadherin. Our data suggest that NGAL may exert a protective effect in modulating the epithelial-to-mesenchymal transition activated following peritonitis.     

Pharmacologic management of acutely agitated pediatric patients

Acute agitation is a state of behavioral dyscontrol that requires intervention. Medications available in rapid delivery formats are frequently administered to treat acute agitation, either as a chemical restraint or on a voluntary basis. Prior to initiating treatment, the etiology of agitation must be evaluated. In choosing a medication, general pharmacologic principles should be followed. Medication should be selected based on the underlying cause in conjunction with weighing the risks, benefits, and side effects of medications. There are three classes of medications administered to children and adolescents to treat agitation: antihistamines, benzodiazepines, and antipsychotics. The most concerning short-term side effects of antipsychotics are their adverse neurologic effects, neuroleptic malignant syndrome, and prolonged corrected QT interval. Compared with typical antipsychotics, atypical antipsychotics have a more favorable short-term side effect profile.     

The effect of Oncotype DX recurrence score on treatment recommendations for patients with estrogen receptor-positive early stage breast cancer and correlation with estimation of recurrence risk by breast cancer specialists

Purpose.

The Oncotype DX assay predicts likelihood of distant recurrence and improves patient selection for adjuvant chemotherapy in estrogen receptor–positive (ER-positive) early stage breast cancer. This study has two primary endpoints: to evaluate the impact of Oncotype DX recurrence scores (RS) on chemotherapy recommendations and to compare the estimated recurrence risk predicted by breast oncology specialists to RS.

Methods.

One hundred fifty-four patients with ER-positive early stage breast cancer and available RS results were selected. Clinicopathologic data were provided to four surgeons, four medical oncologists, and four pathologists. Participants were asked to estimate recurrence risk category and offer their chemotherapy recommendations initially without and later with knowledge of RS results. The three most important clinicopathologic features guiding their recommendations were requested.

Results.

Ninety-five (61.7%), 45 (29.2%), and 14 (9.1%) tumors were low, intermediate, and high risk by RS, respectively. RS significantly correlated with tumor grade, mitotic activity, lymphovascular invasion, hormone receptor, and HER2/neu status. Estimated recurrence risk by participants agreed with RS in 54.2% ± 2.3% of cases. Without and with knowledge of RS, 82.3% ± 1.3% and 69.0% ± 6.9% of patients may be overtreated, respectively (p = 0.0322). Inclusion of RS data resulted in a 24.9% change in treatment recommendations. There was no significant difference in recommendations between groups of participants.

Conclusions.

Breast oncology specialists tended to overestimate the risk of tumor recurrence compared with RS. RS provides useful information that improves patient selection for chemotherapy and changes treatment recommendations in approximately 25% of cases.     

The process of decision-making in home-care case management: implications for the introduction of universal assessment and information technology

Increasingly, jurisdictions are adopting universal assessment procedures and information technology to aid in healthcare data collection and care planning. Before their potential can be realised, a better understanding is needed of how these systems can best be used to support clinical practice. We investigated the decision-making process and information needs of home-care case managers in Ontario, Canada, prior to the widespread use of universal assessment, with a view of determining how universal assessment and information technology could best support this work. Three focus groups and two individual interviews were conducted; questioning focused on decision-making in the post-acute care of individuals recovering from a hip fracture. We found that case managers' decisional process was one of a clinician–broker, combining clinical expertise and information about local services to support patient goals within the context of limited resources. This process represented expert decision-making, and the case managers valued their ability to carry out non-standardised interviews and override system directives when they noted that data may be misleading. Clear information needs were found in four areas: services available outside of their regions, patient medical information, patient pre-morbid functional status and partner/spouse health and functional status. Implications for the use of universal assessment are discussed. Recommendations are made for further research to determine the impact of universal assessment and information technology on the process and outcome of home-care case manager decision-making.     

Estradiol and progesterone differentially regulate the dendritic arbor of neurons in the hypothalamic ventromedial nucleus of the female rat (Rattus norvegicus)

The ventromedial nucleus of the hypothalamus (VMH), with its major subdivisions, the dorsomedial and ventrolateral VMH (dmVMH and vlVMH, respectively), has been studied extensively for its role in female sexual behavior. This behavior is controlled by the vlVMH through the cellular actions of estradiol combined with progesterone. Although the effects of treatment with estradiol alone on neuronal morphology in the vlVMH have been examined, much less is known about the combined effects of estradiol and progesterone on neuronal structure. The present study employed Golgi impregnation to investigate the effects of estradiol treatment alone vs. estradiol combined with progesterone treatment on dendritic arbor of VMH neurons. The dendritic arbor of VMH neurons was somewhat different in the vlVMH vs. the dmVMH, with longer and more dendrites in the vlVMH. Estradiol treatment alone caused a marked reduction in the length of long primary dendrites in the vlVMH, but not in the dmVMH. The estradiol-induced retraction of long primary dendrites in the vlVMH was reversed within 4 hours of progesterone treatment. The differences in the dendritic arbors of dmVMH and vlVMH provide further support for the notion that these two regions have different patterns of neural connectivity. In addition, this study is the first to report opposing effects of estradiol alone vs. estradiol plus progesterone on the dendritic arbor of neurons in the vlVMH. These results suggest a structural mechanism for estradiol alone to have a modest effect on mating behavior while setting the stage for its ample expression.     

Tracking Clerkship Experience: Just What Do Clinical Clerks See on an Elder Care Rotation?

The Schulich School of Medicine, University of Western Ontario, Canada, has created a mandatory clerkship in Elder Care that consists of small group seminars, clinical experiences, and an Elder Care manual. This article describes the use of a paper-based log to track students' clinical encounters to determine whether the Elder Care clerkship offers students the opportunity for a broad range of clinical experiences to address curriculum objectives. Using a paper-based log that was completed after each clinical encounter, students recorded information including the reason for assessment, tests completed, care recommendations, and personal reflections. Each of 70 students completed an average of 5.5 logs. Cognitive/psychiatric, medical, functional, and social problems were reported in more than 83% of the logs. Almost all students saw at least one patient with cognitive decline and one with depressive symptoms. Only six students reported seeing a patient with delirium. Students were able to think reflectively on their experiences. In matching the clerkship objectives to the learning modality(ies) in which they were addressed, it was found that knowledge-related objectives were supported primarily by seminars and manual content. Skills-related objectives were supported primarily by clinical experiences. The clinical experience logs used in this study provided evidence that, in the Elder Care clerkship, for the most part, students are seeing what we think they should be seeing. Study results have informed the revision of the logs, which will be an ongoing method of tracking objectives and students' reflections and ensuring continuous quality improvement.     

Blockade of thrombospondin-1-CD47 interactions prevents necrosis of full thickness skin grafts

BACKGROUND: Skin graft survival and healing requires rapid restoration of blood flow to the avascular graft. Failure or delay in the process of graft vascularization is a significant source of morbidity and mortality. One of the primary regulators of blood flow and vessel growth is nitric oxide (NO). The secreted protein thrombospondin-1 (TSP1) limits NO-stimulated blood flow and growth and composite tissue survival to ischemia. We herein demonstrate a role for TSP1 in regulating full thickness skin graft (FTSG) survival. METHODS AND RESULTS: FTSG consistently fail in wild type C57BL/6 mice but survive in mice lacking TSP1 or its receptor CD47. Ablation of the TSP1 receptor CD36, however, did not improve FTSG survival. Remarkably, wild type FTSG survived on TSP1 null or CD47 null mice, indicating that TSP1 expression in the wound bed is the primary determinant of graft survival. FTSG survival in wild type mice could be moderately improved by increasing NO flux, but graft survival was increased significantly through antibody blocking of TSP1 binding to CD47 or antisense morpholino oligonucleotide suppression of CD47. CONCLUSIONS: TSP1 through CD47 limits skin graft survival. Blocking TSP1 binding or suppressing CD47 expression drastically increases graft survival. The therapeutic applications of this approach could include burn patients and the broader group of people requiring grafts or tissue flaps for closure and reconstruction of complex wounds of diverse etiologies.