Costs and outcomes of patients admitted with chest pain and essentially normal electrocardiograms

Background: Although inroads have been made in the outpatient evaluation of chest pain, the majority of hospitals in the United States do not have chest pain centers and the direct costs associated with hospital admissions in low-risk patients is unknown. Hypothesis: The study was undertaken to evaluate the cost and outcomes of admission to the hospital for patients with acute chest pain and essentially normal electrocardiograms (ECGs). Methods: For that purpose, we reviewed 1,670 patients presenting to our emergency department with chest pain over a 5-month period in 1994. Of these, 567 [34.0%, confidence interval (CI) 95%, 31.7–36.3%] patients were considered to be low risk by ECG criteria alone. Results: Complete clinical and financial data were available in 445 cases of which 152 had a previous history of coronary artery disease (CAD) and 31 (7.0%, CI95%, 4.9-9.6%) were ultimately proven to have acute myocardial infarction (AMI). There were no deaths. All patients initially underwent noninvasive evaluation, and an additional 177 (39.8%) underwent subsequent cardiac catheterization. Of those, 107 (60.5%) had significant CAD (at least one vessel>70% stenosis). We assumed an expected mortality rate of 1% in the AMI group based on previously reported series with all the mortalities preventable by hospitalization. This yielded a valuation of $1.7 million dollars per life saved. Sensitivity analysis revealed the practice of admission and in-patient evaluation for this group of patients was cost ineffective at all assumption levels. Conclusion: The practice of hospital admission for patients with chest pain and essentially normal ECGs is not cost favorable, and all hospital facilities should consider outpatient chest pain evaluation strategies.     

Impact of severe ADAMTS13 deficiency on clinical presentation and outcomes in patients with thrombotic microangiopathies: the experience of the Harvard TMA Research Collaborative

The Harvard TMA Research Collaborative is a multi‐institutional registry‐based effort to study thrombotic microangiopathies (TMA). Laboratory and clinical parameters were recorded for 254 cases of suspected autoimmune thrombotic thrombocytopenic purpura (TTP). Patients with severe ADAMTS13 deficiency (activity ≤10%, N = 68) were more likely to be young, female and without a history of cancer treatment or transplantation. While all patients with severe deficiency were diagnosed with autoimmune TTP, those without severe deficiency frequently had disseminated intravascular coagulation, drug‐associated TMA and transplant‐related TMA. Patients with severe ADAMTS13 deficiency had superior overall survival at 360 d compared to those without severe deficiency (93·0% vs. 47·5%, P < 0·0001). Almost all patients with severe deficiency received therapeutic plasma exchange (TPE), but the use of TPE in patients with ADAMTS13 activity >10% varied significantly across the institutions in our consortium (13·2–63·8%, P < 0·0001). Nevertheless, 90‐d mortality was not different in patients with ADAMTS13 activity >10% between the three hospitals (P = 0·98). Our data show that patients with severe ADAMTS13 deficiency represent a clinically distinct cohort that responds well to TPE. In contrast, TMA without severe ADAMTS13 deficiency is associated with increased mortality that may not be influenced by TPE.     

The Incidence of Major Hemorrhagic Complications After Renal Biopsies in Patients with Monoclonal Gammopathies

Background and objectives: Monoclonal gammopathies frequently cause renal disease, but they may be an incidental finding. Assessment of renal pathology in the context of renal dysfunction and a monoclonal gammopathy therefore serves as a useful diagnostic tool and, in addition, provides prognostic information. There is, however, a theoretical risk of increased hemorrhagic complications from renal biopsies in this setting. The purpose of this study was to determine the incidence of significant hemorrhagic complications after renal biopsies in patients with monoclonal gammopathies.Design, setting, participants, & measurements: The case notes of 1993 unselected patients from four teaching hospitals within the United Kingdom who underwent native or transplant renal biopsies between 1993 and 2008 were reviewed. Subjects were categorized as having a monoclonal gammopathy or not, and the incidence of major hemorrhagic complications between groups was compared.Results: In total, 74 (3.7%) patients (native and transplant biopsies) had a major hemorrhagic complication. One hundred forty-eight subjects with a monoclonal gammopathy were identified. The complication rate in this group was 4.1% compared with 3.9% in the control population (native biopsies only; P = 0.88).Conclusions: In the population studied, the rate of major hemorrhagic complications after percutaneous renal biopsy was not significantly greater in patients with a monoclonal gammopathy.Paraproteins are frequently detected in patients with renal disease, both as an incidental finding and as the underlying cause of the renal injury. The renal disorders associated with paraproteins are well described (1,2). In the context of severe acute kidney injury, cast nephropathy (myeloma kidney) is the most frequent finding (2,3). In contrast, patients presenting with heavy proteinuria and milder renal impairment are more likely to have amyloidosis (2,4) or light chain deposition disease (2,5). The conclusion that the presence of a paraprotein in the context of renal injury equates to a causal association cannot be drawn because of the high frequency of incidental paraproteins in this setting (6). For this reason, assessment of renal pathology is essential. In addition to confirming the underlying disorder and therefore allowing the initiation of disease specific treatment, pathologic features are also prognostic of clinical outcomes (2,5,7).Despite these advantages, many clinicians are reluctant to perform percutaneous renal biopsies in patients with paraproteins because of the theoretical risk of a higher rate of hemorrhagic complications (8,9). Indeed, there are a number of mechanisms by which paraproteins might confer this increased risk (10,11). Therefore, renal histology has not been used as an inclusion criterion for some studies that have investigated the optimal treatment strategies for paraprotein-related renal disease (9). In turn, this makes interpretation of the results of these studies difficult (12–14). However, clear evidence that performing percutaneous renal biopsies in these patients is associated with an actual higher incidence of clinically significant hemorrhagic complications is not well reported. In fact, recent work has implied that the procedure is relatively safe in patients with amyloidosis, traditionally the subgroup considered to be most at risk (15). The purpose of this study was to determine the incidence of major hemorrhagic complications after percutaneous renal biopsies in a large population of patients with monoclonal gammopathies.     

Selective inhibitors of nuclear export for the treatment of non-Hodgkin’s lymphomas

The nuclear export protein chromosome maintenance region 1, found to be elevated in non-Hodgkin’s lymphomas, controls localization of critical tumor suppressor proteins. Nuclear localization of tumor suppressor proteins is necessary for their cell surveillance function. However, their nuclear exclusion by chromosome maintenance region 1 renders them ineffective making this nuclear transporter an attractive therapeutic target. We have identified selective inhibitors of nuclear export that lock tumor suppressor proteins in the cell nucleus leading to apoptosis of lymphoid but not normal cells. Our inhibitors induce tumor suppressor protein nuclear retention-dependent growth inhibition and apoptosis in a panel of non-Hodgkin’s lymphoma cell lines. Western blot of nuclear protein fraction and confocal microscopy analysis demonstrated retention of major tumor suppressor proteins in the cell nucleus. Co-immunoprecipitation studies showed disruption of the tumor suppressor protein-chromosome maintenance region 1 interaction. Small inhibitor RNA knockdown of two major tumor suppressor proteins, p53 in wild-type protein-53 and protein 73 in mutant-protein-53, abrogated inhibitor activity. Oral administration of related inhibitor at 75 and 150 mg/kg resulted in 65 and 70% tumor reduction, respectively and subcutaneous injections of inhibitor (25 and 75 mg/kg) resulted in 70 and 74% suppression of non-Hodgkin’s lymphoma tumor growth with no toxicity; residual tumors showed activation of the protein 73 pathway. Our study verifies chromosome maintenance region 1 as a therapeutic target in non-Hodgkin’s lymphoma, indicating that this nuclear export protein warrants further clinical investigations.     

Reconstruction of floor of mouth defects by the facial artery musculo-mucosal flap following cancer ablation

BACKGROUND: The purpose of this study is to review our experience with the use of the facial artery musculo-mucosal (FAMM) flap for floor of mouth (FOM) reconstruction following cancer ablation to assess its reliability, associated complications, and functional results. METHODS: This was a retrospective analysis of 61 FAMM flaps performed for FOM reconstruction from 1997 to 2006. RESULTS: No total flap loss was observed. Fifteen cases of partial flap necrosis occurred, with 2 of them requiring revision surgery. We encountered 8 other complications, with 4 of them requiring revision surgery for an overall rate of revision surgery of 10% (6/61). The majority of patients resumed to a regular diet (85%), and speech was considered as functional and/or understandable by the surgeon in 93% of the patients. Dental restoration was successful for 83% (24/29) of the patients. CONCLUSION: The FAMM flap is well suited for FOM reconstruction because it is reliable, has few significant complications, and allows preservation of oral function.     

A deficit of brain dystrophin 71 impairs hypothalamic osmostat

Patients with Duchenne muscular dystrophy (DMD) and mdx mice, devoid of dystrophin proteins, show altered ionic homeostasis. To clarify dystrophin's involvement in the central control of osmotic stimuli, we investigated the effect of the disruption of Dp71, the major form of dystrophin in the brain, on the hypothalamoneurohypophysis system (HNHS) osmoregulatory response. Dp71 and Dp140 are the principal DMD gene products in the supraoptic nucleus (SON) and neurohypophysis (NH). They are present in astrocyte and pituicyte end‐feet, suggesting involvement in both intrinsic osmosensitivity of the SON and vasopressin (AVP) release from the NH. In Dp71‐null mice, the cellular distribution of Dp140 was modified, this protein being detected on the membrane of magnocellular soma. The plasma osmolality of Dp71‐null mice was lower than that of wild‐type mice under normal conditions, and this difference was maintained after salt loading, indicating a change in the set point for osmoregulation in the absence of Dp71. The increase in AVP levels detected in the SON and NH of the wild‐type was not observed in Dp71‐null mice following salt loading, and the increase in AVP mRNA levels in the SON was smaller in Dp71‐null than in wild‐type mice. This suggests that Dp71 may be involved in the functional activity of the HNHS. Its astrocyte end‐feet localization emphasizes the importance of neuronal–vascular–glial interactions for the central detection of osmolality. In the SON, Dp71 may be involved in osmosensitivity and definition of the “osmostat,” whereas, in the neurohypopohysis, it may be involved in fine‐tuning AVP release. © 2009 Wiley‐Liss, Inc.     

Biologic predictors of extension of oligoarticular juvenile idiopathic arthritis as determined from synovial fluid cellular composition and gene expression

Objective

To identify biomarkers in the first synovial fluid (SF) aspirate obtained from children with oligoarticular juvenile idiopathic arthritis (JIA), which could be used to identify children whose disease is likely to extend to a more severe phenotype.

Methods

Patients with recent‐onset oligoarticular JIA were identified and grouped according to those whose mild disease persisted (persistent disease) or those whose disease would extend from a mild to more severe phenotype (extended‐to‐be disease) at 1 year after diagnosis. Flow cytometry was used to delineate differences in the mononuclear cell populations between the first blood sample and first SF aspirate from the same patient and between outcome (persistent versus extended‐to‐be) groups. Proportions of lymphocytes in the joint were modeled on chemotaxis of lymphocytes to CCL5, using Transwell migration assays. Levels of CCL5 in the SF were quantified by enzyme‐linked immunosorbent assay. RNA profiles of SF mononuclear cells were compared between groups using the Affymetrix GeneChip hybridization protocol and hierarchical clustering analyses.

Results

Compared with peripheral blood mononuclear cells, SF mononuclear cells displayed an expansion of CD8+ T cells, reduced proportion of B cells, and expansion of CD16− natural killer cells. The lower CD4:CD8 ratio in the SF was recapitulated in vitro by the observed migration of blood T cells in response to CCL5. Synovial CCL5 levels were higher in children whose disease extended to a more severe phenotype. The CD4:CD8 ratio in the SF was significantly lower in patients with extended‐to‐be oligoarticular JIA (0.57 compared with 0.90 in the persistent disease group, difference 0.33, 95% confidence interval 0.04–0.62; P = 0.009). Gene expression profiling revealed that 344 genes were >1.5‐fold differentially expressed between outcome groups (P < 0.05), and these included genes associated with inflammation and macrophage differentiation, which showed increased levels in patients with extended disease at 1 year, and genes associated with immune regulation, which showed increased levels in patients with persistent disease at 1 year.

Conclusion

Analyses of the proportions of synovial lymphocytes, levels of CCL5, and differential gene expression yielded potential biomarkers with which to predict the likelihood of extension of oligoarticular JIA to a more severe disease phenotype.

     

Haploidentical stem cell transplantation as a salvage therapy for cord blood engraftment failure in a patient with Fanconi anemia

A 7‐year‐old male with Fanconi Anemia who developed primary graft failure following one antigen‐mismatched unrelated cord blood transplantation and a nonradiation‐based conditioning, underwent a second hematopoietic stem cell transplantation (HSCT) from his 2‐loci mismatched haploidentical father, using a nonradiation‐based regimen, 79 days after the first HSCT. A sustained hematological engraftment was achieved at 9 days post‐second HSCT. At 15 months post‐second HSCT; the patient demonstrated normal blood counts, sustained donor chimerism, and no evidence of GVHD. Haploidentical HSCTs as primary or secondary sources of stem cells, with appropriate T‐cell depletion, may be a readily available option in the absence of HLA‐matched related or unrelated donors. Pediatr Blood Cancer. 2010;55:580–582. © 2010 Wiley‐Liss, Inc.