Citations

Policy has not adequately addressed the unique circumstances of pediatric subspecialties, many of which are facing workforce shortages. Pediatric subspecialties, which we define to include all medical and surgical subspecialties, are discrete disciplines that differ significantly from each other and from adult medicine subspecialties. Concerns about a current shortage of pediatric subspecialists overall are driven by indicators ranging from recruitment difficulties to long wait times for appointments. The future supply of pediatric subspecialists and patient access to pediatric subspecialty care will be affected by a number of key factors or forces for change. We discuss 5 of these factors: changing physician and patient demographics; debt load and lifestyle considerations; competition among providers of subspecialty care; equitable reimbursement for subspecialty services; and policy to regulate physician supply. We also identify issues and strategies that medical and specialty societies, pediatric subspecialists, researchers, child advocates, policy makers, and others should consider in the development of subspecialty-specific workforce-policy agendas.

Abstract Purpose: The objective of this study was to use gene expression profiling to identify novel biomarkers that are predictive of aggressive behavior in clear cell renal cell carcinoma (CCRCC). Experimental Design: Candidate genes were discovered using Human Genome U133 Plus 2 Arrays and validated on independent samples by quantitative reverse transcription-PCR (RT-PCR). Both the discovery and the validation cohorts included nonaggressive primary CCRCC, aggressive primary CCRCC, metastatic CCRCC, and nonneoplastic kidney adjacent to tumor. Results: Aggressive primary and metastatic CCRCC displayed no significant differences in gene expression. In contrast, we identified significant differences in gene expression between nonaggressive and aggressive CCRCC (including metastatic CCRCC). Thirty-four of the 35 transcripts that displayed the most significant differential expression by microarray analysis also displayed significant differential expression in independent validation studies using quantitative RT-PCR (P < 0.001 for 31 candidates and P < 0.005 for the remaining three candidates). Hierarchical clustering of the quantitative RT-PCR data using our candidate markers accurately grouped 88% (23 of 26) of aggressive and metastatic CCRCC samples, 100% (14 of 14) of nonaggressive CCRCC samples, and 100% (15 of 15) of nonneoplastic samples into separate clusters. Finally, we evaluated the ability of protein expression levels of one of our candidate markers (survivin) to predict survival among a cohort of 183 CCRCC patients treated surgically at Mayo Clinic from 1990 to 1992. In multivariate analysis, expression of survivin (BIRC5) was inversely associated with cancer-specific survival (P = 0.017). Conclusion: We used a combination of genomic profiling and validation by quantitative PCR to identify a panel of candidate biomarkers for determining CCRCC aggressiveness. Our data also indicate that the gene expression alterations that result in aggressive behavior and metastatic potential can be identified in the primary tumor.

PurposeAlthough rare overall, marginal zone B-cell lymphoma (MZBCL) is the most common primary low-grade CNS lymphoma reported in the literature. The aim of this study is to elucidate the biology and genetic features of this unusual tumor.Patients and MethodsFifteen CNS MZBCLs were studied clinically, pathologically, and genetically, including fluorescent in situ hybridization analyses with commercially available MALT1 and IgH break-apart and centromere 3, 7, 12, and 18 probes.ResultsCNS MZBCLs preferentially affect middle-aged women (female-to-male ratio, 4:1), with 93% presenting as dural-based masses mimicking meningioma. Ten patients with 1 to 7.6 years of follow-up after diagnosis showed no evidence of disease after radiation and/or chemotherapy. Like MZBCLs outside of the CNS, they consisted of CD20+, CD3−small B lymphocytes with varying degrees of plasmacytic differentiation and predominantly κ light-chain restriction (78%). Lymphoid follicles with follicular colonization were seen in three patients and deposition of amyloid was noted in samples from two patients, one of which was tumefactive. Neither Bcl-6 protein nor Epstein-Barr virus–encoded RNA was expressed. Trisomy 3 was detected in six of 12 patients, with no rearrangements of MALT1 or IgH and no trisomies of 7, 12, or 18 detected.ConclusionOur data suggest that intracranial MZBCL is an indolent primary CNS lymphoma that typically presents as a meningioma-like dural-based mass. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality that may contribute to the pathogenesis of this CNS lymphoma.

ABSTRACT We evaluated aliquots from 244 clinical blood culture bottles that demonstrated yeasts on Gram stain using a Candida albicans peptide nucleic acid (PNA) fluorescent in situ hybridization (FISH) probe. The sensitivity, specificity, positive predictive value, and negative predictive value of the C. albicans PNA FISH test in this study were 99%, 100%, 100%, and 99.3%, respectively.

Patients with Alzheimer's disease (AD) have abnormally low positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl) in regions of the precuneus and the posterior cingulate, parietotemporal, and frontal cortex. Apolipoprotein E (APOE) ε4 gene dose (i.e., the number of ε4 alleles in a person's APOE genotype) is associated with a higher risk of AD and a younger age at dementia onset. We previously found that cognitively normal late-middle-aged APOE ε4 carriers have abnormally low CMRgl in the same brain regions as patients with probable Alzheimer's dementia. In a PET study of 160 cognitively normal subjects 47–68 years of age, including 36 ε4 homozygotes, 46 heterozygotes, and 78 ε4 noncarriers who were individually matched for their gender, age, and educational level, we now find that ε4 gene dose is correlated with lower CMRgl in each of these brain regions. This study raises the possibility of using PET as a quantitative presymptomatic endophenotype to help evaluate the individual and aggregate effects of putative genetic and nongenetic modifiers of AD risk.

AbstractTherapeutic endoscopy (TE) has provided a new means for treating peptic ulcer disease, prompting a reevaluation of surgery's role. The aim of this study was to determine if surgical therapy of bleeding duodenal ulcers has changed since the advent of TE. This retrospective review involved consecutive time periods during which TE was (1985–1990) and was not (1980–1984) widely available. Exclusion criteria were prior gastric surgery, nonpeptic conditions, and untreated ulcers. Inclusion standards were met by 252 patients (180 men, 72 women) whose mean age was 67 years. Patients were grouped by the initial therapeutic intervention. Groups were similar in age, medical condition (mean APACHE II score 16), and morbidity. Seventy‐five patients had surgery alone during 1980–1984 and 38 during 1985–1990. TE was initially performed on 134 patients during 1985–1990. Bleeding (n=30) and perforation (n=1) prompted emergent operation in 23% of cases following TE. Thus 69 (38+31) patients underwent surgery between 1985 and 1990. Preprocedure transfusions averaged 4.1 units in the endoscopic group and 8.2 units in the operative groups (p<0.0001). Disagreement existed between the endoscopic and surgical descriptions of ulcer location in 53% of cases. Emergent surgery was required in 45% of hemodynamically unstable patients versus 14% of stable patients who initially underwent TE (p<0.0001). Sixty‐one percent of incompletely visualized TE‐treated lesions required operation, and 18% of well visualized ulcers underwent operation (p<0.0001). Hospital mortality was similar (8% versus 16%) in the endoscopic and operated groups (p=0.7). Mean follow‐up was 540 days. The number of operations performed for bleeding duodenal ulcer did not change significantly during the TE era, and a significant subset (23%) of endoscopically treated patients required surgical therapy. TE failure was portended by hemodynamic instability or incomplete endoscopic visualization.

The mechanisms underlying CD4+ T cell depletion in human immunodeficiency virus (HIV) infection are not well understood. Comparative studies of lymphoid tissues, where the vast majority of T cells reside, and peripheral blood can potentially illuminate the pathogenesis of HIV-associated disease. Here, we studied the effect of HIV infection on the activation and depletion of defined subsets of CD4+ and CD8+ T cells in the blood, gastrointestinal (GI) tract, and lymph node (LN). We also measured HIV-specific T cell frequencies in LNs and blood, and LN collagen deposition to define architectural changes associated with chronic inflammation. The major findings to emerge are the following: the GI tract has the most substantial CD4+ T cell depletion at all stages of HIV disease; this depletion occurs preferentially within CCR5+ CD4+ T cells; HIV-associated immune activation results in abnormal accumulation of effector-type T cells within LNs; HIV-specific T cells in LNs do not account for all effector T cells; and T cell activation in LNs is associated with abnormal collagen deposition. Taken together, these findings define the nature and extent of CD4+ T cell depletion in lymphoid tissue and point to mechanisms of profound depletion of specific T cell subsets related to elimination of CCR5+ CD4+ T cell targets and disruption of T cell homeostasis that accompanies chronic immune activation.