BRD4 Bromodomain Gene Rearrangement in Aggressive Carcinoma with Translocation t(15;19)

Translocation t(15;19)(q13;p13.1) defines a lethal midline carcinoma arising adjacent to respiratory tract in young people. To characterize molecular alterations responsible for the distinctly aggressive biological behavior of this cancer, we mapped the chromosome 15 and 19 translocation breakpoints by fluorescence in situ hybridization (FISH) and Southern blotting. To evaluate preliminarily the frequency, anatomical distribution, and histological features of t(15;19) cancer, we developed a FISH assay for paraffin sections. Our findings reveal a novel oncogenic mechanism in which the chromosome 19 translocation breakpoint interrupts the coding sequence of a bromodomain gene, BRD4. These studies implicate BRD4 as a potential partner in a t(15;19)-associated fusion oncogene. In addition, we localized the chromosome 15 breakpoint to a 9-kb region in each of two cases, thereby identifying several candidate oncogenes which might represent the BRD4 fusion partner. FISH evaluation of 13 pediatric carcinomas revealed t(15;19) in one of four sinonasal carcinomas, whereas this translocation was not detected in thymic (n = 3), mucoepidermoid (n = 3), laryngeal (n = 2), or nasopharyngeal (n = 1) carcinomas. Our studies shed light on the oncogenic mechanism underlying t(15;19) and provide further evidence that this highly lethal cancer arises from respiratory mucosa.     

Pre-B cells and other possible precursor lymphoid cell lines derived from patients with X-linked agammaglobulinemia

A group of unique Epstein-Barr virus-containing cell lines was derived from the bone marrow of three patients with X-linked agammaglobulinemia. Efforts to obtain cell lines from the peripheral blood of these patients were uniformly unsuccessful. Immunofluorescence analyses as well as biosynthetic studies with [(35)S]methionine indicated unusual patterns of Ig synthesis in many of these bone marrow derived lines. Seven of the lines were of particular interest in that two produced no Ig of any type; two others showed no Ig by fluorescence but small amounts by [(35)S]methionine labeling; one expressed only cytoplasmic μ chains without any evidence of light chain synthesis, and two produced primarily μ chains with only slight amounts of light chains. One of the lines without membrane or cytoplasmic Ig studied in detail grew like a typical lymphoid line and was carried in intermittent culture over a period of 2 yr without Ig expression. One line grew quite differently and resembled the round cell type described previously, which has been obtained from a variety of sources. The cell line with cytoplasmic μ chains and no light-chain expression had the characteristic properties of pre-B cells. Three normal type Ig-producing cell lines also were obtained from the patients. The accumulated evidence obtained in the present study indicates that these unusual cell lines represent normal precursor cells of the B-cell lineage; these grew out in these cases because of the virtual absence of mature B cells that ordinarily overgrow the culture system. However, the possibility that in certain instances they reflect abnormal Ig synthesis characteristic of the disease has not been ruled out.     

An important risk factor in idiopathic generalized epilepsies

15q13.3 microdeletions increase risk of idiopathic generalized epilepsy
Helbig et al. (2009)
Nature Genetics 41(2):160–162     

Secondary pigmented macular pucker on optical coherence tomography

Purpose: To describe the clinical features, retinal architecture and tomographic configuration of a pigmented epiretinal membrane on optical coherence tomography (OCT). Methods: A 52‐year‐old man presented during a routine examination with an asymptomatic, darkly pigmented, pre‐retinal epiretinal membrane in his right eye. His best corrected visual acuity (BCVA) on Snellen charts was 20/25 in the right eye and 20/20 in the left. The patient complained of no visual symptoms or metamorphopsia. Results: In the fundus periphery there was a small, old, well pigmented retinal hole with pigmentation in its immediate vicinity, without signs of vitreal traction, which required no treatment. The foveal indentation was not apparent on OCT and a well demarcated hyperreflective band defined the pigmented epiretinal membranes (ERMs). Sequential fundus examination over a 2‐year period demonstrated no functional or anatomical deterioration attributable to the disease. Conclusions: Pigmented ERM may have different cellular origins depending on the underlying pathology. Patients with pigmented ERM and full VA should be followed by sequential OCT.     

Multicenter study of whole-blood creatinine, total carbon dioxide content, and chemistry profiling for laboratory and point-of-care testing in critical care in the United States

OBJECTIVES: To introduce a creatinine biosensor and a total carbon dioxide content (TCO2) method for whole-blood measurements, to evaluate the clinical performance of a new transportable analyzer that simultaneously performs these two and six other tests (Na+, K+, Cl-, glucose, urea nitrogen, and hematocrit), and to assess the potential of the new analyzer for point-of-care testing in critical care by comparing results obtained by nonlaboratory personnel and by medical technologists. DESIGN: Multicenter sites compared whole-blood measurements with the transportable analyzer to plasma measurements from the same specimens with local reference instruments. One site compared whole-blood results produced by nonlaboratory personnel vs. medical technologists and evaluated day-to-day and within-day precision at the point of care. SETTINGS AND PATIENTS: Four medical centers in the United States. Venous and arterial specimens from 710 critically ill patients with a variety of diagnoses. Point-of-care testing in the emergency room and operating room. RESULTS: The linear regression analyses at the four medical centers showed the following: creatinine (a) slope, 0.91 to 1.22, (b) y intercept, -0.07 to 0.15 mg/dL, and (c) r2, 0.77 to 1.00; and TCO2: (a) slope, 0.64 to 1.00, (b) y intercept, 1.36 to 9.6 mmol/L, and (c) r2, 0.52 to 0.72 (yi, whole-blood analyses; xi, plasma reference measurements). Bland-Altman plots also were used to assess multicenter creatinine and TCO2 results. Of the other analytes, K+, glucose, and urea nitrogen had the highest r2-values. For the eight chemistry profile tests performed at the point of care (yi, nonlaboratory personnel results; xi, medical technologist results), the average value of r2 was 0.96 (SD 0.08) in the operating room and 0.96 (SD 0.06) in the emergency room, and mean paired differences (yi - xi) were not statistically or clinically significant. Precision was acceptable. CONCLUSIONS: The performance of the creatinine biosensor and the TCO2 method was acceptable for whole-blood samples. Comparisons of whole-blood results from the transportable analyzer and plasma results from the local reference instruments revealed analyte biases that may be attributed to differences between direct whole-blood analyses and indirect-diluted plasma measurements and other factors. Performance of nonlaboratory personnel and medical technologists was equivalent for point-of-care testing in critical care settings. The whole-blood analyzer should be useful when patient care demands immediate results.     

Assessment of an abbreviated odorant identification task for children: a rapid screening device for schools and clinics

To validate the level of olfactory performance of children, we tested 825 volunteers, aged 4–17 years, with an abbreviated form of our pediatric odorant identification task. The test consisted of sniffing and identifying five odorants (baby powder, bubble gum, candy cane, licorice and peach). Mean olfactory scores increased as a function of age, reaching a plateau of about 94–95% correct at 8 years of age. In general, girls out–performed boys. Physicians require a test instrument such as the one we have devised to allow them to diagnose olfactory dysfunction in children. The present task is particularly applicable in screening large numbers of children in clinics or schools because it can be administered easily and rapidly. Adult subjects with olfactory dysfunction also performed poorly on this odorant identification task designed for children. Therefore, we expect that our odorant identification task will also detect children with severe olfactory dysfunction.