Optimization of Ga-67 imaging for detection and estimation tasks: dependence of imaging performance on spectral acquisition parameters

We have compared the use of two (93 and 185 keV) and three (93, 185, and 300 keV) photopeaks for Ga-67 tumor imaging and optimized the placement of each energy window. METHODS: The bases for optimization and evaluation were ideal and Bayesian signal-to-noise ratios (SNR) for the detection of spheres embedded in a realistic anthropomorphic digital torso phantom and ideal SNR for the estimation of their size and activity concentration. Seven spheres of radii ranging from 1 to 3 cm, located at several sites in the torso, were simulated using a realistic Monte Carlo program. We also calculated the ideal SNR for the detection from simple phantom acquisitions. RESULTS: For detection and estimation tasks, the optimum windows were identical for all sphere sizes and locations. For the 93 keV photopeak, the optimal window was 84-102 keV for the detection and 87-102 keV for estimation; these windows are narrower than the 20% window often used in the clinic (83-101 keV). For the 185 keV photopeak, the optimal window was 170-220 keV for the detection and 170-215 keV for estimation; these are substantially different than the 15% window used in our clinic (171-199 keV). For the 300 keV photopeak, the optimal window for detection was 270-320 keV, and for estimation, 280-320 keV. Using the three optimized, rather than only the two lower-energy, windows yielded a 9% increase in the SNR for the detection of the 3 cm diam sphere (a 12% increase for a 2 cm diam sphere) and a 7% increase in the SNR for estimation of its size. For the acquired phantom data, detection also increased by 9%-12% when using three, rather than two, energy windows.     

Invasive micropapillary carcinoma of the breast is associated with chromosome 8 abnormalities detected by comparative genomic hybridization

Invasive micropapillary carcinoma (IMC) of the breast is a rare variant of invasive ductal carcinoma (IDC) characterized by unique histology and an extremely high incidence of lymph node metastases (approximately 95%). Comparative genomic hybridization (CGH) was used to characterize DNA extracted from 16 archival IMC cases to identify clonal genetic changes associated with this unique and highly metastatic cancer subtype. The average number of chromosomal alterations per IMC tumor was 7.4 +/-2.9 (3.4 gains and 3.9 losses), fewer than the number that we have observed in IDCs not otherwise specified (9.5 +/-6.6), IDCs with erbB-2 gene amplification (12.6 +/-5.9), and invasive lobular carcinomas (8.2 +/-5.5). The mean number of changes in IMC was significantly higher than we have observed in the rarely metastasizing tubular subtype of IDC (3.9 +/-2.3, P = 0.001), but less than the more aggressive subset of erbB-2-amplified IDC (P = 0.02). Remarkably, 100% of IMCs demonstrated loss involving the short arm of chromosome 8 (8p). Six cases showed loss of the entire 8p arm, whereas in 10 cases the loss was limited to the distal portion (8p21-pter) with localized gain of proximal 8p (8p11-p12). A reciprocal gain of 8q was detected in 14 cases (88%). Other common alterations included loss of 17p in 50% of tumors and loss of 16q in 50% of IMC cases. Gains of 17q (38%), 1q (31%), and 16p (25%) were also commonly detected. In comparison, IDCs (not otherwise specified), IDCs of the tubular subtype, and invasive lobular carcinomas showed only modest 8p loss (33%, 28%, and 13%, respectively). This region of chromosome 8 may contain 1 or more genes whose loss leads to this particular histology and/or the lymphotrophic phenotype associated with this histopathologic pattern.     

Molecular characterisation of the dominant UK methicillin-resistant Staphylococcus aureus strains,EMRSA-15 and EMRSA-16

Epidemic methicillin-resistant Staphylococcus aureus types 15 and 16 (EMRSA-15 and EMRSA-16) are the dominant types of MRSA found in UK hospitals, but accurate designation of strains has been difficult. Restriction fragment length polymorphism (RFLP) profiles of seven core virulence genes were used to classify unambiguously isolates of MRSA from St George's Hospital into two groups corresponding to EMRSA-15 and EMRSA-16. Variants of both EMRSA-15 and EMRSA-16 isolates occurred that had lost virulence genes encoded on mobile genetic elements. EMRSA-16 isolates had core gene profiles identical to a cluster of previously characterised MSSA (methicillin-sensitive S. aureus) isolates from St George's Hospital, suggesting that they have arisen from this source, or that loss of the accessory genetic element encoding methicillin resistance is frequent. EMRSA-15 and EMRSA-16 strains were distinct from other MRSA strains previously identified in UK hospitals, and always carried a mobile genetic element encoding multiple superantigens. These results contribute to the understanding of the types of MRSA found in UK hospitals, how they vary and how they arose.     

Mutations in a protein target of the Pim-1 kinase associated with the RP9 form of autosomal dominant retinitis pigmentosa

The RP9 form of autosomal dominant retinitis pigmentosa (adRP) maps to a locus on human chromosome 7p14. We now report two different disease associated mutations in a previously unidentified human gene, the mouse orthologue of which has been characterised by its interaction with the Pim-1 oncogene. In the original linked family we identified the missense mutation H137L. A second missense mutation, D170G, was found in a single RP patient. The putative RP9 gene appears to be expressed in a wide range of tissues, but its function is unknown and a pathogenic mechanism remains to be determined.     

Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress

The identification of rare monogenic forms of Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis of this disorder. Heritable mutations in alpha-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.     

Epstein-Barr viral load as a marker of lymphoma in AIDS patients

Epstein-Barr virus (EBV) is implicated in the pathogenesis of acquired immunodeficiency syndrome (AIDS) lymphoma, and viral DNA is present within the malignant cells in about half of affected patients. We examined the extent to which EBV viral load is elevated in the plasma of AIDS lymphoma patients compared to AIDS patients with opportunistic infections. Sixty-one AIDS patients were studied including 35 with lymphoma (24 non-Hodgkin, six Hodgkin, and five brain lymphoma) and 26 with various opportunistic infections. In situ hybridization revealed EBV encoded RNA (EBER) expression in the malignant cells of 17/28 AIDS lymphomas (61%). In 232 serial plasma samples from 35 lymphoma patients and in 128 samples from AIDS controls, EBV viral load was assayed by quantitative-polymerase chain reaction (Q-PCR) using a TaqMan probe targeting the BamH1W sequence. EBV was detected in plasma from all 17 EBER-positive AIDS lymphoma patients, with viral loads ranging from 34 to 1,500,000 copies per ml (median 3,210). Viral load usually fell rapidly upon initiation of lymphoma therapy and remained undetectable except in two patients with persistent tumor. In 11 AIDS patients, whose lymphoma lacked EBER expression, and in 26 control patients without lymphoma, levels of EBV in plasma were usually low or undetectable (range 0-1,995 and 0-2,409, median 0 and 0, respectively). There was no association between EBV viral load and human immunodeficiency virus (HIV) load or CD4 count. In conclusion, EBV viral load shows promise as a tool to assist in diagnosis and management of EBV-related lymphoma patients.     

Racial and gender disparities in receipt of highly active antiretroviral therapy persist in a multistate sample of HIV patients in 2001

BACKGROUND: National data from the mid-1990s demonstrated that many eligible patients did not receive highly active antiretroviral therapy (HAART) and that racial and gender disparities existed in HAART receipt. We examined whether demographic disparities in the use of HAART persist in 2001 and if outpatient care is associated with HAART utilization. METHODS: Demographic, clinical, and pharmacy utilization data were collected from 10 US HIV primary care sites in the HIV Research Network (HIVRN). Using multivariate logistic regression, we examined demographic and clinical differences associated with receipt of HAART and the association of outpatient utilization with HAART. RESULTS: In our cohort in 2001, 84% of patients received HAART and 66% had 4 or more outpatient visits during calendar year (CY) 2001. Of those with 2 or more CD4 counts below 350 cells/mm in 2001, 91% received HAART; 82% of those with 1 CD4 test result below 350 cells/mm received HAART; and 77% of those with no CD4 counts below 350 cells/mm received HAART. Adjusting for care site in multivariate analyses, age >40 years (adjusted odds ratio [AOR] = 1.13), male gender (AOR = 1.23), Medicaid coverage (AOR = 1.16), Medicare coverage (AOR = 1.73), having 1 or more CD4 counts less than 350 cells/mm (AOR = 1.33), and having 4 or more outpatient visits in a year (OR = 1.34) were significantly associated with an increased likelihood of HAART. African Americans (odds ratio [OR] = 0.84) and those with an injection drug use risk factor (OR = 0.86) were less likely to receive HAART. CONCLUSIONS: Although the overall prevalence of HAART has increased since the mid-1990s, demographic disparities in HAART receipt persist. Our results support attempts to increase access to care and frequency of outpatient visits for underutilizing groups as well as increased efforts to reduce persistent disparities in women, African Americans, and injection drug users (IDUs).     

Neurocognitive outcomes in survivors of childhood cancer

OBJECTIVE:s To review issues associated with neurocognitive outcome in survivors of pediatric cancer. Recommendations are made for future research directions. METHODS: A large body of literature pertaining to neurocognitive outcome in cancer survivors was reviewed. Brain development and methodological issues that provide challenges to conducting meaningful research in cancer outcomes also are discussed. RESULTS: Neurotoxic agents used in some cancer therapies produce permanent neurocognitive sequelae, especially in very young children. CONCLUSIONS: The state of neurocognitive research for pediatric cancer survivors needs to move beyond empirical studies of neurocognitive sequelae to research that will identify individual patients at risk for neurocognitive morbidity.     

IP-10 mediates selective mononuclear cell accumulation and activation in response to intrapulmonary transgenic expression and during adenovirus-induced pulmonary inflammation.

CXC chemokines that lack the glutamine-leucine-arginine (ELR) motif, including interferon (IFN)-inducible protein 10 (IP-10 or CXCL10), have been shown to mediate the generation of type 1 immune responses. In this study, we found that the intrapulmonary transient transgenic expression of murine IP-10 in mice using adenoviral gene transfer resulted in the early accumulation of neutrophils, natural killer (NK) cells, and NK T cells within the lung, followed by the delayed accumulation of CD4+ T cells. Adenovirus-mediated transgenic expression of IP-10 also resulted in selective activation of mononuclear cells, including gamma(delta)-T cells and NK cells, as manifest by CD69 expression or induction of cell-associated IFN-gamma. Importantly, the intratracheal (i.t.) administration of a control human type 5 adenovirus also caused significant accumulation of NK, NK T, and CD4+ T cells, which was maximal at 7 days post vector administration and was associated with the induction of IP-10. Neutralization of endogenous IP-10 in animals receiving control adenovirus resulted in decreases in the numbers of NK, CD4+, and CD8+ T cells. These results indicate that IP-10 can direct the accumulation and activation of neutrophils and selected mononuclear cells to the lung and that adenovirus-induced IP-10 contributes to lung inflammatory cell recruitment/activation observed in response to adenoviral vectors used for gene therapy.