Common founder BRCA2 pathogenic variants and breast cancer characteristics in Ethiopian Jews.

PURPOSE: BRCA1/2 founder pathogenic variants (PVs) occur in various populations, but data on the mutational spectrum in Africans are limited. We examined BRCA1/2 PVs in breast cancer patients of Ethiopian Jewish (EJ) origin. METHODS: We retrospectively analyzed BRCA1/2 test results and clinical features of EJ breast cancer patients from seven medical institutions. We obtained heterozygote carrier rates in affected individuals from the laboratories of the largest Israeli HMO (Clalit). Population carrier frequency was determined in EJ controls. RESULTS: We identified three recurrent BRCA2 PVs in 11 EJ breast cancer patients (9 females, 2 males): c.7579delG, c.5159C > A, and c.9693delA. Only c.5159C > A was previously reported in Africans. In women, mean age at diagnosis was 35.7y; 8/9 were diagnosed with advanced disease. All tumors were invasive, 4/9 were triple negative. Only 3/11 carriers had relevant family history. Carrier rate in high-risk breast cancer patients was 11% (3/28; 95%CI [2.3%, 28.2%]). Combined carrier rate among controls was 1.8% (5/280; 95%CI [0.6%, 4.1%]). CONCLUSION: EJs harbor 3 recurrent BRCA2 PVs presenting with relatively severe breast cancer morbidity. Combined with the high BRCA2 carrier rate in the EJ population, these findings merit increasing awareness in this community and suggest that a culturally adapted population screening approach may be warranted.

Comparison of radiation dose between 2D digital stereotactic versus digital breast tomosynthesis-guided breast biopsies.

RATIONALE AND OBJECTIVE: Use of digital breast tomosynthesis (DBT) in breast imaging has necessitated DBT-guided biopsy, however, a single DBT acquisition may result in a greater radiation dose than a single DM acquisition. Our objective was to compare the number of images acquired and the resulting radiation dose of DBT versus DM-guided breast biopsies. METHOD: All biopsies performed on our DM unit from 8/2016 to 1/2017 and on our DM-DBT unit from 8/2017 to 1/2018 were retrospectively reviewed. The number of image acquisitions, average glandular dose (AGD) per acquisition and per procedure were computed and stratified by guidance modality and lesion type. RESULTS: 25 DM-guided biopsies were performed on the DM-only unit, 58 biopsies were performed with DM guidance on the dual unit (DM-DU) and 29 were performed with DBT. The average number of images acquisitions was 10.9 for DM-only unit biopsies, 9.3 images for DM-DU biopsies and 4.3 images for DBT-guided biopsies. Mean procedure AGD for DM-only unit biopsies was 28.77 mGy, versus 22.06 mGy for DM-DU and 10.18 mGy for DBT biopsies. Mean procedure AGD for biopsied calcification-only lesions was 22.3 mGy for DM-DU versus 10.7 mGy for DBT guidance (p < 0.001), with an average of 8.1 images per procedure for DM-DU versus 4.2 for DBT. CONCLUSION: Fewer image acquisitions were obtained with DBT compared with DM guidance, therefore, the overall dose of DBT-guided procedures was less. The dose reduction obtained with DBT is possible across all lesion types, even for calcification-only lesions.

Sports-Related Concussion in Helmeted vs. Unhelmeted Athletes: Who Fares Worse?

In the management of sports-related concussion, little is known about the effect of wearing or not wearing a helmet (i. e., helmet status) on the acute outcomes of concussed athletes. We endeavored to assess acute neurocognitive and symptom changes after SRC in helmeted vs. unhelmeted athletes. In a retrospective study, 1 025 athletes from 2 regional databases sustained a SRC. Athletes were matched by age, gender, number of prior concussions, and days to post-concussion test, yielding a final cohort of 138 athletes. For each group of 69, differences in post-concussion neurocognitive and symptom scores were compared using group mean differences as well as reliable change index (RCI) scores set at the 80% confidence interval. With gender, prior concussions, and days to post-concussion test similar in each group, using group mean change scores and RCI methodology, we found no significant differences between the helmeted and unhelmeted groups in 4 neurocognitive tests and one total symptom score. In a cohort of carefully matched athletes from 2 regional concussion centers, helmet status was unrelated to neurocognitive scores and total symptoms in athletes after suffering a SRC. These findings suggest that acute outcomes in helmeted vs. unhelmeted sports are quite similar.

Attitudes of couples identified through screening as carriers of Gaucher disease type 1.

Gaucher disease (GD) type 1 is the most frequent autosomal recessive disorder among Ashkenazi Jews, but because the phenotype is tremendously variable, including it in the 'Ashkenazi Panel' of carrier screening is controversial. As part of a nationwide study conducted in Israel to evaluate the outcomes of carrier screening for GD, we studied the experience of 65/82 (79%) of the couples identified as being at risk for an affected child. We found that pre-test information was regarded as insufficient and improved in post-result counseling. About 70% of the subjects interpreted the genetic counseling as directive, mostly toward prenatal diagnosis (PND) but against pregnancy termination of affected fetuses. We evaluated the various motivations that had led couples to utilize PND. Subjects' attitudes toward pregnancy termination correlated with their specific genotypes, with their perception of the severity of GD and with attending additional medical consultation. Of the 30 interviewed participants who were faced with having an affected fetus, 80% came to terms with their decision to utilize PND, but about half of the few who terminated the pregnancy regret their decision. Despite questionable benefits of screening, most of the participants did not regret having been tested and supported the continuation of this program. We offer explanations for these findings and suggest extensive genetic and medical counseling for any future carrier screening for low penetrance, treatable disease.

Gamma interferon: a central mediator in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the vasculature with lesions developing in the arterial wall, frequently in the coronary and carotid arteries. The interaction between macrophages and lymphocytes within the atherosclerotic lesion microenvironment exemplifies a site where both innate and adaptive immunity contribute towards disease progression. As gamma interferon (IFN-gamma), the classic macrophage activating factor, has been localized to atherosclerotic lesions, this review will focus on its contribution to plaque pathology and will finally consider how current therapies, as exemplified by HMG CoA reductase inhibitors or statins, may impact this process beyond lipid lowering, in part by inhibiting IFN-gamma dependent processes. IFN-gamma sources within the atheroma as well as receptors, signaling pathways and its effects on macrophages as well as on vascular smooth muscle and endothelial cells will be considered. Therapeutic interventions targeting molecular events associated with IFN-gamma signaling offer novel approaches to the treatment of atherosclerosis.

Inhibition of glycinamide ribonucleotide formyltransferase results in selective inhibition of macrophage cytokine secretion in vitro and in vivo efficacy in rat adjuvant arthritis.

OBJECTIVE: To determine the effects of a glycinamide ribonucleotide formyltransferase (GARFT) inhibitor on macrophage inflammatory processes and in vivo in rat adjuvant arthritis. METHODS: GARFT inhibitors, LY309886 (6S-2',5'-thienyl-5, 10-dideazatetrahydrofolic acid) and LY329201 (R)-N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamatic acid disodium salt, were investigated in vitro and ex vivo on primary murine peritoneal macrophages and in the RAW macrophage cell line for both purine depletion and inhibition of LPS induced monokine secretion. In vivo efficacy following GARFT inhibition was evaluated in modified rat adjuvant arthritis. RESULTS: LY309886 inhibited purine biosynthesis in the RAW cell line with an EC50 of 90 nM, an effect readily reversible with exogenous hypoxanthine. LY309886 and LY329201 also inhibited LPS induced TNF alpha and MIP1 alpha in these cells and in primary macrophages. A similar effect could be demonstrated ex vivo with mice dosed for two days with 3 mg/kg of LY329201. LY329201 as well as methotrexate demonstrated a dose dependent reduction in both paw and spleen weight and improved joint histology following 2 weeks of dosing in a rat adjuvant arthritis study. CONCLUSION: These results suggest that GARFT inhibitors should be tested in the treatment of rheumatoid arthritis by considering their mechanism of action, here successfully tested on activated macrophages.

Verb movement in acquisition and aphasia: same problem, different solutions-evidence from Dutch.

This paper focuses on verb movement in agrammatism and child language. We present data from a sentence completion experiment with 6 Dutch agrammatic aphasics and 21 Dutch-speaking children. The experiment compares completion of matrix clauses (which require verb movement) and embedded clauses (where such movement is not required) in these two populations. The results reveal a clear asymmetry: Both agrammatics and children do very well with embedded clauses but fail in 50% with the matrix clauses. It is concluded that the problem which both populations are facing is one of verb movement rather than verb inflection. An error analysis of the responses reveals that, although both agrammatics and children try to avoid movement, they apply different strategies to achieve this goal.

TGF-beta increases cholesterol efflux and ABC-1 expression in macrophage-derived foam cells: opposing the effects of IFN-gamma.

The regulation of ATP-binding cassette transporter 1 (ABC-1) expression by cytokines present within the microenvironment of the atheroma may play an important role in determining the impact of reverse cholesterol transport on the atherosclerotic lesion. We recently reported that the macrophage-activating cytokine interferon (IFN)-gamma inhibited both cholesterol efflux and ABC-1 expression. In the present study, we investigated the effects of transforming growth factor (TGF)-beta, a cytokine also apparent within the atheroma, on cholesterol efflux, ABC-1 expression, and its ability to antagonize the inhibitory effects of IFN-gamma. TGF-beta significantly increased cholesterol efflux in macrophage-derived foam cells from apolipoprotein E (apoE) knockout mice, with maximal effects apparent at 300 pg/ml. The increases in efflux occurred without any effect on the passive diffusion component of efflux mediated by beta-cyclodextrin. Furthermore, the increase in cholesterol efflux occurred without any changes in free or esterified cholesterol pools and was consistent with an increase in both ABC-1 message and protein. Finally, TGF-beta was also demonstrated to inhibit the IFN-gamma-mediated down-regulation of ABC-1. These results further demonstrate the importance of cytokine cross-talk to impact the process of reverse cholesterol transport through a multitude of processes including the regulation of ABC-1.

Pharmacokinetics of mycophenolic acid after mycophenolate mofetil administration in liver transplant patients treated with tacrolimus.

The pharmacokinetics of mycophenolic acid (MPA) was studied after oral administration of mycophenolate mofetil (MMF) in 8 liver transplant patients. The mean (+/- SD) maximum MPA plasma concentration of 10.6 (+/- 7.5) mg/ml was achieved within 0.5 to 5 hours. The mean (+/- SD) steady-state area under the plasma concentration versus time curve (AUC(0-12)) was 40 (+/- 30.9) mg/ml/h. The mean (+/- SD) half-life was 5.8 (+/- 3.8) hours. There was poor correlation between trough blood concentrations of tacrolimus (r = -0.004) or serum creatinine (r = 0.689) with MPA AUC, while the serum bilirubin concentrations correlated (r = 0.743) well with MPA AUC, suggesting impairment in MPA conjugation in patients with liver dysfunction. The mean (+/- SD) ratio of the AUC of mycophenolic acid glucuronide (MPAG) to MPA was 64 (+/- 84), which correlated significantly with serum creatinine (r = 0.72) but not with serum bilirubin concentrations (r = 0.309), indicating accumulation of MPAG in patients with renal dysfunction. In 7 primary liver transplant patients on the same dose of MMF, the trough plasma concentrations of MPA during the first week of therapy ranged from < 0.3 to 1.5 microg/ml. The MPA concentrations increased by several folds during the next few weeks, which correlates well with increases in serum albumin concentrations. Changes in albumin appear to partially contribute to the variations in the pharmacokinetics of MPA in liver transplant patients.

TGF-beta reduced binding of high-density lipoproteins in murine macrophages and macrophage-derived foam cells.

The expression of macrophage scavenger receptors is regulated by intracellular cholesterol levels, as well as by cytokines affecting macrophage effector functions. CD36, a member of the type B scavenger receptor family, will bind a variety of nonlipoprotein and lipoprotein ligands including high-density lipoprotein (HDL). Transforming growth factor-beta (TGF-beta) has been demonstrated to modulate macrophage effector functions and is present within atherosclerotic lesions. In the present study, the effect of TGF-beta on HDL binding by both macrophages and macrophage-derived foam cells was evaluated. TGF-beta, in a dose-dependent manner, reduced the binding of flurochrome-labeled HDL to both macrophages and foam cells. These effects were observed in macrophages derived from nonatherosclerotic (BALB/c) as well as from macrophages obtained from both apolipoprotein E and low-density lipoprotein receptor knockout mice. The decrease in HDL binding was consistent with a significant reduction in CD36 message levels. The effect of TGF-beta on type B scavenger receptor expression was not limited to CD36 as SR-BI message was also downregulated, although the effect was more modest. A similar reduction in HDL binding and CD36 message was also observed with the immunosuppressive glucocorticoid dexamethasone. These results suggest that within the microenvironment of an atherosclerotic lesion, TGF-beta and other agents that inhibit macrophage inflammatory responses may impact lesion progression through mechanisms that include the modulation of HDL-foam cell interactions.

The effect of changing state health policy on hospital uncompensated care.

This paper examines the effect of changing state policy, such as Medicaid eligibility, payment generosity, and HMO enrollment on provision of hospital uncompensated care. Using national data from the American Hospital Association for the period 1990 through 1995, we find that not-for-profit and public hospitals' uncompensated care levels respond positively to Medicaid payment generosity, although the magnitude of the effect is small. Not-for-profit hospitals respond negatively to Medicaid HMO penetration. Public and for-profit hospitals respond negatively to increases in Medicaid eligibility. Results suggest that public insurance payment generosity is an effective but inefficient policy instrument for influencing uncompensated care among not-for-profit hospitals. Further, in localities with high HMO penetration or high penetration of for-profit hospitals, it may be necessary to establish explicit payments for care of the uninsured.

Confirming insurance coverage in a telephone survey: evidence from the National Survey of America's families.

Until recently, most surveys of insurance coverage have classified people as uninsured if they have not been assigned some coverage in response to one of a series of questions about specific types of insurance. This "residual" approach to measuring uninsurance rates has not required respondents to either verify their insurance status or confirm that they are uninsured. Using the 1997 National Survey of America's Families, this paper examines the impact of a question confirming whether individuals for whom no insurance coverage is reported are, in fact, uninsured. The results of our analysis suggest that a confirmation question as part of a telephone-based survey works to lower estimates of the uninsured.

The effect of gamma-interferon to inhibit macrophage-high density lipoprotein interactions is reversed by 15-deoxy-delta12,14-prostaglandin J2.

Macrophage activation has been recognized as playing a central role in chronic inflammatory diseases in general and, more specifically, in the vascular wall during the progression of atherosclerotic lesions. Macrophage-activating factors present within the atherosclerotic lesion include the colony-stimulating factors and gamma interferon (IFNgamma). In the present study, the effects of IFNgamma on macrophage binding and uptake of fluorochrome-labeled high density lipoprotein (HDL) were investigated by flow cytometry and by measuring the amount of the type B scavenger receptors CD36 and scavenger receptor type B (SR-BI) by Northern blot analysis. IFNgamma-, but not granulocyte macrophage colony-stimulating factor (GM-CSF)-treated murine peritoneal macrophages displayed a two- to threefold decrease in Dil-labeled HDL uptake. This effect was observed in the absence of a comparable decrease in SR-BI message and protein or CD36 message. This decrease in both HDL binding and uptake was reversed by the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, 15-deoxy-delta12,4-prostaglandin J2 (15d-PGJ2), which also inhibited the IFNgamma induction of the beta2 integrin CD11a. Furthermore, 15d-PGJ2 increased the expression of SR-BI and CD36 message and SR-BI protein which was reflected in an increase in HDL binding and uptake. These results suggest a role for PPARgamma agonists in modulating the IFNgamma-mediated macrophage effector functions relevant to atherosclerotic disease progression.

Trends in Medicaid physician fees, 1993-1998.

This study uses data on Medicaid physician fees in 1993 and 1998 to document variation in fees across the country, describe changes in these fees, and contrast how they changed relative to those in Medicare. The results show that 1998 Medicaid fees varied widely. Medicaid fees grew 4.6 percent between 1993 and 1998, lagging behind the general rate of inflation. This growth was greater for primary care services than for other services studied. Relative to Medicare physician fees, Medicaid fees fell by 14.3 percent between 1993 and 1998. Medicaid's low fees and slow growth rates suggest that potential access problems among Medicaid enrollees remain a policy issue that should be monitored.

Interferon-gamma induces downregulation of Tangier disease gene (ATP-binding-cassette transporter 1) in macrophage-derived foam cells.

Cholesterol efflux is a fundamental process that serves to mitigate cholesterol accumulation and macrophage foam cell formation. Recently, we reported that cholesterol efflux to high density lipoprotein subfraction 3 was reduced by interferon-gamma (IFN-gamma) and that this decrease was associated with an increase in acyl coenzyme A:cholesterol acyltransferase (ACAT) expression. In the present study, although treatment of murine peritoneal macrophages with IFN-gamma resulted in a 2-fold decrease in HDL-mediated cholesterol efflux, efflux to lipid-free apolipoprotein A-I was reduced >4-fold and approached basal levels. This decrease was associated with a 3- to 4-fold reduction in ATP-binding-cassette transporter 1 (ABC1) mRNA content, the gene responsible for the defect in Tangier disease. Consistent with the reduction in cholesterol and phospholipid efflux in Tangier fibroblasts, downregulation of ABC1 expression by IFN-gamma also resulted in reduced phosphatidylcholine and sphingomyelin efflux to apolipoprotein A-I. Whereas foam cells had a 3-fold increase in ABC1 mRNA, the decrease in ABC1 message levels by IFN-gamma was observed in foam cells and control macrophages. This effect of IFN-gamma was independent of general macrophage activation (inasmuch as similar changes were not detected with granulocyte-macrophage colony-stimulating factor) and was not observed with other ABC transporters (inasmuch as the expression of the transporter in antigen processing was upregulated 4-fold in these same cells). Therefore, by decreasing cholesterol efflux through pathways that include the upregulation of ACAT and the downregulation of ABC1, IFN-gamma can shift the equilibrium between macrophages and foam cells and thus impact the progression of an atherosclerotic lesion.

Regulation of cholesterol distribution in macrophage-derived foam cells by interferon-gamma.

The Th1-derived cytokine gamma interferon, IFN-gamma, is present within the microenvironment of an atheromatous lesion and likely contributes to lesion progression through macrophage activation. While the inflammatory effects of IFN-gamma are well known, the role of this cytokine in cholesterol metabolism in macrophage derived foam cells is unclear. In the present study, the incubation of foam cells with IFN-gamma resulted in the reduction of HDL(3)-mediated cholesterol efflux. The decrease in cholesterol efflux was not observed with other macrophage-activating factors as colony-stimulating factors failed to demonstrate a similar effect. The reduction in cholesterol efflux was independent of apoE synthesis or SR-BI expression and was associated with a redistribution of intracellular cholesterol with an increase in cholesteryl ester accumulation. The increase in the esterified pool, primarily in cholesterol eicosapentadenoate, docosapentaenoate, arachidonate, and linoleate was associated with a 2-fold increase in acyl-CoA:cholesterol-O-acyltransferase, ACAT, activity and message without any change in neutral cholesteryl ester hydrolase activity. While CD36 message was reduced in IFN-gamma-treated foam cells, the ability to reverse the decrease in efflux by the ACAT inhibitor A58035 in a dose-dependent manner suggests that the IFN-gamma effect on efflux is primarily through the modulation of ACAT expression. Therefore, in addition to its inflammatory effects, IFN-gamma can contribute to the progression of an atherosclerotic lesion by altering the pathway of intracellular cholesterol trafficking in macrophage derived foam cells.

The National Survey of America's Families: an overview of the health policy component.

This report describes one aspect of "Assessing the New Federalism," a multi-year research project, started by the Urban Institute in 1996, to analyze the devolution of responsibility for social programs from the federal government to the states. The project combines case studies in 13 diverse states with analyses of data drawn from a wide range of sources, including a new household survey--the National Survey of America's Families (NSAF). The NSAF, which contains nationally representative data from almost 45,000 families, was fielded in 1997 and 1999, and is planned for 2001 and again at subsequent two-year intervals. In this paper, we provide an overview of the NSAF's purpose; the sampling approach and methods; the questionnaire content, with particular emphasis on questions of interest to health policy researchers; health policy research planned by Urban Institute staff; and the timetable for public release of the NSAF data.