Biomedical subjects
S Stone
Publications and source records attributed to S Stone.
Placentation, antiphospholipid syndrome and pregnancy outcome.
The antiphospholipid antibodies (aPLs) are a diverse group of autoantibodies associated with a pattern of disease known as antiphospholipid syndrome (APS). Pregnancy complications secondary to placental insufficiency are key features of this disease. The mechanisms underlying the placental pathology remain unclear. In this article the process of placentation in healthy and pathological pregnancies is reviewed. The evidence for defective placentation in APS pregnancies and involvement of aPLs in this process is summarized. Finally hypotheses based on the interpretation of these studies are discussed.
The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG.
Fanconi anemia (FA) is a chromosomal instability syndrome associated with a strong predisposition to cancer, particularly acute myeloid leukemia and squamous cell carcinoma. At the cellular level, FA is characterized by spontaneous chromosomal breakage and a unique hypersensitivity to DNA cross-linking agents. Complementation analysis has indicated that at least seven distinct genes are involved in the pathogenesis of FA. Despite the identification of four of these genes (FANCA, FANCC, FANCF and FANCG), the nature of the 'FA pathway' has remained enigmatic, as the FA proteins lack sequence homologies or motifs that could point to a molecular function. To further define this pathway, we studied the subcellular localizations and mutual interactions of the FA proteins, including the recently identified FANCF protein, in human lymphoblasts. FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG. These interactions were detected in wild-type and FA-D lymphoblasts, but not in lymphoblasts of other FA complementation groups. This implies that each of the FA proteins, except FANCD, is required for these complexes to form. Similarly, we show that the interaction between FANCA and FANCC is restricted to wild-type and FA-D cells. Furthermore, we document the subcellular localization of FANCA and the FANCA/FANCG complex in all FA complementation groups. Our results, along with published data, culminate in a model in which a multi-protein FA complex serves a nuclear function to maintain genomic integrity.
Study of charmless hadronic B meson decays to pseudoscalar-vector final states.
We report results of searches for charmless hadronic B meson decays to pseudoscalar( pi(+/-), K+/-, pi(0), or K(0)(S))-vector( rho, K(*), or omega) final states. By using 9.7x10(6) BB pairs collected with the CLEO detector, we report the first observation of B(-)--->pi(-)rho(0), B(0)-->pi(+/-)rho(-/+), and B(-)-->pi(-)omega, which are expected to be dominated by hadronic b-->u transitions. The measured branching fractions are (10.4(+3.3)(-3.4)+/-2.1)x10(-6), (27.6(+8.4)(-7.4)+/-4.2)x10(-6), and (11.3(+3.3)(-2.9)+/-1. 4)x10(-6), respectively. Branching fraction upper limits are set for all of the other decay modes investigated.
Feedback is necessary in strategies to reduce hospital acquired infection.
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Observation of B --> K(+/-) pi(0) and B --> (K)0 pi(0), and evidence for B --> pi(+)pi(-).
We have studied charmless hadronic decays of B mesons into two-body final states with kaons and pions and observe three new processes with the following branching fractions: beta(B-->pi(+)pi(-)) = (4.3(+1. 6)(-1.4)+/-0.5)x10(-6), beta(B-->K(0)pi(0)) = (14.6(+5.9+2.4)(-5.1-3. 3))x10(-6), and beta(B-->K(+)/-pi(0)) = (11.6(+3.0+1.4)(-2.7-1.3))x10(-6). We also update our previous measurements for the decays B-->K(+)/-pi(-/+) and B+/--->K(0)pi(+/-).
Two-body B meson decays to eta and eta('): observation of B --> eta K*.
In a sample of 19 x 10(6) produced B mesons, we have observed the decays B-->eta K(*) and improved our previous measurements of B-->eta'K. The branching fractions we measure for these decay modes are B(B+-->eta K(*+)) = (26.4(+9.6)(-8.2)+/-3.3)x10(-6), B(B(0)-->eta K(*0)) = (13.8(+5.5)(-4.6)+/-1.6)x10(-6), B(B(+)-->eta'K(+) = (80(+10)(-9)+/-7)x10(-6), and B(B(0)-->eta'K0) = (89(+18)(-16)+/-9)x10(-6). We have searched with comparable sensitivity for related decays and report upper limits for these branching fractions.
Measurement of charge asymmetries in charmless hadronic B meson decays.
We search for CP-violating charge asymmetries (alpha(CP)) in the B meson decays to K(+/-)pi(-/+), K(+/-)pi(0), K(0)(S)pi(+/-), K(+/-)eta('), and omega pi(+/-). Using 9.66 million upsilon(4S) decays collected with the CLEO detector, the statistical precision on alpha(CP) is in the range of +/-0.12 to +/-0.25 depending on decay mode. While CP-violating asymmetries of up to +/-0.5 are possible within the standard model, the measured asymmetries are consistent with zero in all five decay modes studied.
Posttranscriptional cell cycle-dependent regulation of human FANCC expression.
The Fanconi Anemia (FA) Group C complementation group gene (FANCC) encodes a protein, FANCC, with a predicted M(r) of 63,000 daltons. FANCC is found in both the cytoplasmic and the nuclear compartments and interacts with certain other FA complementation group proteins as well as with non-FA proteins. Despite intensive investigation, the biologic roles of FANCC and of the other cloned FA gene products (FANCA and FANCG) remain unknown. As an approach to understanding FANCC function, we have studied the molecular regulation of FANCC expression. We found that although FANCC mRNA levels are constant throughout the cell cycle, FANCC is expressed in a cell cycle-dependent manner, with the lowest levels seen in cells synchronized at the G1/S boundary and the highest levels in the M-phase. Cell cycle-dependent regulation occurred despite deletion of the 5' and 3' FANCC untranslated regions, indicating that information in the FANCC coding sequence is sufficient to mediate cell cycle-dependent regulation. Moreover, inhibitors of proteasome function blocked the observed regulation. We conclude that FANCC expression is controlled by posttranscriptional mechanisms that are proteasome dependent. Recent work has demonstrated that the functional activity of FA proteins requires the physical interaction of at least FANCA, FANCC, and FANCG, and possibly of other FA and non-FA proteins. Our observation of dynamic control of FANCC expression by the proteasome has important implications for understanding the molecular regulation of the multiprotein complex. (Blood. 2000;95:3970-3977)
Pneumococcal vaccine and the elderly.
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Prenatal alcohol exposure increases TNFalpha-induced cytotoxicity in primary astrocytes.
We examined the effect of prenatal alcohol exposure (PAE) on tumor necrosis factor-alpha-(TNFalpha) induced cell death in primary astrocyte cultures. Flow cytometry revealed that PAE increased the sensitivity of astrocytes to the cytotoxic effects of TNFalpha when compared to astrocytes prepared from pair-fed and chow-fed controls. In a number of cell types, TNFalpha regulates cell growth or death, in part, by the hydrolysis of sphingomyelin to ceramide and sphingosine-1-phosphate (SPP). Using a 3-(4. 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxic assay we found that PAE increased the sensitivity of astrocytes to the cytotoxic effects of TNFalpha, sphingomyelinase (SMase), and C(2)- and C(6)-ceramide. The increasing cellular concentrations of SPP, a sphingolipid metabolic that induces cell growth, protected the cells from TNFalpha-induced cell death. N, N-dimethylsphingosine (DMS), which inhibits SPP production, and N-oleoylethanolamine, which inhibits acid ceramidases, increased TNFalpha-induced cytotoxicity in astrocytes prepared from PAE rats. These studies suggest that PAE shifts the balance of sphingolipid metabolism in favor of a pathway that increases the susceptibility of astrocytes to the cytotoxic effect of TNFalpha.
Sentinel node biopsy for staging of aggressive digital papillary adenocarcinoma.
BACKGROUND: Aggressive digital papillary adenocarcinoma is a rare malignancy with a propensity for metastases and recurrence. The role of lymph node staging in this tumor is poorly defined. We describe the use of sentinel lymph node mapping and biopsy in staging this tumor. OBJECTIVE: To describe and discuss the use of lymphatic mapping in staging aggressive digital papillary adenocarcinoma. METHODS: Sentinel lymph node mapping and biopsy was performed after excision of an aggressive digital papillary adenocarcinoma of the toe. RESULTS: Metastatic tumor cells were absent in sentinel lymph nodes by hematoxylin and eosin staining and immunocytochemistry analysis. CONCLUSION: We describe the first reported case of staging lymph nodes in a patient with aggressive digital papillary adenocarcinoma utilizing sentinel lymph node mapping and biopsy.
Antibiotic prescribing for patients with colds, upper respiratory tract infections, and bronchitis: A national study of hospital-based emergency departments.
STUDY OBJECTIVE: Antibiotics are often used to treat viral upper respiratory tract infections, even though they are usually ineffective. However, frequent inappropriate antibiotic use contributes to the emergence of drug-resistant bacterial pathogens. This study used a national database to evaluate antibiotic use in treating upper respiratory tract infections in emergency departments. METHODS: Data were obtained from the 1996 National Hospital Ambulatory Medical Care Survey. Antibiotic prescribing rates were examined for colds, upper respiratory tract infections, and acute bronchitis. Patients with comorbid conditions or secondary diagnoses, such as chronic obstructive pulmonary disease, pneumonia, sinusitis, and HIV, were excluded. Bivariate and multivariate analyses were used to assess predictors of antibiotic use. RESULTS: Overall, there were an estimated 2.7 million ED visits for colds, upper respiratory tract infections, and bronchitis by children and adults in 1996. Antibiotics were prescribed for 24.2% (95% CI 18.9, 29.5) of patients with common colds and upper respiratory tract infections and for 42.2% (95% CI 35.2, 49.2) of patients with bronchitis. There were no significant associations between antibiotic use and patient race, sex, Hispanic ethnicity, geographic location, or source of payment. Antibiotics were prescribed less often by interns or residents than by staff or other physicians (odds ratio 0.43; 95% CI 0.19, 0.98), and patients younger than 18 years were less likely to receive antibiotics than adults (odds ratio 0.32; 95% CI 0.20, 0.52). Smokers were 4.3 (95% CI 2.2, 8.3) times more likely to receive antibiotics than nonsmokers. CONCLUSION: Antibiotics are commonly prescribed for ED patients with upper respiratory tract infections even though they are usually ineffective in otherwise healthy adults. Efforts should be made to reduce inappropriate antibiotic use for the sake of containing costs, preventing side effects, and limiting the spread of antibiotic resistance.
A normal livebirth after intracytoplasmic sperm injection for globozoospermia without assisted oocyte activation: case report.
The successful outcome of intracytoplasmic sperm injection (ICSI) with round-headed spermatozoa (globozoospermia) is reported. A couple with infertility secondary to globozoospermia received ICSI treatment. Fertilization, cleavage and pregnancy outcomes were recorded. This couple experienced 40, 10 and 42% fertilization rates after ICSI in their first, second and third cycles respectively. Pregnancy did not occur in the first or second cycle but was successfully achieved after the third ICSI cycle. It is concluded that current ICSI procedures may overcome the infertility associated with globozoospermia and result in normal healthy livebirth without assisted oocyte activation.
Ethanol increases the neurotoxic effect of tumor necrosis factor-alpha in cultured rat astrocytes.
BACKGROUND: The central nervous system is particularly sensitive to the cytotoxic effect of ethanol. In vivo and in vitro studies indicate that ethanol decreases cell proliferation in a number of cells types, including neurons and glial cells in the central nervous system. The cellular mechanisms involved in ethanol-induced cell toxicity, however, are unclear. In this study, we examined the effect of ethanol on tumor necrosis factor-alpha (TNFalpha)-induced cell death in a homogeneous population of cultured rat astrocytes. METHODS: Flow cytometric and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenytetrazolium bromide (MTT) dye reduction analyses were performed on cultured rat astrocytes to determine the effect of alcohol on TNFalpha-induced cell death. RESULTS: Flow cytometric analysis revealed that, in quiescent astrocytes, high concentrations of ethanol were required to increase DNA fragmentation and decrease cell viability. Preexposure of astrocytes to low concentrations of ethanol (10 to 50 mM), however, increased the sensitivity of astrocytes to TNFalpha with low TNFalpha concentrations (25 to 50 ng/ml) resulting in increased DNA fragmentation. Furthermore, MTT dye reduction analysis revealed that exposure of astrocytes to 5 mM ethanol was sufficient to increase the susceptibility of astrocytes to the cytotoxic effect of ethanol. In a number of cell types, TNFalpha receptor binding results in the activation of specific signal transduction cascades, including the hydrolysis of sphingomyelin to ceramide. We show that preexposure of astrocytes to a low concentration of ethanol increased the sensitivity of astrocytes to sphingomyelinase, and C2-ceramide resulting in increased DNA fragmentation and decreased cell viability. More importantly, astrocytes prepared from rats exposed to ethanol prenatally showed increased susceptibility to TNFalpha-induced cell death. CONCLUSIONS: These studies suggest that ethanol increases the susceptibility of astrocytes to TNFalpha-induced cell death by shifting the balance of sphingolipid metabolism in favor of a pathway that increases the susceptibility of astrocytes to the cytotoxic effect of TNFalpha.
Ethanol inhibits prolactin- and tumor necrosis factor-alpha-, but not gamma interferon-induced expression of intercellular adhesion molecule-1 in human astrocytoma cells.
In humans, alcohol consumption has multiple effects on the immune system. Despite an increase in our understanding of the effects of alcohol on the immune system, little is known about the effect of alcohol on the neuroimmune response. In the central nervous system (CNS), astrocytes and microglial function as immune effector cells. In response to infection of injury, astrocytes increase in number and size, express several proinflammatory cytokines, MHC class I and II antigens, and several adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1). Interactions between ICAM-1 and its counter-receptors play an important role in the regulation of neuroimmune response. In this study, cultured human astrocytoma cells were used to examine the effect of ethanol on ICAM-1 expression. Western blot analyses show that quiescent astrocytes express, at least, four immunoreactive ICAM-1 proteins with apparent molecular weights 55, 67, 82, and 90 kDa. Incubation of human astrocytoma cells with tumor necrosis factor-alpha (TNF-alpha) or prolactin (PRL) resulted in marked increases in all four immunoreactive ICAM-1 proteins. In the presence of ethanol, however, PRL- and TNF-alpha-induced increases in all four immunoreactive ICAM-1 proteins were markedly inhibited. ICAM-1 is a cell surface transmembrane glycoprotein. Using a cell surface specific ICAM-1 adhesion assay we found that in human astrocytoma cells TNF-alpha, interferongamma (IFN-gamma) and PRL increased cell surface ICAM-1 expression. Consistent with our Western blot analyses, ethanol significantly inhibited TNF-alpha- and PRL-induced cell surface ICAM-1 expression. By contrast, IFN-gamma-induced ICAM-1 expression was not inhibited by exposure of the cells to ethanol. Expression of ICAM-1 is regulated predominantly at the transcriptional level. In the present report, we show that TNF-alpha increased ICAM-1 mRNA levels in human astrocytoma cells and that ethanol markedly blocked TNF-alpha-induced increases in ICAM-1 mRNA levels. Further, we found that PRL-induced ICAM-1 expression was, at least in part, due to a PRL-induced increase in TNF-alpha syntheses and secretion. Our results clearly indicate that ethanol has a pronounced effect on ICAM-1 expression in human astrocytoma cells, thus suggesting that ETOH exposure may impair the immune response in the CNS by blocking leukocytes adhesion and migration into the CNS in response to injury or infection.
A nursing association's leadership in primary health care: policy, projects, and partnerships in the 1990s.
This paper documents the work of one provincial nursing association, the Registered Nurses Association of British Columbia (RNABC), to promote primary health care (PHC) as the foundation of the health-care system. In 1990 the RNABC embarked on a comprehensive policy program to influence change from a nursing perspective. A wide array of strategies was used over a 10-year period to help make PHC a reality in British Columbia's health-care system. Successful strategies used during this period included: writing and distributing policy papers, conducting and evaluating demonstration projects, and developing partnerships with other groups. Some of the projects and their outcomes are highlighted, followed by a critical reflection on lessons learned through the various initiatives. Although remarkable achievements were made from the RNABC's policy work during the 1990s, the advancement of PHC requires further collaborative efforts using multiple strategies.
Risk factors for injury to women from domestic violence.
BACKGROUND: Domestic violence is the most common cause of nonfatal injury to women in the United States. To identify risk factors for such injuries, we examined the socioeconomic and behavioral characteristics of women who were victims of domestic violence and the men who injured them. METHODS: We conducted a case-control study at eight large, university-affiliated emergency departments. The 256 intentionally injured women had acute injuries resulting from a physical assault by a male partner. The 659 controls were women treated for other conditions in the emergency department. Information was collected with a standardized questionnaire; no information was obtained directly from the male partners. RESULTS: The 256 intentionally injured women had a total of 434 contusions and abrasions, 89 lacerations, and 41 fractures and dislocations. In a multivariate analysis, the characteristics of the partners that were most closely associated with an increased risk of inflicting injury as a result of domestic violence were alcohol abuse (adjusted relative risk, 3.6; 95 percent confidence interval, 2.2 to 5.9); drug use (adjusted relative risk, 3.5; 95 percent confidence interval, 2.0 to 6.4); intermittent employment (adjusted relative risk, 3.1; 95 percent confidence interval, 1.1 to 8.8); recent unemployment (adjusted relative risk, 2.7; 95 percent confidence interval, 1.2 to 6.5); having less than a high-school-graduate's education (adjusted relative risk, 2.5; 95 percent confidence interval, 1.4 to 4.4); and being a former husband, estranged husband, or former boyfriend (adjusted relative risk, 3.5; 95 percent confidence interval, 1.5 to 8.3). CONCLUSIONS: Women at greatest risk for injury from domestic violence include those with male partners who abuse alcohol or use drugs, are unemployed or intermittently employed, have less than a high-school-graduate's education, and are former husbands, estranged husbands, or former boyfriends of the women.