The role of ABC transporters in ovarian cancer progression and chemoresistance.

Over 80% of ovarian cancer patients develop chemoresistance which results in a lethal course of the disease. A well-established cause of chemoresistance involves the family of ATP-binding cassette transporters, or ABC transporters that transport a wide range of substrates including metabolic products, nutrients, lipids, and drugs across extra- and intra-cellular membranes. Expressions of various ABC transporters, shown to reduce the intracellular accumulation of chemotherapy drugs, are increased following chemotherapy and impact on ovarian cancer survival. Although clinical trials to date using ABC transporter inhibitors have been disappointing, ABC transporter inhibition remains an attractive potential adjuvant to chemotherapy. A greater understanding of their physiological functions and role in ovarian cancer chemoresistance will be important for the development of more effective targeted therapies. This article will review the role of the ABC transporter family in ovarian cancer progression and chemoresistance as well as the clinical attempts used to date to reverse chemoresistance.

Does adopting a prenatal substance use protocol reduce racial disparities in CPS reporting related to maternal drug use? A California case study.

OBJECTIVE: This study examined whether adopting a standardized prenatal substance use protocol (protocol) in a hospital labor and delivery unit reduced racial disparities in reporting to child protective services (CPS) related to maternal drug use during pregnancy. STUDY DESIGN: This study used an interrupted time series design with a non-equivalent control. One hospital adopted a protocol and another hospital group serving a similar geographic population did not change protocols. Data on CPS reporting disparities from these hospitals over 3.5 years were analyzed using segmented regression. RESULT: In the hospital that adopted the protocol, almost five times more black than white newborns were reported during the study period. Adopting the protocol was not associated with reduced disparities. CONCLUSION: Adopting a protocol cannot be assumed to reduce CPS reporting disparities. Efforts to encourage hospitals to adopt protocols as a strategy to reduce disparities may be misguided. Other strategies to reduce disparities are needed.

Substance abuse treatment linked with prenatal visits improves perinatal outcomes: a new standard.

OBJECTIVE: To evaluate the impact of Early Start, an obstetric clinic-based prenatal substance abuse treatment program, on perinatal outcomes. STUDY DESIGN: Subjects were 49 985 women who completed Prenatal Substance Abuse Screening Questionnaires at obstetric clinics between 1 January 1999 and 30 June 2003, had urine toxicology screening tests and either live births or intrauterine fetal demises (IUFDs). Four groups were compared: women screened/assessed positive and treated by Early Start ('SAT', n=2073); women screened/assessed positive without treatment ('SA', n=1203); women screened positive only ('S', n=156); controls who screened negative (n=46,553). Ten neonatal and maternal outcomes were studied. RESULT: SAT women had either similar or slightly higher rates than the control women on most outcomes but significantly lower rates than S women. SA women generally had intermediate rates to the SAT and S groups. In multivariate analysis, the S group had significantly worse outcomes than the SAT group: preterm delivery (odds ratio (OR)=2.1, 1.3 to 3.2), placental abruption (OR=6.8, 3.0 to 15.5) and IUFD (OR=16.2, 6.0 to 43.8). CONCLUSION: Substance abuse treatment integrated with prenatal visits was associated with a positive effect on maternal and newborn health.

Unstudied infants: outcomes of moderately premature infants in the neonatal intensive care unit.

BACKGROUND: Newborns of 30-34 weeks gestation comprise 3.9% of all live births in the United States and 32% of all premature infants. They have been studied much less than very low birthweight infants. OBJECTIVE: To measure in-hospital outcomes and readmission within three months of discharge of moderately premature infants. DESIGN: Prospective cohort study including retrospective chart review and telephone interviews after discharge. SETTING: Ten birth hospitals in California and Massachusetts. PATIENTS: Surviving moderately premature infants born between October 2001 and February 2003. MAIN OUTCOME MEASURES: (a) Occurrence of assisted ventilation during the hospital stay after birth; (b) adverse in-hospital outcomes-for example, necrotising enterocolitis; (c) readmission within three months of discharge. RESULTS: With the use of prospective cluster sampling, 850 eligible infants and their families were identified, randomly selected, and enrolled. A total of 677 families completed a telephone interview three months after hospital discharge. During the birth stay, these babies experienced substantial morbidity: 45.7% experienced assisted ventilation, and 3.2% still required supplemental oxygen at 36 weeks. Readmission within three months occurred in 11.2% of the cohort and was higher among male infants and those with chronic lung disease. CONCLUSIONS: Moderately premature infants experience significant morbidity, as evidenced by high rates of assisted ventilation, use of oxygen at 36 weeks, and readmission. Such morbidity deserves more research.

Rehospitalisation after birth hospitalisation: patterns among infants of all gestations.

AIM: To analyse rehospitalisation of newborns of all gestations. METHODS: A total of 33,276 surviving infants of all gestations born between 1 October 1998 and 31 March 2000 at seven Kaiser Permanente Medical Care Program (KPMCP) delivery services were studied retrospectively. RESULTS: Rehospitalisation rates within two weeks after nursery discharge ranged from 1.0% to 3.7%. The most common reason for rehospitalisation was jaundice. Among babies > or =34 weeks, the most important factor with respect to rehospitalisation was use of home phototherapy. Among babies who were not rehospitalised for jaundice, African-American race (adjusted odds ratio (AOR) = 0.56), and having a scheduled outpatient visit (AOR = 0.73) or a home visit (AOR = 0.59) within 72 hours after discharge were protective. Factors associated with increased risk were: being small for gestational age (AOR = 1.83), gestational age of 34-36 weeks without admission to the neonatal intensive care unit (AOR = 1.65), Score for Neonatal Acute Physiology, version II, > or =10 (AOR = 1.95), male gender (AOR = 1.24), having both a home as well as a clinic visit within 72 hours after discharge (AOR = 1.84), and birth facility (range of AORs = 1.52-2.36). Asian race was associated with rehospitalisation (AOR = 1.49) when all hospitalisations were considered, but this association did not persist if hospitalisations for jaundice were excluded. CONCLUSIONS: In this insured population with access to integrated care, rehospitalisation rates for jaundice were strongly affected by availability of home phototherapy and by follow up. For other causes, moderate prematurity and follow up visits played a large role, but variation between centres persisted even after controlling for multiple factors. Future research should include development of better process measures for evaluation of follow up strategies.

CD83-positive dendritic cells are present in occasional perivascular cuffs in multiple sclerosis lesions.

Multiple sclerosis (MS) has a wide spectrum of clinical courses, characterized by multifocal central nervous system (CNS) damage, postulated to be mediated by CNS antigen-specific T cells. Dendritic cells (DC), the most potent antigen-presenting cell, play a pivotal role in the decision between T-cell activation or anergy. Monoclonal antibodies to CD1a (immature DC) and CD83 (mature DC) were used to screen lesions with evidence of recent demyelinating activity and chronic plaque and normal appearing white matter (NAWM) tissue sections from 12 MS cases by immunocytochemistry. No CD1a-positive cells were detected in the MS or control CNS tissue blocks investigated. CD83-positive cells were not detected in tissues from any of the control cases or in the majority of perivascular cuffs in the MS tissue sections. However; in eight of the MS tissue blocks with evidence of recent demyelination, and in one block each from chronic plaque and NAWM, small numbers of distinct CD83-positive cells were present within occasional perivascular cuffs. In one area only of MS NAWM were CD83-positive cells detected in the tissue parenchyma, in an area of intense immunological activity. DC in MS tissue may originate in the peripheral circulation as monocytes or immature DC and migrate to areas of plaque in response to signals received from CNS-produced chemokines.

Xenon has no effect on cytokine balance and adhesion molecule expression within an isolated cardiopulmonary bypass system.

BACKGROUND: Although almost inert chemically, xenon is not unreactive biologically. It interacts with receptors involved in the expression of cytokines and adhesion molecules. The effect of xenon on the immune function in whole blood has not been studied. METHODS: We examined the effects of 70% xenon in oxygen on cytokine balance and expression of adhesion molecules in an isolated cardiopulmonary bypass (CPB) system, which simulates an evolving inflammatory response. Whole blood from 10 healthy male volunteers was circulated in a CBP system supplied with either 70% xenon in oxygen, or oxygen-enriched air - FO(2)=0.3 (control). We took samples of blood after 30, 60 and 90 min of simulated CBP. We measured interleukin (IL)-1beta, tumour necrosis factor (TNF)alpha, IL-8, IL-10, IL-1ra and TNF-sr-2 levels, and the expression of HLA-DR and the adhesion molecules L-selectin, CD18 and CD11b on monocytes, granulocytes and lymphocytes. RESULTS: IL-8 concentrations were increased significantly, TNF-sr-2 concentrations decreased significantly and IL-10 levels decreased during bypass. There were no significant differences between the groups for any measured variable. CONCLUSION: In an isolated CPB system, xenon and oxygen-enriched air had similar effects on cytokine production and expression of adhesion molecules.

Vascular endothelial growth factor levels in serum and plasma following esophageal cancer resection--relationship to platelet count.

In patients with cancer circulating vascular endothelial growth factor (VEGF) may be tumor-derived and have prognostic significance. Activated platelets may also be a source of VEGF, releasing it in serum formation. Debate exists as to whether serum or plasma VEGF (S-VEGF, P-VEGF) is the most appropriate surrogate marker of tumor angiogenesis. As healing wounds produce VEGF that can spill over into the circulation, we aimed to investigate the potential confounding effects of cancer surgery on both perioperative S-VEGF and P-VEGF levels and to evaluate their relationship with platelet count. S-VEGF, P-VEGF and platelet counts were measured in 23 patients undergoing esophageal cancer resection. Samples were taken preoperatively and six weeks following surgery. Seven patients were also sampled on postoperative days 1, 5 and 10. VEGF was assayed using a commercial enzyme linked immunosorbent assay. S-VEGF and P-VEGF both rose after surgery (S-VEGF; day 5: 1017 [446-1224] pg/mL and day 10: 1231 [626-2046] pg/mL versus pre-op: 329 [189-599] pg/mL. P-VEGF; day 1: 55 [46-104] pg/mL and day 10: 58 [20-154] pg/mL versus pre-op: 23 [13-46] pg/mL), falling towards preoperative levels by six weeks. Platelet count correlated with S-VEGF (rho=0.281; p<0.05, Spearman's rank) and P-VEGF (rho=0.330; p<0.01, Spearman's rank). Platelets may contribute to VEGF levels in plasma as well as in serum. The effects of surgery on S-VEGF or P-VEGF levels are mainly transient. Care must be exercised when interpreting circulating VEGF levels in the early postoperative period.

Plasma and urinary cytokine homeostasis and renal function during cardiac surgery without cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) significantly contributes to the plasma pro-inflammatory cytokine response at cardiac surgery. Complementary plasma and urinary anti-inflammatory cytokine responses have been described. The pro-inflammatory cytokines interleukin 8 (IL-8), tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) have lower molecular weights than the anti-inflammatory cytokines interleukin 10 (IL-10), interleukin 1 receptor antagonist (IL-1ra) and TNF soluble receptor 2 (TNFsr2) and thus undergo glomerular filtration more readily. In vitro work suggests that proximal tubular cells are vulnerable to pro-inflammatory cytokine mediated injury. Accordingly, this study investigated the hypothesis that cardiac surgery without CPB would not have significant changes in plasma and urinary cytokines and proximal renal dysfunction. Eight patients undergoing coronary artery bypass grafting (CABG) without CPB were studied. Blood and urine samples were analysed for pro- and anti-inflammatory cytokines. Proximal tubular dysfunction was measured using urinary Nu-acetyl-beta-D-glucosaminidase (NAG)/creatinine and alpha(1)-microglobulin/creatinine ratios. Plasma IL-8, IL-10, IL-1ra and TNFsr2 were significantly elevated compared with baseline. Urinary IL-1ra and TNFsr2 were significantly elevated, as were urinary NAG/creatinine and alpha(1)-microglobulin/creatinine ratios. Two hours following revascularization, urinary IL-1ra correlated with urinary alpha(1)-microglobulin/creatinine ratios (P<0.05). As previously reported in CABG surgery with CPB, we now report that non-CPB cardiac surgery also has significant changes in plasma and urinary cytokine homeostasis and early proximal tubular injury. The correlation between urinary IL-1ra and alpha(1)-microglobulin/creatinine ratios is consistent with earlier suggestions of a mechanistic link between cytokine changes and proximal tubular dysfunction. The relative roles of CPB and non-CPB processes in producing inflammation still require definition.

Monocyte-derived dendritic cells: a potential target for therapy in multiple sclerosis (MS).

Monocytes can differentiate into dendritic cells (DC), cells with a pivotal role in both protective immunity and tolerance. Defects in the maturation or function of DC may be important in the development of autoimmune disease. We sought to establish if there were differences in the cytokine (granulocyte-macrophage colony-stimulating factor and IL-4)-driven maturation of monocytes to DC in patients with MS and whether drugs used to treat MS affected this process in vitro. We have demonstrated that there is no defect in the ability of magnetic activated cell sorting (MACS)-purified monocytes from patients with MS to differentiate to DC, but equally they show no tendency to acquire a DC phenotype without exogenous cytokines. Interferon-beta1a prevents the acquisition of a full DC phenotype as determined by light and electron microscopy and by flow cytometry. Methylprednisolone not only prevents the development of monocyte-derived DC but totally redirects monocyte differentiation towards a macrophage phenotype. Evidence is evolving for a role for DC in central nervous system immunity, either within the brain or in cervical lymph nodes. The demonstrated effect of both drugs on monocyte differentiation may represent an important site for immune therapy in MS.

Interferon-beta1a administration results in a transient increase of serum amyloid A protein and C-reactive protein: comparison with other markers of inflammation.

Putative markers of inflammation such as serum beta2-microglobulin and neopterin have been shown to be transiently upregulated following interferon-beta (IFN-beta) administration to multiple sclerosis (MS) patients. However, to date the role of the important inflammatory mediators serum amyloid A protein (SAA) and C-reactive protein (CRP) have not been described. Here we show that SAA but not CRP is elevated in relapsing-remitting MS patients compared to normal healthy individuals, and furthermore that both are transiently upregulated following intramuscular injection with IFN-beta1a (Avonex). This pattern of expression was found to parallel that of beta2-microglobulin and neopterin following injection and was mirrored by a selective activation of peripheral monocytes with respect to upregulation of receptors known to be involved in the inflammatory response (HLA-DR, CD16 and CD86). Injection of saline solution intramuscularly to six healthy control individuals did not produce a similar upregulation of any of the inflammatory markers investigated. Following IFN-beta1a injection, all inflammatory responses were attenuated at week 12 of therapy in comparison to those following the initial injection in a group of follow-up patients. In addition, IFN-beta1a injected on a weekly basis did not produce a sustained modulation of any of the markers investigated in patients treated for 32 weeks.

Early Start: an obstetric clinic-based, perinatal substance abuse intervention program.

Maternal substance abuse is a serious problem with significant adverse effects to mothers, fetuses, and children. The Early Start Program provides pregnant women in a managed care organization with screening and early identification of substance abuse problems, early intervention, ongoing counseling, and case management by a licensed clinical social worker located in the prenatal clinic, where she is an integral part of the prenatal team. We describe the development of the Early Start Program, its administrative history, and how it has interfaced with clinicians and administrators. We also highlight two important program characteristics: the partnership with a perinatal health services research unit and the degree to which the program could be "exported" to other managed care settings.

Utilization of health services among patients referred to an alcohol treatment program.

This study assessed utilization of health services among 1,317 adults referred to an outpatient Psychiatry Department alcohol treatment program from July, 1988 through December, 1989. The mean number of visits/year for 1 year before and 4 years after treatment referral were compared for all outpatient clinics combined and 4 clinic subgroups; the mean number of hospitalizations and number of days hospitalized were also analyzed. Overall, utilization was higher before treatment than after, except for Psychiatry Department visits. Amount of treatment received had little effect on utilization. These results suggest that alcoholism treatment contributes to a reduction in higher cost health services utilization.

Plasma and urinary cytokine homeostasis and renal dysfunction during cardiac surgery.

BACKGROUND: Cardiac surgery induces changes in plasma cytokines. Proinflammatory cytokines have been associated with a number of renal diseases. The proinflammatory cytokines interleukin 8 (IL-8), tumor necrosis factor alpha (TNFalpha), and interleukin 1beta (IL-1beta) are smaller than the antiinflammatory cytokines interleukin 10 (IL-10), interleukin 1 receptor antagonist (IL-1ra), and TNF soluble receptor 2 (TNFsr2), and thus undergo glomerular filtration more readily. Accordingly, this study investigated the relation between plasma and urinary cytokines and proximal renal dysfunction during cardiac surgery. METHODS: Twenty patients undergoing coronary artery bypass grafting with cardiopulmonary bypass (CPB) were studied. Blood and urine samples were analyzed for proinflammatory and antiinflammatory cytokines. Proximal tubular dysfunction was measured using urinary N-acetyl-beta-d-glucosaminidase (NAG)/creatinine and alpha1-microglobulin/creatinine ratios. RESULTS: Plasma IL-8, IL-10, IL-1ra, and TNFsr2 values were significantly elevated compared with baseline. Urinary IL-1ra and TNFsr2 were significantly elevated. Urinary NAG/creatinine and alpha1-microglobulin/creatinine ratios were also elevated. Plasma TNFalpha at 2 h correlated with urinary NAG/creatinine ratio at 2 and 6 h (P < 0.05) and with urinary IL-1ra at 2 h (P < 0.05). Plasma IL-8 at 2 h correlated with NAG/creatinine at 6 h (P < 0.05). Urinary IL-1ra correlated with urinary NAG/creatinine ratio after cross-clamp release and 2 and 6 h after CPB (P < 0.05). CONCLUSIONS: Cardiac surgery using CPB leads to changes in plasma and urinary cytokine homeostasis that correlate with renal proximal tubular dysfunction. This dysfunction may be related to the renal filtration of proinflammatory mediators. Renal autoprotective mechanisms may involve the intrarenal generation of antiinflammatory cytokines.

Neonatal sepsis workups in infants >/=2000 grams at birth: A population-based study.

BACKGROUND: Few data are available on the outcome of neonatal sepsis evaluations in an era when intrapartum antibiotic therapy is common. METHODS: We identified all newborns weighing >/=2000 g at birth who were ever evaluated for suspected bacterial infection at 6 Kaiser Permanente hospitals between October 1995 and November 1996, reviewed their records and laboratory data, and tracked them to 1 week after discharge. We analyzed the relationship between key predictors and the presence of neonatal bacterial infection. RESULTS: Among 18 299 newborns >/=2000 g without major congenital anomalies, 2785 (15.2%) were evaluated for sepsis with a complete blood count and/or blood culture. A total of 62 (2.2%) met criteria for proven, probable, or possible bacterial infection: 22 (.8%) had positive cultures and 40 (1.4%) had clinical evidence of bacterial infection. We tracked all but 10 infants (.4%) to 7 days postdischarge. There were 67 rehospitalizations (2.4%; 2 for group B streptococcus bacteremia). Among 1568 infants who did not receive intrapartum antibiotics, initial asymptomatic status was associated with decreased risk of infection (adjusted odds ratio [AOR]:.26; 95% confidence interval [CI]:.11-.63), while chorioamnionitis (AOR: 2. 40; 95% CI: 1.15-5.00), low absolute neutrophil count (AOR: 2.84; 95% CI: 1.50-5.38), and meconium-stained amniotic fluid (AOR: 2.23; 95% CI: 1.18-4.21) were associated with increased risk. Results were similar among 1217 infants who were treated, except that maternal chorioamnionitis was not significantly associated with neonatal infection. CONCLUSIONS: The risk of bacterial infection in asymptomatic newborns is low. Evidence-based observation and treatment protocols could be defined based on a limited set of predictors: maternal fever, chorioamnionitis, initial neonatal examination, and absolute neutrophil count. Many missed opportunities for treating mothers and infants exist.

The role of reactive oxygen intermediates in the regulation of cytokine-induced ICAM-1 surface expression on endothelial cells.

ICAM-1 upregulation by endothelial cells plays a pivotal role in many disease processes, but signalling mechanisms leading to increased expression are poorly understood. In the current study we investigated the regulatory capacity of reactive oxygen intermediates (ROIs) in ICAM-1 activation by stimulating endothelial cells with the pro-inflammatory cytokines IL-1 beta, TNF alpha, IFN gamma, IL-2, and IL-4 prior to antioxidant treatment. ICAM-1 was expressed constitutively and upregulated on ECV304 by IL1-beta, IL2, and IFN gamma and on SKHEP-1 by IFN gamma, IL1-beta, and TNF alpha. Phenanthroline (PHE) and disulfiram (DIS) showed the greatest ability to inhibit cytokine-stimulated ICAM-1 expression and in a dose-dependent manner. The alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) conversion assay showed that PHE and DIS had zero ability to scavenge free radicals and thus no known antioxidant activity. However, both are known metal chelators and our findings therefore suggest a unique role for metal ions in the control of cytokine-induced ICAM-1 expression on endothelial cells.

Risk of pulmonary embolism and/or deep venous thrombosis in Asian-Americans.

Several reports from Asian countries suggest a low prevalence of pulmonary embolism (PE) and deep venous thrombosis (DVT) in Asians, and sparse US data show that a slightly higher prevalence of PE/DVT in "nonwhites" than in whites is evident in all geographic regions except the Pacific region (California, Oregon, and Washington) where "nonwhites" include a larger proportion of Asians and Hispanics than in other US locations. We prospectively studied PE/DVT hospitalizations in 128,934 persons in relation to traits determined at health examinations in 1978 to 1985. Through 1994, 337 persons were subsequently hospitalized for PE and/or DVT (for PE first, n = 206). Cox proportional-hazards models with 9 covariates were used. In multivariate models, the following RRs (95% confidence intervals) were found for PE/DVT combined: black/white = 1.1 (0.4 to 1.4); Hispanic/white = 0.7 (0.3 to 1.5); and Asian/white = 0.2 (0.1 to 0. 5; p = 0.002). The lower risk of Asians was present in each sex and for persons first hospitalized for either PE or DVT. Covariates with significant positive relations to risk were age, male sex, body mass index, and a composite coronary disease risk/symptom variable; covariates not significantly related were education, marital status, smoking, and alcohol. These data suggest that Asians have very low risk of PE/DVT, which may account for US geographic variations in white/non-white risk differences. Possible explanations include the absence of hazardous mutations or unspecified PE/DVT protective traits in Asians.