Inflammatory breast cancer defined: proposed common diagnostic criteria to guide treatment and research.

PURPOSE: Inflammatory breast cancer is a deadly and aggressive type of breast cancer. A key challenge relates to the need for a more detailed, formal, objective definition of IBC, the lack of which compromises clinical care, hampers the conduct of clinical trials, and hinders the search for IBC-specific biomarkers and treatments because of the heterogeneity of patients considered to have IBC. METHODS: Susan G. Komen, the Inflammatory Breast Cancer Research Foundation, and the Milburn Foundation convened patient advocates, clinicians, and researchers to review the state of IBC and to propose initiatives to advance the field. After literature review of the defining clinical, pathologic, and imaging characteristics of IBC, the experts developed a novel quantitative scoring system for diagnosis. RESULTS: The experts identified through consensus several "defining characteristics" of IBC, including factors related to timing of onset and specific symptoms. These reflect common pathophysiologic changes, sometimes detectable on biopsy in the form of dermal lymphovascular tumor emboli and often reflected in imaging findings. Based on the importance and extent of these characteristics, the experts developed a scoring scale that yields a continuous score from 0 to 48 and proposed cut-points for categorization that can be tested in subsequent validation studies. CONCLUSION: To move beyond subjective 'clinical diagnosis' of IBC, we propose a quantitative scoring system to define IBC, based on clinical, pathologic, and imaging features. This system is intended to predict outcome and biology, guide treatment decisions and inclusion in clinical trials, and increase diagnostic accuracy to aid basic research; future validation studies are necessary to evaluate its performance.

Contribution of comorbidities to obesity-related asthma in children.

Children with obesity are at increased risk for developing asthma that is difficult to control. A complicating factor to asthma management among these children is likely the commonplace co-morbidities that also result from obesity. We discuss three common obesity-related comorbidities which appear to complicate the effective management of asthma, including hypovitaminosis D, obstructive sleep apnea and gastro-esophageal reflux. Each conditions requires more research to understand their effects on asthma management.

Quantum Bath Control with Nuclear Spin State Selectivity via Pulse-Adjusted Dynamical Decoupling.

Dynamical decoupling (DD) is a powerful method for controlling arbitrary open quantum systems. In quantum spin control, DD generally involves a sequence of timed spin flips (π rotations) arranged to either average out or selectively enhance coupling to the environment. Experimentally, errors in the spin flips are inevitably introduced, motivating efforts to optimize error-robust DD. Here we invert this paradigm: by introducing particular control "errors" in standard DD, namely, a small constant deviation from perfect π rotations (pulse adjustments), we show we obtain protocols that retain the advantages of DD while introducing the capabilities of quantum state readout and polarization transfer. We exploit this nuclear quantum state selectivity on an ensemble of nitrogen-vacancy centers in diamond to efficiently polarize the ^{13}C quantum bath. The underlying physical mechanism is generic and paves the way to systematic engineering of pulse-adjusted protocols with nuclear state selectivity for quantum control applications.

Imaging Correlations in Heterodyne Spectra for Quantum Displacement Sensing.

The extraordinary sensitivity of the output field of an optical cavity to small quantum-scale displacements has led to breakthroughs such as the first detection of gravitational waves and of the motions of quantum ground-state cooled mechanical oscillators. While heterodyne detection of the output optical field of an optomechanical system exhibits asymmetries which provide a key signature that the mechanical oscillator has attained the quantum regime, important quantum correlations are lost. In turn, homodyning can detect quantum squeezing in an optical quadrature but loses the important sideband asymmetries. Here we introduce and experimentally demonstrate a new technique, subjecting the autocorrelators of the output current to filter functions, which restores the lost heterodyne correlations (whether classical or quantum), drastically augmenting the useful information accessible. The filtering even adjusts for moderate errors in the locking phase of the local oscillator. Hence we demonstrate the single-shot measurement of hundreds of different field quadratures allowing the rapid imaging of detailed features from a simple heterodyne trace. We also obtain a spectrum of hybrid homodyne-heterodyne character, with motional sidebands of combined amplitudes comparable to homodyne. Although investigated here in a thermal regime, the method's robustness and generality represents a promising new approach to sensing of quantum-scale displacements.

Effect of obesity on sinonasal disease in asthma.

OBJECTIVE: Sinonasal disease can contribute to poor asthma control. There are reports that link obesity with an increased prevalence of sinonasal disease, but no studies evaluating the severity of sinonasal disease in obese asthmatics, and how this impacts asthma control. The purpose of the current study was to determine if obesity is associated with increased severity of sinonasal disease, and/or affects response to nasal corticosteroid treatment in asthma. METHODS: This study included 236 adults participating in a 24-week randomized, double-masked, placebo-controlled study of nasal mometasone for the treatment of poorly controlled asthma. Sinonasal disease severity was assessed using validated questionnaires, and compared in participants of differing BMIs. Eosinophilic inflammation was assessed using markers in nasal lavage, serum and exhaled nitric oxide. Response to treatment was compared in different BMI groups. RESULTS: Obesity had no effect on the severity of sinonasal disease symptoms in asthmatics (Sino-Nasal Outcome Test 22 (SNOT 22) score [mean ± SD] 35.4 ± 18.5, 40.2 ± 22.8, and 39.1 ± 21.7, p = 0.43, in lean, overweight and obese participants), nor on nasal, bronchial or systemic markers of allergic inflammation. Nasal steroids had some limited effects on symptoms, lung function and inflammatory markers in lean participants, but no detectable effect was found in obese patients. CONCLUSIONS: Obesity does not affect severity of sinonasal disease in patients with asthma; the association of sinonasal disease symptoms with increased asthma severity and markers of Type 2 inflammation are consistent across all BMI groups. The response of obese patients to nasal corticosteroids requires further study.

Early-life antibiotic exposure increases the risk of developing allergic symptoms later in life: A meta-analysis.

This study systematically reviewed and quantified the relationship between exposure to antibiotics during the first 2 years of life and the risk of allergies/atopies including hay fever, eczema, food allergy, positive skin prick testing (SPT), or elevated allergen-specific serum/plasma immunoglobulin (Ig) E levels later in life. PubMed and Web of Science databases were searched for observational studies published from January 1966 through November 11, 2015. Overall pooled estimates of the odds ratios (ORs) were obtained using fixed or random-effects models. Early-life exposure to antibiotics appears to be related to an increased risk of allergic symptoms of hay fever, eczema, and food allergy later in life. The summary OR for the risk of hay fever (22 studies) was 1.23, 95% confidence interval (CI):1.13-1.34; I2 : 77.0%. The summary OR for the risk of eczema (22 studies) was 1.26, 95% CI: 1.15-1.37; I2 : 74.2%, and the summary OR for food allergy (3 studies) was 1.42, 95% CI: 1.08-1.87; I2 : 80.8%. However, no association was found for antibiotics exposure early in life and objective atopy measurements including positive SPT or elevated allergen-specific serum/plasma IgE levels.

ALOX5 polymorphism associates with increased leukotriene production and reduced lung function and asthma control in children with poorly controlled asthma.

BACKGROUND: Identification of risk factors for reduced asthma control could improve the understanding and treatment of asthma. A promoter polymorphism in the 5-lipoxygenase gene affects gene expression and response to asthma therapy, but its impact on disease control remains unclear. OBJECTIVE: We sought to determine if the ALOX5 promoter SP1 tandem repeat polymorphism was associated with changes in cysteinyl leukotriene production, lung function, airway inflammation and asthma control score. METHODS: We analysed 270 children, 6- to 17-years old, with poorly controlled asthma enrolled in a 6-month clinical trial (NCT00604851). In secondary analysis, we associated the ALOX5 promoter SP1 tandem repeat polymorphism genotype (rs59439148) with asthma outcomes using both additive and recessive genetic models. We evaluated FEV1 percent predicted, symptom control, exhaled nitric oxide and urinary LTE4 levels. RESULTS: Of all children, 14.8% (40/270) (and 28% (38/135) of African Americans) carried two non-5-repeat variant alleles of rs59439148. Children who were homozygous for variant alleles had significantly higher urinary LTE4 levels (38 vs. 30 nmol/mol creatinine, P = 0.0134), significantly worse FEV1% predicted (84 vs. 91, P = 0.017) and a trend towards worse asthma control. FEV1% predicted values were significantly negatively correlated with urinary LTE4 (r = -0.192, P = 0.009). CONCLUSION AND CLINICAL RELEVANCE: Carrying two copies of a minor variant ALOX5 promoter SP1 tandem repeat allele contributes to increased cysLT exposure as determined by urinary LTE4 levels, reduced lung function and potentially worse asthma control. ALOX5 promoter SP1 tandem repeat genotype may be a risk factor for worse asthma outcomes.

Robotic systems in orthopaedic surgery.

Robots have been used in surgery since the late 1980s. Orthopaedic surgery began to incorporate robotic technology in 1992, with the introduction of ROBODOC, for the planning and performance of total hip replacement. The use of robotic systems has subsequently increased, with promising short-term radiological outcomes when compared with traditional orthopaedic procedures. Robotic systems can be classified into two categories: autonomous and haptic (or surgeon-guided). Passive surgery systems, which represent a third type of technology, have also been adopted recently by orthopaedic surgeons. While autonomous systems have fallen out of favour, tactile systems with technological improvements have become widely used. Specifically, the use of tactile and passive robotic systems in unicompartmental knee replacement (UKR) has addressed some of the historical mechanisms of failure of non-robotic UKR. These systems assist with increasing the accuracy of the alignment of the components and produce more consistent ligament balance. Short-term improvements in clinical and radiological outcomes have increased the popularity of robot-assisted UKR. Robot-assisted orthopaedic surgery has the potential for improving surgical outcomes. We discuss the different types of robotic systems available for use in orthopaedics and consider the indication, contraindications and limitations of these technologies.

Effect of citrus juice and SLCO2B1 genotype on the pharmacokinetics of montelukast.

Previously the authors found that a common polymorphism, rs12422149 (SLCO2B1{NM_007256.2}:c.935G>A), in the gene coding for OATP2B1, was associated with absorption of and response to montelukast in humans. In vitro studies showed that citrus juice could reduce the permeability of montelukast consistent with known inhibition of organic anion-transporting polypeptides. To study the clinical significance of c.935G>A, the authors conducted a single-dose, pharmacokinetic study of montelukast co-ingested with citrus juice. On average, co-ingestion with either orange juice or 4× concentrated grapefruit juice had a minimal effect on the area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC(0→∞)) of montelukast relative to co-ingestion with Gatorade control (n = 24). However when the data were stratified by genotype at c.935 (G/G n = 21, A/G n = 5), a significant reduction in AUC(0→∞) was detected with orange juice in G/G homozygotes (AUC(0→∞), G/G, Gatorade = 2560 ± 900 ng·h·mL(-1) vs AUC(0→∞), G/G, orange juice = 2010 ± 650 ng·h·mL(-1), P = .032). Significantly, A/G heterozygotes showed reduced AUC(0→∞) relative to G/G homozygotes, independent of treatment (AUC(0→∞), G/G, combined treatments = 2310 ± 820 ng·h·mL(-1) vs AUC(0→∞), A/G, combined treatments = 1460 ± 340 ng·h·mL(-1), P = 2.0 × 10(-5)) replicating previous observations.

Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30.

We studied 31 nondiabetic, habitually (> or =5 years) morbidly obese subjects (mean +/- SD body mass index [BMI] 43 +/- 8.7, median 43). Our specific aim was to determine whether metformin (2.55 g/d for 28 weeks) would ameliorate morbid obesity and reduce centripetal obesity; lipid and lipoprotein cholesterol, insulin, and leptin levels; and plasminogen activator inhibitor activity (PAI-Fx), risk factors for coronary heart disease (CHD). The patients were instructed to continue their prestudy dietary and exercise regimens without change. After 2 baseline visits 1 week apart, the 27 women and 4 men began receiving metformin, 2.55 g/d, which was continued for 28 weeks with follow-up visits at study weeks 5, 13, 21, and 29. Daily food intake was recorded by patients for 7 days before visits then reviewed with a dietitian. Kilocalories per day and per week were calculated. At each visit, fasting blood was obtained for measurement of lipid profile, insulin, leptin, and PAI-Fx. The mean +/- SD kilocalories consumed per day, 1,951 +/- 661 at entry, fell by week 29 to 1,719 +/- 493 (P =.014) but did not differ at weeks 5, 13, and 21 from that at week 29 (P >.2). Weight fell from 258 +/- 62 pounds at entry to 245 +/- 54 pounds at week 29 (P =.0001). Girth was reduced from 51.8 +/- 6.2 to 49.2 +/- 4.5 inches (P =.0001). Waist circumference fell from 44.0 +/- 6.4 inches to 41.3 +/- 5.9 (P =.0001). The waist/hip ratio fell from 0.85 +/- 0.09 to 0.84 +/- 0.09 (P =.04). Fasting serum insulin, 28 +/- 15 microU/mL at entry, fell to 21 +/- 11 microU/mL at week 29 (P =.0001), and leptin fell from 79 +/- 33 ng/mL to 55 +/- 27 ng/mL (P =.0001). On metformin, there were linear trends in decrements in weight, girth, waist circumference, waist/hip ratio, insulin, and leptin throughout the study period (P <.007). Low-density lipoprotein (LDL) cholesterol, 126 +/- 34 mg/dL at study entry, fell to 112 +/- 43 mg/dL at week 29 (P =.001), with a linear trend toward decreasing levels throughout (P =.036). By stepwise linear regression, the higher the entry weight, the larger the reduction in weight on metformin therapy (partial R(2) = 31%, P =.001). The greater the reduction in kilocalories consumed per day, the greater the decrease in weight on metformin therapy (partial R(2) = 15%, P =.011). The higher the waist/hip ratio at entry, the greater its reduction on metformin therapy (partial R(2) = 11%, P =.004). The higher the entry serum leptin, the greater its reduction on metformin therapy (partial R(2) = 29%, P =.002). The greater the reduction in insulin on metformin, the greater the reduction in leptin (partial R(2) = 8%, P =.03). The higher the entry PAI-Fx, the greater the reduction in PAI-Fx on metformin (partial R(2) = 43%, P =.0001). Metformin safely and effectively reduces CHD risk factors (weight, fasting insulin, leptin, LDL cholesterol, centripetal obesity) in morbidly obese, nondiabetic subjects with BMI > 30, probably by virtue of its insulin-sensitizing action.

Interaction of estrogen replacement therapy with the thrombophilic 20210 G/A prothrombin gene mutation for atherothrombotic vascular disease: a cross-sectional study of 275 hyperlipidemic women.

In a consecutive case series, cross-sectional study of 275 women referred for therapy of hyperlipidemia, (75 [27%] on estrogen replacement therapy [ERT]), our specific aim was to determine whether ERT-mediated thrombophilia and heterozygosity for the thrombophilic 20210 G/A prothrombin gene mutation interacted as risk factors for atherothrombotic cardiovascular disease (ATCVD). Of the 275 women, 100 (36%) had ATCVD; 10 (3.6%) were heterozygous for the 20210 G/A prothrombin gene mutation. In women without the 20210 G/A prothrombin gene mutation, 15 of 71 (21%) on ERT had ATCVD versus 78 of 194 (40%) not on ERT (X(2) = 8.31, P =.004). By stepwise logistic regression, in 261 women with ATCVD risk factor data, positive explanatory variables for ATCVD included the 20210 G/A prothrombin mutation (risk odds ratio, 5.8; 95% confidence intervals [CI], 1.4 to 30.2; P =.021) and a 20210 G/A prothrombin gene mutation*ERT interaction term (risk odds ratio, 2.70; 95% CI, 1.4 to 5.4; P =.004). ATCVD events were more likely in 2 subgroups of women (ERT minus [-] and 20210 G/A prothrombin gene mutation -) or (ERT plus [+] and 20210 G/A prothrombin gene mutation +), P =.004. Other positive explanatory variables for ATCVD events included age (P =.004), triglycerides (P =.012), lipoprotein (a) (P =.03), and homocysteine (P =.032). ERT may be protective against ATCVD when the thrombophilic 20210 G/A prothrombin gene mutation is absent, whereas the 20210 G/A prothrombin gene mutation may increase risk for ATCVD, particularly in the presence of ERT. We suggest that the 20210 G/A prothrombin gene mutation be measured in all women on ERT or before beginning ERT to identify those heterozygous for the thrombophilic prothrombin gene mutation (4%) in whom ERT is contraindicated because of increased risk for ATCVD and thromboembolism, and a second, much larger group of women without the 20210 G/A prothrombin gene mutation (96%) in whom ERT may possibly reduce risk for ATCVD.

Use of a supermarket shelf-labeling program to educate a predominately minority community about foods that promote heart health.

OBJECTIVE: The purpose of this study was to evaluate the awareness and use of a supermarket-shelf labeling program designed to encourage shoppers to make food choices that promote heart health. DESIGN: A shelf-labeling program was implemented in 18 supermarkets serving minority communities in Detroit, Mich. Customers were given an exit survey to determine awareness and use of the program. SUBJECTS/SETTING: Three hundred sixty-one subjects were sampled. Sixty-six percent of the sample was female, 67% African-American, and the sample population had a mean age of 51.6 years +/- 18.5 SD. RESULTS: Overall awareness of the program was 28.8%. Awareness among minorities was significantly higher when compared with whites (35.3% vs 20.8%; P = .02). Gender, age, and education level were not predictive of program awareness but people screened for cardiovascular disease risk factors (elevated low-density lipoprotein or total cholesterol levels and/or elevated blood pressure) in the previous year had greater awareness than those not screened (32.6% vs 13.6%, P = .06). Use of the program was 56% among subjects aware of the program. This did not differ significantly by gender, age, or ethnicity. STATISTICAL ANALYSIS: Awareness and use were evaluated with respect to ethnicity, gender, education, race, age, and previous screening history. For purposes of analysis, African-American, Hispanic, and Asian-American respondents were combined into one group called "all minorities." The other group of respondents was called "whites." Between-group differences in categorical variables were analyzed using a chi 2 statistic. CONCLUSIONS: Awareness of the shelf-labeling program was modest, but highest among African-Americans. Subjects recently screened for cardiovascular disease risk had greater program awareness. This difference was not statistically significant. Use was relatively high among those aware of the program, suggesting that shelf labels have the potential to increase the selection of foods that promote heart health in predominately low-income, minority populations.

Contribution of fasting hyperinsulinemia to prediction of atherosclerotic cardiovascular disease status in 293 hyperlipidemic patients.

In a cross-sectional study of 293 nondiabetic patients (169 men and 124 women) referred for the diagnosis and treatment of hyperlipidemia, our specific aim was to determine whether fasting serum insulin independently contributes to the prediction of atherosclerotic cardiovascular disease (ASCVD) status. Of the 169 men and 124 women, 65 (38%) and 44 (35%), respectively, had ASCVD with at least one of the following: unstable angina, myocardial infarction (MI), angioplasty, coronary artery bypass graft (CABG), claudication, transient ischemic attack, or ischemic stroke. In addition, 42% and 38% had fasting hyperinsulinemia (> or =20 microU/mL). Fasting serum insulin of 20 microU/mL or higher was very common in women (59% to 100%) and men (67% to 88%) when hypertension, obesity, top-decile triglyceride (TG), and bottom-decile high-density lipoprotein cholesterol (HDLC) were concurrent in various combinations. ASCVD events (present or absent) were dependent variables in a stepwise logistic regression model with explanatory variables including age, gender, race, hypertension, cigarette smoking, ASCVD in first-degree relatives at age 55 years or less, Quetelet Index, fasting serum insulin, a gender x insulin interaction term, anticardiolipin antibodies (ACLAs) IgG and IgM, total cholesterol to HDLC ratio, TG, lipoprotein(a) [Lp(a)], and homocysteine. The risk odds ratio for ASCVD (109 events and 184 nonevents) for subjects with top-decile insulin (vthe bottom nine deciles) was 3.71, with a 95% confidence interval (CI) of 1.62 to 8.9 (P = .002). For patients with MI and/or CABG and/or angioplasty ([MCA] 63 events and 184 nonevents), the risk odds ratio for top-decile insulin versus the rest was 5.07 (95% CI, 1.83 to 14.8, P = .002). For patients with MCA at age 55 or less, the gender x insulin interaction term was significant (P = .0004); the risk odds ratio for men with top-decile insulin was 13.28 (95% CI, 3.82 to 51.65, P = .0001). Hyperinsulinemia is very common in nondiabetic hyperlipidemic women and men. Fasting serum insulin, a crude, simple, practical, and inexpensive measure, independently and uniformly improved the prediction of ASCVD status beyond traditional risk factors and lipid variables in patients referred for treatment of hyperlipidemia.

Effect of exogenous estrogen on atherothrombotic vascular disease risk related to the presence or absence of the factor V Leiden mutation (resistance to activated protein C).

Estrogen replacement therapy (ERT), which produces acquired resistance to activated protein C when superimposed on heritable resistance to activated protein C (the mutant Factor V Leiden trait), may promote venous and arterial thrombosis. In a cross-sectional study of 423 women referred for hyperlipidemic therapy (93 of whom [22%] were on ERT), our specific aim was to determine whether ERT and heterozygosity for the Factor V Leiden mutation and/or resistance to activated protein C interacted as risk factors for atherothrombosis. Of the 423 women, 168 (40%) had atherothrombosis, 19 (4%) were heterozygous for Factor V Leiden mutation or had resistance to activated protein C <2 (Factor V Leiden mutation+), and 404 were wild-type normal for the Factor V gene and/or had resistance to activated protein C > or =2 (Factor V Leiden mutation-). By stepwise logistic regression, positive explanatory variables for atherothrombosis included hypertension (p = 0.002), age (p = 0.003), relatives with atherothrombosis (p = 0.002), anticardiolipin antibody immunoglobulin-M (p = 0.02), and a Factor V Leiden mutation*ERT interaction term where atherothrombosis events were more likely in 2 subgroups of women (ERT- and Factor V Leiden mutation-) or (ERT+ and Factor V Leiden mutation+) (p = 0.02). High-density lipoprotein cholesterol was inversely associated with atherothrombosis (p = 0.004). In a separate logistic regression model for the 213 women with a polymerase chain reaction measurement of the Factor V gene, ERT was protective (p = 0.008); the Factor V Leiden mutation was positively associated with atherothrombosis (p = 0.05). The atherothrombosis odds ratio risk for ERT (yes vs no) was 0.36 (95% confidence intervals [CI] 0.16 to 0.74, p = 0.007). The atherothrombosis risk odds ratio in women heterozygous for the Factor V Leiden mutation (vs normal) was 2.00 (95% CI 1.02 to 4.22, p = 0.05). ERT may be protective against atherothrombosis when the Factor V Leiden mutation is absent, whereas the Factor V Leiden mutation may increase risk for atherothrombosis, particularly in the presence of ERT. We suggest that the Factor V Leiden mutation be measured in all women on ERT or before beginning ERT to identify those heterozygous for the Factor V Leiden mutation (4%), in whom ERT is relatively or absolutely contraindicated because of increased risk for atherothrombosis and thromboembolism. A second, much larger group of women will also be identified without the factor V Leiden mutation (96%), in whom ERT may reduce the risk for atherothrombosis.

Evidence that anticardiolipin antibodies are independent risk factors for atherosclerotic vascular disease.

Thrombophilic anticardiolipin antibodies (ACLAs) are independent risk factors for atherosclerotic vascular disease. We suggest that ACLAs IgG and IgM be routinely measured as ancillary atherothrombotic risk factors in all patients with atherosclerotic vascular disease events, in those at high risk for atherosclerotic vascular disease, and in those in whom thrombosis is a major pathoetiology.

Induction of apoptosis by c-Fos protein.

The role of c-Fos in apoptosis was examined in two Syrian hamster embryo cell lines (sup+I and sup-II) and a human colorectal carcinoma cell line (RKO), using the chimeric Fos-estrogen receptor fusion protein c-FosER. As previously reported, contrasting responses were observed when these two cell lines were placed under growth factor deprivation conditions; sup+I cells were highly susceptible to apoptosis, whereas sup-II cells were resistant. In this report, we show that the activated c-FosER protein induces apoptosis in sup-II preneoplastic cells in serum-free medium, indicating that c-Fos protein can induce apoptotic cell death in these cells. c-Fos-induced apoptosis was not blocked by the protein synthesis inhibitor cycloheximide, suggesting that the c-Fos transcriptional activation activity is not involved. This conclusion was further supported by the observation that overexpression of v-Fos, which is highly proficient in transcriptional activation but deficient in the transcriptional repression activity associated with c-Fos, did not induce apoptosis. Constitutively expressed Bcl-2 delayed the onset of low-serum-induced apoptosis in sup+I cells and enhanced survival in sup-II cells. Further, coexpression of Bcl-2 and c-FosER in sup+I or sup-II cells protected the cells from c-FosER-induced apoptosis. The possibility that c-FosER-induced apoptosis requires a p53 function was examined. Colorectal carcinoma RKOp53+/+ cells, which do not normally undergo apoptosis in serum-free medium, showed apoptotic DNA fragmentation upon expression and activation of c-FosER. Further, when the wild-type p53 protein was diminished in the RKO cells by infection with the papillomavirus E6 gene, subsequent c-FosER-induced apoptosis was blocked. The data suggest that c-Fos protein plays a causal role in the activation of apoptosis in a p53-dependent manner. This activity does not require new protein synthesis and is blocked by overexpression of Bcl-2 protein.

Evidence that homocysteine is an independent risk factor for atherosclerosis in hyperlipidemic patients.

In 482 patients sequentially referred for diagnosis and therapy of hyperlipidemia, our specific aim was to determine the prevalence of homocysteinemia, to assess whether it was independently associated with atherosclerotic vascular disease, and to determine how effectively high homocysteine could be treated with folic acid and pyridoxine. Of the 482 patients, 18 (3.7%) had high homocysteine (> or = 16.2 mumol/L, median = 19), 31 had high cystathionine (> or = 342 nmol/L) with normal homocysteine (median = 12), and 433 had normal cystathionine and homocysteine (median = 9). Of the 18 patients with high homocysteine, 13 (72%) had atherosclerotic vascular disease, much higher than the 44% (192 of 433 patients) with normal homocysteine (chi-square = 5.4, p = 0.02). In the 18 kindreds with a homocysteinemic proband, 14 (78%) had > or = 1 first-degree relatives with atherosclerotic vascular disease before age 65, compared with 50% (215 of 433) of the families where the proband had normal homocysteine (chi-square = 5.5, p = 0.02). In the 482 patients already at high risk for atherosclerotic vascular disease by virtue of hyperlipidemia, when assessed by logistic regression, homocysteine was an independent positive predictor of atherosclerotic vascular disease (p = 0.007); relative risk for atherosclerotic events was 2.8 times higher (p = 0.0004) in patients with top (> or = 11.4 mumol/L) than with bottom (< 6.9 mumol/L) quintile homocysteine. After 15 weeks of folic acid (5 mg/day) and pyridoxine (100 mg/day) therapy in 10 patients with high homocysteine, median homocysteine normalized, decreasing from 18 to 11 mumol/L (p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)