Low rate of cetuximab hypersensitivity reactions in Northeast Tennessee: An Appalachian effect?

PURPOSE: Cetuximab is a monoclonal antibody with a known risk of hypersensitivity reactions. Early studies showed hypersensitivity reaction rates of 3%, but there appears to be a higher incidence in the southeastern United States. To confirm the findings from nearby institutions that cetuximab-associated hypersensitivity reactions occur in approximately 20% of patients in the southeastern United States. METHODS: A retrospective chart review was conducted at Johnson City Medical Center in Johnson City, Tennessee. Each patient's first infusion was analyzed for hypersensitivity reaction, as well as for demographic information such as allergy and smoking history, pre-medications, and malignancy type. RESULTS: Data from the first infusion of cetuximab were collected for a total of 71 patients with various malignancies. The overall rate of grade 3 or higher hypersensitivity reaction was 1.4%, and total rate of hypersensitivity reaction was 8.5%. These findings more closely correlate to the early clinical trials and package insert. Both severe (p = 0.001) and any-grade (p = 0.002) hypersensitivity reaction occurred less frequently in one Southeastern Appalachian medical center compared to academic medical centers directly to the east and west. CONCLUSIONS: Patients in southern Appalachia may be less likely to develop cetuximab hypersensitivity reactions compared to surrounding areas in the Southeastern U.S. These results lend support to the theory that exposure to lonestar ticks (Amblyomma americanum) may be responsible for the development of IgE antibodies to cetuximab that cause hypersensitivity reactions. The development of quick and reliable bedside predictors of cetuximab hypersensitivity reactions may aid clinicians considering the use of cetuximab.

Using a discrete choice experiment to value the QLU-C10D: feasibility and sensitivity to presentation format.

PURPOSE: To assess the feasibility of using a discrete choice experiment (DCE) to value health states within the QLU-C10D, a utility instrument derived from the QLQ-C30, and to assess clarity, difficulty, and respondent preference between two presentation formats. METHODS: We ran a DCE valuation task in an online panel (N = 430). Respondents answered 16 choice pairs; in half of these, differences between dimensions were highlighted, and in the remainder, common dimensions were described in text and differing attributes were tabulated. To simplify the cognitive task, only four of the QLU-C10D's ten dimensions differed per choice set. We assessed difficulty and clarity of the valuation task with Likert-type scales, and respondents were asked which format they preferred. We analysed the DCE data by format with a conditional logit model and used Chi-squared tests to compare other responses by format. Semi-structured telephone interviews (N = 8) explored respondents' cognitive approaches to the valuation task. RESULTS: Four hundred and forty-nine individuals were recruited, 430 completed at least one choice set, and 422/449 (94 %) completed all 16 choice sets. Interviews revealed that respondents found ten domains difficult but manageable, many adopting simplifying heuristics. Results for clarity and difficulty were identical between formats, but the "highlight" format was preferred by 68 % of respondents. Conditional logit parameter estimates were monotonic within domains, suggesting respondents were able to complete the DCE sensibly, yielding valid results. CONCLUSION: A DCE valuation task in which only four of the QLU-C10D's ten dimensions differed in any choice set is feasible for deriving utility weights for the QLU-C10D.

A randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine (Lu AA21004), on actual driving and cognition.

The aim of this study was to assess the effects of a novel antidepressant, vortioxetine 10 mg, on driving, cognitive, and psychomotor performance in 24 healthy subjects in a double-blind, placebo-controlled, three-way crossover design. Mirtazapine 30 mg was included as an active comparator. Drugs were administered in the evening of 15 consecutive days. Performance was measured in the morning of days 2 and 16, using standardized tests measuring on-the-road driving, memory, tracking, divided attention, and vigilance. The statistical analysis on the primary measure of driving, i.e., SD of lateral position showed noninferiority of vortioxetine on days 2 and 16, and inferiority for mirtazapine on day 2. Vortioxetine did not cause cognitive or psychomotor impairment. Mirtazapine, however, impaired cognitive and psychomotor performance on day 2. Most of these effects disappeared after multiple doses of mirtazapine. To conclude, vortioxetine did not impair driving, cognitive, or psychomotor performance after single or multiple doses.

Survival gains needed to offset persistent adverse treatment effects in localised prostate cancer.

BACKGROUND: Men diagnosed with localised prostate cancer (LPC) face difficult choices between treatment options that can cause persistent problems with sexual, urinary and bowel function. Controlled trial evidence about the survival benefits of the full range of treatment alternatives is limited, and patients' views on the survival gains that might justify these problems have not been quantified. METHODS: A discrete choice experiment (DCE) was administered in a random subsample (n=357, stratified by treatment) of a population-based sample (n=1381) of men, recurrence-free 3 years after diagnosis of LPC, and 65 age-matched controls (without prostate cancer). Survival gains needed to justify persistent problems were estimated by substituting side effect and survival parameters from the DCE into an equation for compensating variation (adapted from welfare economics). RESULTS: Median (2.5, 97.5 centiles) survival benefits needed to justify severe erectile dysfunction and severe loss of libido were 4.0 (3.4, 4.6) and 5.0 (4.9, 5.2) months. These problems were common, particularly after androgen deprivation therapy (ADT): 40 and 41% overall (n=1381) and 88 and 78% in the ADT group (n=33). Urinary leakage (most prevalent after radical prostatectomy (n=839, mild 41%, severe 18%)) needed 4.2 (4.1, 4.3) and 27.7 (26.9, 28.5) months survival benefit, respectively. Mild bowel problems (most prevalent (30%) after external beam radiotherapy (n=106)) needed 6.2 (6.1, 6.4) months survival benefit. CONCLUSION: Emerging evidence about survival benefits can be assessed against these patient-based benchmarks. Considerable variation in trade-offs among individuals underlines the need to inform patients of long-term consequences and incorporate patient preferences into treatment decisions.

FDA regulation of dietary supplements and requirements regarding adverse event reporting.

In 1994, the Dietary Supplement Health and Education Act (DSHEA) amended the Federal Food, Drug, and Cosmetic Act (FDC Act) to set up a distinct regulatory framework for what we now call dietary supplements. The DSHEA was passed with the intent of striking a balance between providing consumers access to safe dietary supplements to help maintain or improve their health and giving the US Food and Drug Administration (FDA) authority to regulate and take action against manufacturers of supplements or supplement ingredients that present safety problems, are presented with false or misleading claims, or are adulterated or misbranded. This article will present FDA's recent experience in collecting and evaluating dietary supplement adverse event data for the purpose of assuring the public that the dietary supplements they purchase are safe.

The relationship of respiratory and cardiovascular hospital admissions to the southern California wildfires of 2003.

OBJECTIVE: There is limited information on the public health impact of wildfires. The relationship of cardiorespiratory hospital admissions (n = 40 856) to wildfire-related particulate matter (PM(2.5)) during catastrophic wildfires in southern California in October 2003 was evaluated. METHODS: Zip code level PM(2.5) concentrations were estimated using spatial interpolations from measured PM(2.5), light extinction, meteorological conditions, and smoke information from MODIS satellite images at 250 m resolution. Generalised estimating equations for Poisson data were used to assess the relationship between daily admissions and PM(2.5), adjusted for weather, fungal spores (associated with asthma), weekend, zip code-level population and sociodemographics. RESULTS: Associations of 2-day average PM(2.5) with respiratory admissions were stronger during than before or after the fires. Average increases of 70 microg/m(3) PM(2.5) during heavy smoke conditions compared with PM(2.5) in the pre-wildfire period were associated with 34% increases in asthma admissions. The strongest wildfire-related PM(2.5) associations were for people ages 65-99 years (10.1% increase per 10 microg/m(3) PM(2.5), 95% CI 3.0% to 17.8%) and ages 0-4 years (8.3%, 95% CI 2.2% to 14.9%) followed by ages 20-64 years (4.1%, 95% CI -0.5% to 9.0%). There were no PM(2.5)-asthma associations in children ages 5-18 years, although their admission rates significantly increased after the fires. Per 10 microg/m(3) wildfire-related PM(2.5), acute bronchitis admissions across all ages increased by 9.6% (95% CI 1.8% to 17.9%), chronic obstructive pulmonary disease admissions for ages 20-64 years by 6.9% (95% CI 0.9% to 13.1%), and pneumonia admissions for ages 5-18 years by 6.4% (95% CI -1.0% to 14.2%). Acute bronchitis and pneumonia admissions also increased after the fires. There was limited evidence of a small impact of wildfire-related PM(2.5) on cardiovascular admissions. CONCLUSIONS: Wildfire-related PM(2.5) led to increased respiratory hospital admissions, especially asthma, suggesting that better preventive measures are required to reduce morbidity among vulnerable populations.

Interstitial pH in human skeletal muscle during and after dynamic graded exercise.

1. In this study a new method has been used to measure interstitial pH continuously in human muscle during graded exercise. Human subjects performed 5 min of one-legged knee-extensor exercise at power outputs of 30, 50 and 70 W. Muscle interstitial pH was measured continuously in microdialysis dialysate using the pH-sensitive fluorescent dye 2',7'-bis-(2-carboxyethyl)-5-(and -6)-carboxyfluorescein (BCECF). 2. The mean interstitial pH at rest was 7.38 +/- 0.02. Interstitial pH gradually reduced during exercise in a nearly linear manner. The mean value (range) of the lowest interstitial pH at 30, 50 and 70 W exercise was 7.27 (7.18-7.34), 7.16 (7.05-7.24) and 7.04 (6.93-7.12), respectively. 3. The lowest pH was obtained 1 min after exercise, irrespectively of the workload, after which interstitial pH recovered in a nearly exponential manner. The mean half-time for recovery was 5.2 min (range 4.1-6.1 min). The changes in interstitial pH exceeded the changes in venous blood pH. 4. The present study showed that interstitial pH decreased during exercise in relation to intensity. These pH changes could have implications for blood flow regulation as well as for modulations of membrane transport systems.

Recalls of foods and cosmetics due to microbial contamination reported to the U.S. Food and Drug Administration.

In the U.S., food product recalls serve as an important intervention in stemming the consumption of food products contaminated with infectious disease agents. We summarize the number and nature of foods and cosmetics recalled as a result of microbial contamination reported to the U.S. Food and Drug Administration (FDA) for the period 1 October 1993 through 30 September 1998. During this period, microbial contamination of food and cosmetic products was the leading cause for recalls, accounting for a total of 1,370 recalls (36% of all products recalled). Listeria monocytogenes accounted for the greatest number of food products recalled because of microbial contamination, whereas Pseudomonas aeruginosa was the most common microbe associated with recalls of cosmetic products. Dairy products, followed by seafood and pastry items, were the types of products most often associated with recalls due to microbial contamination. The FDA was the entity most often responsible for detecting microbial contamination of foods and cosmetics (33% of all such recalls), followed by state regulatory agencies (24%), and manufacturers/retailers (21%). Nineteen percent of recalls were associated with at least one reported case of illness. Salmonella was the pathogen most often implicated in reports of illness associated with these recalled products.

Endometrial lysosomal enzyme activity in ovulatory dysfunctional uterine bleeding, IUCD users and post-partum women.

The aim of this study was to evaluate the role of lysosomal enzymes in excessively heavy menstruation by comparing women with menorrhagia due to dysfunctional bleeding or intrauterine contraceptive device (IUCD) use with those with normal menstrual periods or with amenorrhoea associated with breastfeeding. This was a prospective cohort investigation of the activity of four endometrial lysosomal enzymes in three contrasting groups: (i) women with ovulatory dysfunctional uterine bleeding and users of intrauterine contraceptive devices; (ii) breastfeeding post-partum women in whom there are long periods of amenorrhoea, particularly in the early months post-partum; and (iii) normal cycling women. It was found that the total activity of lysosomal enzymes, particularly acid phosphatase and N-acetyl-beta-D-glucosaminidase, was markedly elevated (P < 0.001) in IUCD-exposed endometrium, and endometrium from women with dysfunctional uterine bleeding when compared with endometrium from women with a history of entirely normal menstrual periods or that in post-partum breastfeeding women. The activity of alpha-L-fucosidase was moderately elevated in IUCD users (P < 0.05) and ovulatory dysfunctional uterine bleeding (P < 0.05), whereas alphaD-mannosidase activity was elevated in ovulatory dysfunctional uterine bleeding (P < 0.05), but decreased in IUCD users (P < 0.01). No significant differences were observed in the lysosomal enzyme activities of breastfeeding post-partum women and normal cycling women. These results show that total endometrial tissue activity of four lysosomal enzymes was substantially increased throughout the cycle in most circumstances in women with two different causes for increased menstrual bleeding. This suggests a contributory role to the increased bleeding.

The effect of topical ciprofloxacin on postoperative otorrhea after tympanostomy tube insertion.

OBJECTIVE: This study aimed to evaluate the effectiveness of prophylactic ciprofloxacin drops in decreasing the incidence of otorrhea after tympanostomy tube insertion. STUDY DESIGN: The study design was a single-blind, randomized clinical trial. SETTING: The study was conducted at a tertiary care referral center. PATIENTS: One hundred fifty-four patients aged 6 months to 14 years undergoing tympanostomy tube insertion participated. INTERVENTION: For each subject, one ear was randomly assigned to receive topical ciprofloxacin, placed in the middle and external ear after surgery, while the contralateral ear served as a control. MAIN OUTCOME MEASURE: Posttympanostomy otorrhea occurring during the period from 24 hours after surgery until 2 weeks after surgery was measured. RESULTS: Topical ciprofloxacin application after tympanostomy tube insertion was associated with a significantly lower incidence of early posttympanostomy otorrhea. The rates of otorrhea for control and treatment ears were 9.1% and 3.9%, respectively (p = 0.029). CONCLUSIONS: The topical administration of a single dose of ciprofloxacin solution after surgery is an effective treatment for the prevention of early posttympanostomy otorrhea.

Endometrial lysosomal enzyme activity in normal cycling endometrium.

The objective of this study was to evaluate the possible role of four lysosomal enzymes in endometrial function and remodelling during the normal menstrual cycle by fluorimetric measurement (acid phosphatase, N-acetyl-beta-D-glucosaminidase, alpha-L-fucosidase and alpha-D-mannosidase). A prospective study was conducted of 45 endometrial biopsies obtained from women with normal menstrual cycles. Activity of all four enzymes was identified in human endometrium. Activity of acid phosphatase and N-acetyl-beta-D-glucosaminidase was relatively high, whilst that of alpha-L-fucosidase and alpha-D-mannosidase was low. There was no significant change in the activity of any of the four enzymes from the proliferative to the secretory phase of the cycle. This study suggests that the activity of these enzymes remains constant throughout a major portion of the normal cycle.

Symptoms in pediatric asthmatics and air pollution: differences in effects by symptom severity, anti-inflammatory medication use and particulate averaging time.

Experimental research in humans and animals points to the importance of adverse respiratory effects from short-term particle exposures and to the importance of proinflammatory effects of air pollutants, particularly O(subscript)3. However, particle averaging time has not been subjected to direct scientific evaluation, and there is a lack of epidemiological research examining both this issue and whether modification of air pollutant effects occurs with differences in asthma severity and anti-inflammatory medication use. The present study examined the relationship of adverse asthma symptoms (bothersome or interfered with daily activities or sleep) to O(3) and particles (less than or equal to)10 micrometer (PM10) in a Southern California community in the air inversion zone (1200-2100 ft) with high O(3) and low PM (R = 0.3). A panel of 25 asthmatics 9-17 years of age were followed daily, August through October 1995 (n = 1,759 person-days excluding one subject without symptoms). Exposures included stationary outdoor hourly PM10 (highest 24-hr mean, 54 microgram/m(3), versus median of 1-hr maximums, 56 microgram/m(3) and O(3) (mean of 1-hr maximums, 90 ppb, 5 days (greater than or equal to)120 ppb). Longitudinal regression analyses utilized the generalized estimating equations (GEE) model controlling for autocorrelation, day of week, outdoor fungi, and weather. Asthma symptoms were significantly associated with both outdoor O(3) and PM(10) in single pollutant- and co-regressions, with 1-hr and 8-hr maximum PM(10) having larger effects than the 24-hr mean. Subgroup analyses showed effects of current day PM(10) maximums were strongest in 10 more frequently symptomatic (MS) children: the odds ratios (ORs) for adverse symptoms from 90th percentile increases were 2.24 [95% confidence interval (CI), 1.46-3.46] for 1-hr PM10 (47 microgram/m(3); 1.82 (CI, 1.18-2.81) for 8-hr PM10 (36 microgram/m(3); and 1.50 (CI, 0.80-2.80) for 24-hr PM10 (25 microgram/m(3). Subgroup analyses also showed the effect of current day O(subscript)3 was strongest in 14 less frequently symptomatic (LS) children: the ORs were 2.15 (CI, 1.04-4.44) for 1-hr O(3) (58 ppb) and 1.92 (CI, 0.97-3.80) for 8-hr O(3) (46 ppb). Effects of 24-hr PM10 were seen in both groups, particularly with 5-day moving averages (ORs were 1.95 for MS and 4. 03 for LS; p(less than or equal to)0.05). The largest effects were in 7 LS children not on anti-inflammatory medications [5-day, 8-hr PM10, 9.66 (CI, 2.80-33.21); current day, 1-hr O(3), 4.14 (CI, 1.71-11.85)]. Results suggest that examination of short-term particle excursions, medication use, and symptom severity in longitudinal studies of asthma yields sensitive measures of adverse respiratory effects of air pollution.

Regulation of human papillomavirus type 18 in vivo: effects of estrogen and progesterone in transgenic mice.

We examined the in vivo effect of estrogen, progesterone, RU 486, and pregnancy on the upstream regulatory region (URR) of human papillomavirus (HPV) 18 transgenic mice. The mice contain the bacterial reporter beta-galactosidase gene under control of the HPV 18 URR. Pregnant transgenic mice were sacrificed on various days of gestation and the level of URR activation was determined. Another group of female transgenic mice was ovariectomized at 4 to 6 weeks of age. Pellets of estradiol, progesterone, progesterone + RU 486, or placebo were implanted 1 to 2 weeks after ovariectomy. Mice were sacrificed after pellet implantation to examine acute and chronic effects. Marked increases in URR activation during pregnancy were observed. Progesterone was found to activate the URR acutely. Significantly higher activation was demonstrated at 24 hr in the progesterone group compared to placebo (P < 0.01). Activation with progesterone at 24 hr was significantly higher than at any other time point (P < 0.001). A trend toward decreasing activation over time was demonstrated in the progesterone group (r = -0.87, P = 0.0001). RU 486 does not block the activation of progesterone in our model. Estradiol activates the URR acutely compared to placebo (P = 0.034). This in vivo model demonstrates activation of the URR in response to exogenous estrogen, progesterone, and pregnancy. These data may have clinical implications for women who harbor high-risk HPV.

The effect of outdoor fungal spore concentrations on daily asthma severity.

The relationship between day-to-day changes in asthma severity and combined exposures to community air pollutants and aeroallergens remains to be clearly defined. We examined the effects of outdoor air pollutants, fungi, and pollen on asthma. Twenty-two asthmatics ages 9-46 years were followed for 8 weeks (9 May-3 July 1994) in a semirural Southern California community around the air inversion base elevation (1,200 ft). Daily diary responses included asthma symptom severity (6 levels), morning and evening peak expiratory flow rates (PEFR), and as-needed beta-agonist inhaler use. Exposures included 24-hr outdoor concentrations of fungi, pollen, and particulate matter with a diameter < 10 microns (PM10; maximum = 51 micrograms/m3) and 12-hour day-time personal ozone (O3) measurements (90th percentile = 38 ppb). Random effects longitudinal regression models controlled for autocorrelation and weather. Higher temperatures were strongly protective, probably due to air conditioning use and diminished indoor allergens during hot, dry periods. Controlling for weather, total fungal spore concentrations were associated with all outcomes: per minimum to 90th percentile increase of nearly 4,000 spores/m3, asthma symptom scores increased 0.36 (95% CI, 0.16-0.56), inhaler use increased 0.33 puffs (95% CI, -0.02-0.69), and evening PEFR decreased 12.1 l/min (95% CI, -1.8-22.3). These associations were greatly enhanced by examining certain fungal types (e.g., Alternaria, basidiospores, and hyphal fragments) and stratifying on 16 asthmatics allergic to tested deuteromycete fungi. There were no significant associations to low levels of pollen or O3, but inhaler use was associated with PM10 (0.15 inhaler puffs/10 micrograms/m3; p < 0.02). These findings suggest that exposure to fungal spores can adversely effect the daily respiratory status of some asthmatics.

Interferon-gamma enhances susceptibility of cervical cancer cells to lysis by tumor-specific cytotoxic T cells.

Recently we have demonstrated that tumor-specific cytotoxic T lymphocytes (CTLs) can be activated by cervical carcinoma cells expressing the costimulatory molecule CD80, which may be used as a therapeutic vaccine for patients with cervical cancer. For activated CTLs to be effective, appropriate amounts of MHC class I expression are required on target tumor cells. In this study, we found that some cervical carcinoma cells expressed only low levels of MHC class I and adhesion molecules such as CD54. We further demonstrated that tumor cells (CaSki and SiHa) expressing low levels of MHC class I were more resistant to lysis by specific CTLs than tumor cells (HeLa) expressing high levels of MHC class I. Treatment of CaSki or SiHa cells with interferon-gamma resulted in an increased expression of MHC class I, MHC class II, and CD54. Expression of CD58 and CD80 was not up-regulated or induced. Treatment of the tumor cells with interferon-gamma significantly enhanced the lysis of the tumor cells by specific CTLs which had been activated by the respective CD80-expressing tumor cells. The enhancement of cytolysis could be blocked by monoclonal antibodies to MHC class I and CD54, but not by that to MHC class II. Furthermore, we found that interferon-gamma induced apoptosis in cervical carcinoma cells but not in tumor-specific CTLs.

Special interests or citizens' rights? "Senior power," Social Security, and Medicare.

Conventional political analysts and mainstream media accounts attribute substantial political power to the elderly in the United States. This attribution of "senior power" is usually made in the context of the politics of Social Security and Medicare. This article contrasts the conventional construction of elderly political actors as a special interest with a more critical perspective that views Social Security and Medicare as citizens' rights. Critical examination of the welfare state's role in creating age as a potential political cleavage and the politics of Social Security and Medicare reveals that there is no undifferentiated politics of aging in the United States. Rather, age interacts with a variety of other statuses such as race/ethnicity, gender, and class to condition citizens' political mobilization. Welfare state policies--social insurance programs like Social Security and Medicare, means--tested programs like Medicaid and Supplemental Security Income, and targeted tax expenditures for private pensions and health insurance--differentially empower particular subgroups of elderly citizens and routinely disadvantage the most vulnerable elderly, including minority elders, women, and the oldest old.