Dexamethasone significantly attenuates sub-arachnoid hemorrhage-induced elevation in cerebrospinal fluid citrulline and leukocytes.

AIM: Cerebral vasospasm is a leading cause of death and disability following aneurysmal subarachnoid hemorrhage (SAH). Nitric oxide (NO) is a potent mediator of vasodilation, and citrulline is a known contributor to NO production. The leukocytosis inflammatory response can increase vasoconstrictive compounds that may also contribute to vasospasm. Dexamethasone is a glucocorticosteroid commonly administered after SAH, which may alter the production of leukocytes and citrulline. The goal of this project was to study the effects of dexamethasone on leukocytosis, citrulline, and angiographic vasospasm. METHODS: Experimental SAH was induced in 18 New Zealand white rabbits. Intravenous dexamethasone was administered to one group (N.=9) at 2 mg/kg/day. A placebo group (N.=9) was given a saline infusion with otherwise identical procedures. CSF citrulline, leukocytes, protein, and glucose, as well as plasma citrulline were measured at baseline and 3 days post-SAH in a blinded fashion. Basilar artery angiography was performed at baseline and repeated 3 days post-SAH. RESULTS: The change in CSF citrulline from day 0 to day 3 was significantly lower in the dexamethasone group compared to controls (P=0.002). The change in CSF white blood cells was also significantly lower (P=0.005). There was no significant change in plasma citrulline levels or angiographic vasospasm. CONCLUSION: Dexamethasone significantly decreases CSF citrulline and CSF leukocytosis after experimental SAH. It is possible this could lead to a relative vasoconstriction and vasodilation, respectively. These processes could cancel-out opposing effects of dexamethasone on cerebral vasospasm, partially contributing to the recognized, multifactorial, inconsistent effects of glucocorticoids on vasospasm.

Activity of fulvestrant in HER2-overexpressing advanced breast cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) overexpression increases the aggressiveness of breast cancer cells resulting in poorer prognosis. Patients with HER2-positive disease are less responsive to endocrine therapies. Trastuzumab monotherapy results in objective responses in only approximately 15% of patients. Fulvestrant retains activity in cells overexpressing HER2 that are resistant to other endocrine treatments. This retrospective study evaluated response to fulvestrant treatment among HER2-positive patients with advanced breast cancer (ABC). PATIENTS AND METHODS: Clinical experience data from 10 treatment centres were pooled. Postmenopausal patients with predominantly hormone receptor-positive and HER2-positive disease were included. Clinical benefit (CB) was defined as the proportion of patients achieving a response to treatment (partial or complete) or stable disease lasting >/=6 months. RESULTS: Data for 102 patients were analysed. Fulvestrant resulted in an overall CB rate of 42% (43/101) in HER2-positive patients and 40% (25/63) in patients with visceral disease. Median duration of treatment was 14.5 months (range 6-44 months). Fulvestrant showed activity up to the fourth line of endocrine therapy and up to the seventh line of overall therapy. CONCLUSIONS: Results indicate that fulvestrant may be a suitable treatment option in extensively pre-treated patients with HER2-positive, hormone receptor-positive ABC. Further exploration of its use in this patient population is warranted.

Optimization of cytochrome P4502D6 (CYP2D6) phenotype assignment using a genotyping algorithm based on allele frequency data.

Cytochrome P4502D6 (CYP2D6) is a highly polymorphic gene locus with > 50 variant alleles which lead to a wide range in enzymatic activity. So called poor metabolizers are carriers of any two non-functional alleles of the CYP2D6 gene. CYP2D6 genotyping is cumbersome and the question of how much genotyping is necessary for an accurate phenotype prediction is still debated. The goal of this study was to determine the optimum amount of genotyping required to accurately predict the phenotype at a reasonable cost in a white North American population. To address this issue, we designed a polymerase chain reaction (PCR)/restriction fragment length polymorphism-based genotyping strategy to detect 'key' mutations linked to extensive metabolizer or poor metabolizer associated alleles in combination with extra-long PCR (XL-PCR). All mutations with the exception of gene deletions and duplications are detectable by simple restriction digestion analysis and agarose gel electrophoresis. In addition, we utilized a genotyping algorithm based on our own and published allele frequency data and phenotype analysis to calculate the probability of a correct genotype (and thus, phenotype) assignment. As little as one XL-PCR reaction followed by a maximum of six reamplification reactions allows an accurate prediction of an individual's genotype to 99.15%. As few as four reamplification reactions identify 97.9% of poor metabolizer individuals. We evaluated our model in 208 white North Americans by testing for the presence of 'key' mutations linked to CYP2D6*2, *3, *4, *6, *7, *8, *9, *10, *11, *12, *15, *17 and *18 alleles and the *5, *13 and *16 gene deletions. For all individuals, the correct phenotype has been predicted. Discordant phenotype assignment occurred in only two individuals which subsequently was attributed to CYP2D6 inhibition by concomitant drug therapy.

Should all infertile males undergo urologic evaluation before assisted reproductive technologies? Two cases of testicular cancer presenting with infertility.

OBJECTIVE: To report two cases of testicular cancer in patients presenting with infertility. DESIGN: Case reports. SETTING: University-affiliated urology practice. PATIENT(S): Two men presenting with infertility. INTERVENTION(S): Complete history and physical, hormonal assays, semen analysis, scrotal ultrasound, radical orchiectomy. MAIN OUTCOME MEASURE(S): Testicular pathology specimens. RESULT(S): Testicular cancer was diagnosed in two men sent to a urology clinic for infertility treatment. CONCLUSION(S): A thorough evaluation should be completed in all males in couples presenting with infertility.

Is the randomized clinical trial the gold standard of research?

All research has flaws. Some flaws are so trivial that the research can still stand as the definitive study. Other flaws prevent a study from being definitive, but the study still provides useful guidance in the context of other research. Some flaws are so serious that the research provides no useful information at all. The tricky part is not finding flaws in the research but in deciding to what extent the flaws erode the credibility of the research. In general, the use of RCTs can add substantial credibility to a research study. There are calls for greater use of RCTs in many areas, such as surgery (Baum, 1999) and psychiatry (Andrews, 1999). Of course, nonrandomized trials are an important complement to RCTs when the latter are ethically inappropriate or logistically impossible (Black, 1996). Failure to use randomization or blinding, however, is not a fatal flaw. Furthermore, the artificial nature of RCTs will often restrict their applicability to overly simple interventions. When RCTs focus on narrow patient groups or exclude important segments of the population, there may be difficulty in generalizing their results. So it would be a mistake to label the RCT as a gold standard for all research. A silver standard may be a more appropriate label.

Interpreting positive studies.

When examining the results of a positive research study, one needs to consider two issues of clinical relevance. First, is the outcome measure of direct interest to patients, or is it clearly linked to a measure of direct interest to patients? Second, is the difference large enough to lie outside the range of clinical indifference? Don't accept the findings of a positive research study without a careful consideration of clinical relevance.

Understanding the odds ratio and the relative risk.

Both the odds ratio and the relative risk compare the relative likelihood of an event occurring between two groups. The relative risk is easier to interpret and is consistent with general intuition. Some designs, however, allow only for the calculation of the odds ration. Covariate adjustment is easier for an odds ratio. Finally, the odds ratio avoids ambiguity by being invariant to lthe labeling of the outcome measure. The Table summarizes the advantages and disadvantages of the odds ratio and relative risk. Whe reading research that summarizes data using odds ratios, or relative risks, be aware of the limitations of booth of these measures.

Longitudinal study of semen quality of unexposed workers. Sperm motility characteristics.

As part of a longitudinal study of human semen characteristics of unexposed workers, sperm motility measurements were made using computer-assisted sperm analysis. Motility analyses were conducted on monthly samples from 46 men for 9 months. Measurements of curvilinear velocity, straight-line velocity (VSL), linearity, amplitude of lateral head displacement (ALH), and beat-cross frequency were collected in eight microscope fields for each semen sample. The variability within a sample, between samples from the same individual (between monthly samples), and between individuals were calculated using a nested analysis of variance. For all sperm motility measurements, at least 90% of the variation was observed between cells within a semen sample. For all variables, the component of variation between subjects was the smallest percentage (ranging from 1.3% for ALH to 4.0% for VSL). When sample means were used in the nested analysis of variation, at least 75% of the variation was observed between samples from the same individual. These results will be useful in power calculations for future studies.

Longitudinal study of semen quality of unexposed workers: sperm head morphometry.

As part of a longitudinal study of human semen characteristics of unexposed workers, sperm head measurements were made using image analysis (Image Technologies Corp., Deer Park, NY). Morphometry was conducted on monthly samples from 45 men for 9 months. Measurements of area, perimeter, length, width, the width-length ratio, and the oval factor (4 [pi] area/perimeter) of 100 sperm heads per sample were obtained. The variability within a sample, between monthly samples from the same individual, and between individuals were calculated for each parameter. Tolerance intervals for each parameter were calculated, and are expected to contain 75% of all individual measurements. Similar intervals were calculated for the means and coefficients of variation of a semen sample. The largest source of variability was attributed to individual cell variation within a semen sample.

Longitudinal study of semen quality of unexposed workers. I. Study overview.

A longitudinal study of 45 men was conducted evaluating the semen quality of monthly samples collected over 9 months. The statistical variation of sperm count, semen volume, percentage of motile sperm, sperm velocity, sperm morphology, and sperm viability, assessed by both the vital stain and the hypoosmotic swelling (HOS) assay, were each evaluated using intraclass correlations and coefficients of variation. Sperm count and semen volume had large intraclass correlations (62% and 60%, respectively), indicating that if a subject has a high count or volume he will tend to continue to have high counts or volumes. On the other hand, sperm velocity had an intraclass correlation of only 16% indicating that fluctuations within a subject were nearly as large as fluctuations from subject to subject. The remaining parameters had intraclass correlations ranging from 42% to 47%. Sperm count, percent motile sperm, and semen volume each had large coefficients of variation (both between and within subjects). These variables, especially count, had relatively poor precision. Sperm velocity, percent motile sperm, percent normal morphology, the HOS assay, and the vital stain assay had lower coefficients of variation, indicating greater precision.

Semen analysis of military personnel associated with military duty assignments.

A collaborative study between the U.S. Army Biomedical Research and Development Laboratory (USABRDL) and the National Institute for Occupational Safety and Health (NIOSH) was designed to assess fecundity of male artillery soldiers with potential exposures to airborne lead aerosols. Potential exposure assessment was based upon information provided in an interactive questionnaire. It became apparent from extensive questionnaire data that many soldiers in the initial control population had potentially experienced microwave exposure as radar equipment operators. As a result, a third group of soldiers without potential for lead or microwave exposures, but with similar environmental conditions, was selected as a comparison population. Blood hormone levels and semen analyses were conducted on artillerymen (n = 30), radar equipment operators (n = 20), and the comparison group (n = 31). Analysis of the questionnaire information revealed that concern about fertility problems motivated participation of some soldiers with potential artillery or microwave exposures. Although small study population size and the confounding variable of perceived infertility limit the reliability of the study, several statistically significant findings were identified. Artillerymen who perceived a possible fertility concern demonstrated lower sperm counts/ejaculate (P = 0.067) and lower sperm/mL (P = 0.014) than the comparison group. The group of men with potential microwave exposures demonstrated lower sperm counts/mL (P = 0.009) and sperm/ejaculate (P = 0.027) than the comparison group. Variables used to assess endocrine, accessory sex gland, and sperm cell function were not different than the comparison group. Additional studies, incorporating larger numbers of individuals, should be performed in order to more optimally characterize potential lead and microwave exposure effects on male fecundity.

Male reproductive effects of lead, including species extrapolation for the rabbit model.

The effects of elevated blood lead on semen quality were evaluated in the rabbit model and compared to published effects in humans. Mature, male rabbits were given lead acetate by subcutaneous injection in the dose range of 0 to 3.85 mg/kg on a Monday-Wednesday-Friday basis. In each of eight treatment groups, a dosing regimen was developed to produce blood lead levels of 0, 20, 40, 50, 70, 80, 90, and 110 microg/dL. A 5-week pre-exposure period was followed by a 15-week exposure testing period allowing for response through six cycles of the seminiferous epithelium. Semen analyses revealed that increased blood lead levels were associated with adverse changes in the sperm count, ejaculate volume, percent motile sperm, swimming velocities, and morphology. Hormonal responses were minimal. Testicular pathology revealed a dose-dependent inhibition of spermiation. For six measures of semen quality, threshold estimates ranged from 16 to 24 microg/dL. Using the species extrapolation factor derived in this study, a rabbit dose would have to be divided by 1.56 to obtain the equivalent human dose for an equal percentage decrease in sperm concentration; however, rabbits are 3.75 more sensitive in terms of absolute decrease in sperm count for a given blood lead level.

Reproductive function in relation to duty assignments among military personnel.

As a follow-up to the pilot study of semen quality of soldiers with various military assignments a larger, more complete study was conducted. Soldiers were recruited at Fort Hood, Texas. Thirty-three men were exposed to radar as part of their duty assignment in the Signal Corps, 57 men were involved with firing the 155 mm howitzer (potential lead exposure), and 103 soldiers had neither lead nor radar exposure and served as the comparison control group. Both serum and urinary follicle-stimulating hormone and luteinizing hormone and serum, salivary, and urine testosterone levels were determined in all men. A complete semen analysis was conducted on each soldier. For statistical analysis, the primary study variables were: sperm concentration, sperm/ejaculate, semen volume, percent normal morphology, percent motile, percent viable (both vital stain and hypoosmotic swelling), curvilinear velocity, straight-line velocity, linearity, sperm head length, width, area, and perimeter. Variables were adjusted for significant confounders (e.g., abstinence, sample age, race). No statistical differences (P < 0.05) were observed in any measurement. While these results are in agreement with two previous studies assessing soldiers firing the 155-mm howitzer, they contradict our previous report indicating that radar exposure caused a significant decrease in sperm numbers. A possible explanation is that the radar exposure in this study was that used in Signal Corps operations while the men in the previous study were using different radar as part of military intelligence operations. The data presented here in men firing the 155-mm howitzer combined with the results from the previous studies confirms that there are no deficits in semen quality in these men. The contradiction between the results of the radar exposure studies indicates that more data are needed to evaluate the relationship of military radar and male reproductive health.

Phase II trial of etoposide (V), adriamycin (A), and cisplatinum (P) in patients with metastatic gastric cancer.

The efficacy and toxicity of a combination of etoposide (100 mg/m2 i.v. on days 1 to 3), Adriamycin (20 mg/m2 i.v. on days 1 and 8) and cisplatinum (40 mg/m2 i.v. on days 2 and 8) repeated every 4 weeks as an outpatient regimen were assessed in 29 consecutive patients with metastatic gastric cancer with measurable disease. Five of these patients were refractory to 5-Fluorouracil, Adriamycin, and Mitomycin C. Three of these previously treated patients responded to the etoposide. Adriamycin, cisplatinum (VAP) therapy. An overall objective response rate of 72.5% was achieved, including 14% that were complete responses. The median duration of response was 6.0 months; median overall survival was 7.2 months, overall one-year survival was 34.4%. Hematologic toxicity was intense, particularly among patients with lower performance status. Three patients died as a consequence of nadir sepsis episodes.

Semen quality and hormone levels among radiofrequency heater operators.

Approximately 9,000,000 US workers are occupationally exposed to radiofrequency (RF) radiation; over 250,000 operate RF dielectric heaters. Our purpose was to determine whether male RF heater operators experience increased adverse reproductive effects reflected in reduced semen quality or altered hormone levels. We measured incident RF heater radiation exposures and RF-induced foot currents at four companies. For 12 male heater operators and a comparison group of 34 RF-unexposed men, we measured 33 parameters of semen quality and four serum hormones. Despite wide variation in individual exposure levels, near field strengths and induced foot currents did not exceed current standard levels and guidelines. We observed minor semen quality and hormonal differences between the groups, including a slightly higher mean follicle-stimulating hormone level for exposed operators (7.6 vs 5.8 mIU/mL). Further occupational studies of RF-exposed men may be warranted.

Transitioning preterm infants with nasogastric tube supplementation: increased likelihood of breastfeeding.

OBJECTIVE: To compare nasogastric tube and bottle supplementation as two means of transitioning preterm infants to breastfeeding within an established breastfeeding support program. DESIGN: Prospective, randomized controlled trial; mothers and health care providers, who were not blinded. SETTING: Metropolitan private regional perinatal center; 40-bed intensive-care nursery. PARTICIPANTS: Eighty-four preterm breastfed infants whose birth weight was 1,000-2,500 g. MAIN OUTCOME MEASURES: Rates of exclusive and partial breastfeeding at discharge from the intensive-care nursery, and at 3 days, 3 months, and 6 months after discharge. RESULTS: Compared with infants receiving bottle supplements, infants receiving nasogastric tube supplements were more likely to be breastfeeding at discharge and at 3 days, 3 months and 6 months, after adjusting for confounding variables. Odds ratios (confidence intervals = 95%) showed that the group receiving nasogastric supplements was 4.5 times (1.4 to 15) more likely to be breastfed at discharge and 9.4 times more likely to be fully breastfed (3.1 to 28.4). There were significantly fewer apnea and bradycardia episodes in the group receiving nasogastric supplements, although they had more episodes that required stimulation for resolution. Groups were not different with respect to length of hospitalization and infant weight at discharge. CONCLUSIONS: Using nasogastric tube supplementation during transition to oral feedings increases the likelihood of breastfeeding at discharge, 3 days, 3 months, and 6 months. This intervention requires a program with skilled personnel and an environment that allows the mother and infant to be in close physical proximity. Further study should investigate differences in the effects on maternal confidence, imprinting, and suck mechanism when preterm infants are bottle fed and breastfed.

Duration of breast-feeding patterns established in the hospital. Influencing factors. Results from a national survey.

Data from a national survey of new mothers were analyzed to determine the effect that demographic characteristics, breast-feeding instructions, and infant formula discharge kits had on breast-feeding patterns established in the hospital. Results indicated that mothers who exclusively breast-fed their infant were more likely to be affluent, college educated, and not working outside the home. Mothers who exclusively breast-fed their infants in the hospital and subsequently practiced partial breast-feeding or formula, or cow's milk feeding were more likely to return to the work force within the first 6 postpartum months. Mothers who partially breast-fed their infants in the hospital were more likely to have a low-birth-weight neonate. Stepwise logistic regression analysis indicated that greater total family income, a better education, and having more than one child had positive significant effects on exclusive breast-feeding by the first and fourth month. Women who received a formula discharge kit compared with those who did not had a slightly higher probability of initiating partial breast-feeding (10 vs. 7% by the first month; 27 vs. 25% by the fourth month). Maternal employment had a large impact on duration of exclusive breast-feeding. By the fourth month, mothers who were employed had a higher probability of initiating partial breast-feeding (43 vs. 19%) compared with mothers who were not in the work force.

The use of skull X-rays in the accident and emergency department.

The notes of all patients attending the accident and emergency department at the Royal Berkshire Hospital with a head injury from 1-30 September 1999 were analysed for the indications for skull X-ray, the report on film, and the outcome of the consultation. Using the existing Royal Berkshire Hospital guidelines, 50% (193/385) of all patients had skull X-rays performed. One fracture was detected. If the recent guidelines from The Royal College of Surgeons of England Working Party for the use of skull X-rays in institutions which possess a CT scanner were applied, the number of skull X-rays performed would reduce from 193 to 14 without detriment to any patient.

Capitation: selecting the method, determining the rates. Can providers share risk without excessive financial exposure?

Healthcare providers in markets with a high degree of managed care penetration, such as western states, are aggressively pursuing capitated contracts that are comprehensive in scope and that assume a significant amount of risk sharing. Providers in other parts of the country, however, still are determining how much risk they can assume safely. Integral to this assessment is consideration of two factors: the form of the capitated payment and the capitation rate. Providers must understand the two forms of capitated payment--per member per month and percent of premium--and how each is affected by changes in market levels before they can choose the one best suited to the amount of risk they can assume. Findings from a study of capitation rates utilized by 10 large national or multiregional HMOs may serve as a point of reference for providers.

Is your organization ready to share financial risk with HMOs?

Of growing importance in healthcare delivery is the issue of how the risk of providing services to healthcare maintenance organizations (HMOs) enrollees should be shared by the provider and the HMO. Understanding and monitoring risk-sharing arrangements and how they are developing is critical. This article reviews the trends in managed care and risk sharing and examines regulation of capitation and risk sharing as it varies form state to state.