Detection of a knockdown mutation in the voltage-sensitive sodium channel associated with permethrin tolerance in Sarcoptes scabiei var. hominis mites.

BACKGROUND: Increasing evidence has sparked a debate on the loss of sensitivity of scabies mites to conventional permethrin therapy. Mutations in the voltage-sensitive sodium channels (VSSC) were associated with knockdown resistance (kdr) in many arthropods, but have never been identified in Sarcoptes scabiei variatio (var.) hominis mites. OBJECTIVES: To identify factors contributing to therapy failure. METHODS: Sixty-seven mites were collected from 64 scabies-infested patients in Vienna, Austria, of whom 85.9% were refractory to prior permethrin-based treatments, and genotyped for the presence of nucleotide polymorphisms in Domain II of the VSSC, known to be associated with kdr. Information regarding previous antiscabietic therapies, decontamination procedures and possible re-infestations by contacts as well as the response to re-imposed therapies were obtained. RESULTS: Sequence alignment comparisons revealed previously unidentified mutations in the coding region of Domain II of the VSSC. A novel A1663T transversion was detected in 97.0% of the mites, resulting in a non-synonymous substitution from methionine to leucine, M918L, a mutation known to confer kdr in other arthropods. In addition, a synonymous G1659A transition was identified in one mite, which otherwise showed a nucleotide sequence identical to the wild-type reference. No major inconsistencies were observed within the previous therapeutic and decontamination procedures, which could have accounted for the observed non-responsiveness to permethrin-based therapies. Subsequent cure of infestation was achieved in 65.6% of the participants, predominantly by combination therapies with topical permethrin and systemic ivermectin. However, in 14.6% of the cured cases, permethrin monotherapy sufficed for eradication of scabies, albeit in some cases prolonged exposure was necessary. CONCLUSIONS: The kdr-associated M918L mutation in the VSSC gene has now emerged in S. scabiei var. hominis mites. Hence, loss of sensitivity to permethrin due to kdr-type resistance may be more prevalent than anticipated and may be decisive for the therapy responsiveness of scabies-infested patients.

Fitness, obesity and risk of asthma among Army trainees.

BACKGROUND: Epidemiological data suggest an association between overweight/obesity and asthma. However, less is known about the relationship between physical fitness and asthma. AIMS: To enumerate new-onset asthma diagnoses in Army recruits during the first 2 years of service and determine associations with fitness and excess body fat (EBF) at military entrance. METHODS: New asthma diagnoses over 2 years in Army recruits at six entrance stations were obtained from military health and personnel records. Poisson regression models were used to determine associations of asthma diagnosis with pre-accession fitness testing, EBF and other potential factors. RESULTS: In 9979 weight-qualified and 1117 EBF entrants with no prior history of asthma, 256 new cases of asthma were diagnosed within 2 years of military entry. Low level of fitness, defined by a step test and EBF, was significantly associated with new asthma diagnosis [adjusted incidence rate ratio (IRR), 1.47; 95% confidence interval (CI) 1.11-1.96 and adjusted IRR, 1.53; 95% CI 1.06-2.20, respectively]. CONCLUSIONS: Individuals with low fitness levels, EBF or both are at higher risk of asthma diagnosis in the first 2 years of military service.

Striatal dopamine release in schizophrenia comorbid with substance dependence.

Dopamine (DA) has a role in the pathophysiology of schizophrenia and addiction. Imaging studies have indicated that striatal DA release is increased in schizophrenia, predominantly in the precommissural caudate (preDCA), and blunted in addiction, mostly in the ventral striatum (VST). Therefore, we aimed to measure striatal DA release in patients with comorbid schizophrenia and substance dependence. We used [(11)C]raclopride positron emission tomography and an amphetamine challenge to measure baseline DA D2-receptor availability (BPND) and its percent change post-amphetamine (ΔBPND, to index amphetamine-induced DA release) in striatal subregions in 11 unmedicated, drug-free patients with both schizophrenia and substance dependence, and 15 healthy controls. There were no significant group differences in baseline BPND. Linear mixed modeling using ΔBPND as the dependent variable and striatal region of interest as a repeated measure indicated a significant main effect of diagnosis, F(1,24)=8.38, P=0.008, with significantly smaller ΔBPND in patients in all striatal subregions (all P ≤ 0.04) except VST. Among patients, change in positive symptoms after amphetamine was significantly associated with ΔBPND in the preDCA (rs=0.69, P=0.03) and VST (rs=0.64, P=0.05). In conclusion, patients with comorbid schizophrenia and substance dependence showed significant blunting of striatal DA release, in contrast to what has been found in schizophrenia without substance dependence. Despite this blunting, DA release was associated with the transient amphetamine-induced positive-symptom change, as observed in schizophrenia. This is the first description of a group of patients with schizophrenia who display low presynaptic DA release, yet show a psychotic reaction to increases in D2 stimulation, suggesting abnormal postsynaptic D2 function.

Fitness, obesity and risk of heat illness among army trainees.

BACKGROUND: Exertional heat illness (EHI) affects military personnel, athletes and occupational groups such as agricultural workers, despite knowledge of preventive measures. AIMS: To evaluate EHI diagnoses during US Army basic training and its associations with fitness and body fat on entering military service. METHODS: From February 2005 to September 2006, US Army recruits at six different military entrance stations took a pre-accession fitness test, including a 5-min step test scored as pass or fail. Subsequent EHI incidence and incidence rate ratios were analysed with reference to subjects' fitness (step test performance) and whether they met (weight qualified [WQ]) or exceeded body fat (EBF) standards. RESULTS: Among the 8621 WQ and 834 EBF male subjects, there were 67 incidents of EHI within 180 days of entering military service. Among WQ subjects, step test failure was significantly associated with EHI (odds ratio [OR] 2.00, 95% confidence interval [CI] 1.13, 3.53). For those passing the step test, the risk of EHI was significantly higher in EBF than in WQ subjects (OR 3.98, 95% CI 2.17, 7.29). Expected ORs for the joint effects of step test failure and EBF classification under additive and multiplicative models were 4.98 and 7.96, respectively. There were too few women to evaluate their data in detail. CONCLUSIONS: This study demonstrated that fitness and body fat are independently associated with incident EHI, and the effect of both was substantially higher. Those with low fitness levels and/or obesity should be evaluated further before engaging in intense physical activity, especially in warmer months.

HIV Infection Progression Monitoring System Based on CD4 Counts and Wishart Distribution.

The human immunodeficiency virus (HIV) is a viral infection that destroys the human immune system, resulting in the acquired immunodeficiency syndrome (AIDS). The management and care of patients on antiretroviral therapy (ART) consumes a large portion of the health budget of many countries. ART improves the lives of the HIV patients. However, benefiting from the treatment remains to be low due to the nonadherence, adverse events, and treatment failure associated with the transmitted drug resistance mutations (TDRMs). Extra care is therefore required in prescribing switch of ART regimens for HIV-naive patients. We propose a disease monitoring system, which depends on how the HIV-naive patients respond to the ART regimen. We model cluster of differentiation 4 (CD4) counts data measured at every 3 months in a period of 48 weeks on a cohort of 87 HIV-naive patients on ART, from Zambia. We demonstrate how to apply the Bayesian Wishart distribution to model CD4 counts, leading to an informative HIV progression monitoring system. We found a steady increase in the average of the CD4 counts (from 219 to 315) for HIV-naive patients on the ART regimen. The average was still below the expected 500 CD4 counts for a normal person. The derived precision matrix shows an increase in probability of potency of the ART regimen, which ranges from 0.1261 to 0.8678. An early detection is crucial as it allows for timely switch of regimen from first to second line or to the third line. The proposed HIV disease progression monitoring system for HIV-naive patients on ART regimen that is based on CD4 counts could enable physicians make informed decisions on the management and care of the patients.

Designing early detection programs for ovarian cancer.

Human epididymis protein 4 (HE4) shows promise as a serum marker that complements CA125 in the early detection of epithelial ovarian cancer, either as a first-line screen or as a second-line screen in a multimodal strategy. Incorporation of symptoms in a screening strategy that includes CA125 and HE4 may warrant further research.

Musculoskeletal injuries among overweight army trainees: incidence and health care utilization.

BACKGROUND: Musculoskeletal injuries are a major cause of morbidity in military training. They are more common among overweight/obese individuals, and the prevalence of overweight/obesity in the military has increased. During strong economic periods, the military can be challenged to recruit enough qualified personnel, and physical standards are sometimes relaxed. AIMS: This study was conducted to compare the incidence of and outpatient utilization for training-related overuse injuries among men who were over body fat (OBF) standards compared with those who were weight qualified (WQ). METHODS: All study subjects were men ≥18 years old, who were classified as OBF or WQ and were followed for 90 days. During this period, everyone entering through the study sites was required to take a physical fitness test (5 min step test). Only individuals passing the fitness test were included in these analyses. RESULTS: There were 812 OBF and 6511 WQ study participants. OBF were 47% more likely to experience a musculoskeletal injury and had 49% higher health care utilization. Other significant factors included age >19 and a history of smoking. CONCLUSIONS: Among this population who had passed a fitness test, those who were OBF had a substantially higher risk of injury and higher utilization for these injuries. Because the recruiting environment is much better, military entrance standards have been tightened, but should the economy improve substantially the military may again be challenged to recruit adequate numbers of personnel, and the lessons learned in this project may prove valuable.

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease.

Brain-derived neurotrophic factor (BDNF) is the main candidate for neuroprotective therapeutic strategies for Huntington's disease. However, the administration system and the control over the dosage are still important problems to be solved. Here we generated transgenic mice overexpressing BDNF under the promoter of the glial fibrillary acidic protein (GFAP) (pGFAP-BDNF mice). These mice are viable and have a normal phenotype. However, intrastriatal administration of quinolinate increased the number of reactive astrocytes and enhanced the release of BDNF in pGFAP-BDNF mice compared with wild-type mice. Coincidentally, pGFAP-BDNF mice are more resistant to quinolinate than wild-type mice, suggesting a protective effect of astrocyte-derived BDNF. To verify this, we next cultured astrocytes from pGFAP-BDNF and wild-type mice for grafting. Wild-type and pGFAP-BDNF-derived astrocytes behave similarly in nonlesioned mice. However, pGFAP-BDNF-derived astrocytes showed higher levels of BDNF and larger neuroprotective effects than the wild-type ones when quinolinate was injected 30 days after grafting. Interestingly, mice grafted with pGFAP-BDNF astrocytes showed important and sustained behavioral improvements over time after quinolinate administration as compared with mice grafted with wild-type astrocytes. These findings show that astrocytes engineered to release BDNF can constitute a therapeutic approach for Huntington's disease.

Discovery and characterization of a positive allosteric modulator of transient receptor potential canonical 6 (TRPC6) channels.

The non-selective second messenger-gated cation channel TRPC6 (transient receptor potential canonical 6) is activated by diacylglycerols (DAG) in a PKC-independent manner and plays important roles in a variety of physiological processes and diseases. In order to facilitate novel therapies, the development of potent inhibitors as well as channel-activating agents is of great interest. The screening of a chemical library, comprising about 17,000 small molecule compounds, revealed an agent, which induced increases in intracellular Ca2+ concentrations ([Ca2+]i) in a concentration-dependent manner (EC50 = 2.37 ± 0.25 µM) in stably TRPC6-expressing HEK293 cells. This new compound (C20) selectively acts on TRPC6, unlike OAG (1-oleoyl-1-acetyl-sn-glycerol), which also activates PKC and does not discriminate between TRPC6 and the closely related channels TRPC3 and TRPC7. Further evaluation by Ca2+ assays and electrophysiological studies revealed that C20 rather operated as an enhancer of channel activation than as an activator by itself and led to the assumption that the compound C20 is an allosteric modulator of TRPC6, enabling low basal concentrations of DAG to induce activation of the ion channel. Furthermore, C20 was tested in human platelets that express TRPC6. A combined activation of TRPC6 with C20 and OAG elicited a robust increase in [Ca2+]i in human platelets. This potentiated channel activation was sensitive to TRPC6 channel blockers. To achieve sufficient amounts of C20 for biological studies, we applied a one-pot synthesis strategy. With regard to studies in native systems, the sensitizing ability of C20 can be a valuable pharmacological tool to selectively exaggerate TRPC6-dependent signals.

Correction: Responses of deposition and bioaccumulation in the Great Lakes region to policy and other large-scale drivers of mercury emissions.

Correction for 'Responses of deposition and bioaccumulation in the Great Lakes region to policy and other large-scale drivers of mercury emissions' by J. A. Perlinger et al., Environ. Sci.: Processes Impacts, 2018, 20, 195-209.

Responses of deposition and bioaccumulation in the Great Lakes region to policy and other large-scale drivers of mercury emissions.

Mercury (Hg) emissions pose a global problem that requires global cooperation for a solution. However, neither emissions nor regulations are uniform world-wide, and hence the impacts of regulations are also likely to vary regionally. We report here an approach to model the effectiveness of regulations at different scales (local, regional, global) in reducing Hg deposition and fish Hg concentrations in the Laurentian Great Lakes (GL) region. The potential effects of global change on deposition are also modeled. We focus on one of the most vulnerable communities within the region, an Indigenous tribe in Michigan's Upper Peninsula (UP) with a high fish consumption rate. For the GL region, elements of global change (climate, biomass burning, land use) are projected to have modest impacts (<5% change from the year 2000) on Hg deposition. For this region, our estimate of the effects of elimination of anthropogenic emissions is a 70% decrease in deposition, while our minimal regulation scenario increases emissions by 35%. Existing policies have the potential to reduce deposition by 20% with most of the reduction attributable to U.S. policies. Local policies within the Great Lakes region show little effect, and global policy as embedded in the Minamata Convention is projected to decrease deposition by approximately 2.8%. Even within the GL region, effects of policy are not uniform; areas close to emission sources (Illinois, Indiana, Ohio, Pennsylvania) experience larger decreases in deposition than other areas including Michigan's UP. The UP landscape is highly sensitive to Hg deposition, with nearly 80% of lakes estimated to be impaired. Sensitivity to mercury is caused primarily by the region's abundant wetlands. None of the modeled policy scenarios are projected to reduce fish Hg concentrations to the target that would be safe for the local tribe. Regions like Michigan's UP that are highly sensitive to mercury deposition and that will see little reduction in deposition due to regulations require more aggressive policies to reduce emissions to achieve recovery. We highlight scientific uncertainties that continue to limit our ability to accurately predict fish Hg changes over time.

Sediment radioisotope dating across a stratigraphic discontinuity in a mining-impacted lake.

Application of radioisotope sediment dating models to lakes subjected to large anthropogenic sediment inputs can be problematic. As a result of copper mining activities, Torch Lake received large volumes of sediment, the characteristics of which were dramatically different from those of the native sediment. Commonly used dating models (CIC-CSR, CRS) were applied to Torch Lake, but assumptions of these methods are violated, rendering sediment geochronologies inaccurate. A modification was made to the CRS model, utilizing a distinct horizon separating mining from post-mining sediment to differentiate between two focusing regimes. (210)Pb inventories in post-mining sediment were adjusted to correspond to those in mining-era sediment, and a sediment geochronology was established and verified using independent markers in (137)Cs accumulation profiles and core X-rays.

[Influence of the riding discipline and riding intensity on the incidence of back pain in competitive horseback riders]. / Einfluss der Reitdisziplin und -intensität auf die Inzidenz von Rückenschmerzen bei Reitsportlern.

INTRODUCTION: The connection between morphologic changes of the spine and the intensity of training has been assessed for a number of sport activities. The influence of horseback riding on the spine has only rarely been evaluated. The aim of our study was to evaluate to what degree horseback riders suffer from back pain and whether there is an association between this parameter and the category i. e. the intensity of horseback riding. Furthermore we wanted to judge whether riding may have a positive effect on pre-existent back pain. METHODS: 508 horseback riders (63.2 % females; 36.8 % males) competing in either dressage, showjumping or vaulting were interviewed using a questionnaire. Apart from biometric data, the intensity with which riding was performed and the localisation and intensity (VAS) of back pain was assessed. Furthermore, in the case of existing back pain, riders were asked whether different riding disciplines and paces changed the intensity of pain. RESULTS: 300 dressage riders (59.1 %), 188 showjumpers (37.0 %) and 20 vaulters (3.9 %) with an average age of 33.5 Jahre (12 - 77 years) were questioned. The incidence of back pain was 72.5 %. A significant correlation between back pain and riding discipline respectively gender or riding level could not be found. Discrepancies in VAS-score for dressage riders (3.95 +/- 0.13), show jumpers (4.10 +/- 0.16) and vaulters (3.76 +/- 0.5) were marginal and not significant (p > 0.05). Overall 58.7 % resp. 15.2 % reported to have pain in the lumbar i.e cervical spine. Despite the fact that a large fraction of dressage riders claimed to have problems in these spine areas with 57.7 % resp. 68.8 %, this finding was not significant compared to the other riding disciplines. While 61.6 % of dressage riders reported an improvement of their back pain when riding, this was only the case in 40.9 % of show jumpers. CONCLUSION: Compared to the general population, a high incidence of back pain is found among riders. A significant correlation between the intensity of riding or the riding discipline and frequency or severity of back pain could not be found. For riders with pre-existent back pain the pace "walk" seems to have a positive influence on pain intensity.

[Correlation of back pain and magnetic resonance imaging of the lumbar spine in elite horse vaulters]. / Zusammenhang zwischen Rückenschmerzen und kernspintomografischen LWS-Befunden bei Hochleistungsvoltigierern.

INTRODUCTION: A connection between morphologic lesions of the spine and specific sport disciplines incorporating torsional and hyperextension forces has been found. Although vaulting incorporates a significant amount of figures known from gymnastics, little is known about the influence of this sport on the lower back. The aim of our study was to assess to what extent vaulters suffer from back pain and whether these symptoms correlate to findings in magnetic resonance imaging (MRI) of the lumbar spine. METHODS: 20 high level vaulters ( [see text] age 21.95 [15 - 36] years) were included in the study. Using a standardised questionnaire biometric data, training intensity, localisation as well as intensity of back pain (VAS) was assessed. 12 of these vaulters agreed to an MRI scan of their lumbar spine. Scans were evaluated for morphologic changes using a semiquantative score and the results were correlated to clinical symptoms. RESULTS: 17 / 20 (85 %) reported of back pain of which 15 (75 %) had daily pain, the remaining 2 only occasionally. The average pain intensity on the visual analogue scale (VAS) was reported to be 3.76 +/- 0.53. The MRI scans revealed only slight degenerative changes of the lumbar spine. Statistical analysis of the data (Spearman's rank test) could not show a significant correlation between clinical symptoms and morphologic MRI-changes. CONCLUSION: Vaulters, compared to riders of other disciplines, seem to suffer from recurrent back pain to a greater extent. Despite the fact that the lumbar spine is confronted with repetitive torsional and hyperextension forces, vaulters do not show undue early degenerative changes or marked lesions of the lumbar spine. Recurrent back pain in the vaulter is most likely due to functional problems. It seems unlikely that is based on manifest morphologic changes of the lower back.

Stage, age, comorbidity, and direct costs of colon, prostate, and breast cancer care.

PURPOSE: This study was conducted to evaluate the effect of stage at diagnosis, age, and level of comorbidity (presence of other illness) on the costs of treating three types of cancer among members of a health maintenance organization. METHODS: Among 388,000 members enrolled anytime during 1990 and 1991 in Group Health Cooperative (GHC) of Puget Sound (Washington State), we estimated the total and net direct costs of medical care for colon, prostate, and breast cancers, including both incident (290, 554, and 645 patients, respectively) and prevalent (1046, 1295, and 2299 patients, respectively) cases. We summarized costs for initial, continuing, and terminal phases of care. Net costs were the difference between the costs of the care of each case subject and the average costs of the care for all enrollees without the cancer of interest who were of the same sex and in the same 5-year age group. Differences in estimated total and net costs by stage at diagnosis, age, and comorbidity were separately evaluated using multivariate regression modeling. All P values were two-sided. Comorbidity was based on a score calculated from 1988 pharmacy data. RESULTS: Total costs of initial care increased with stage at diagnosis for colon (P = .0013) and breast (P < .0001) cancer cases, but not for prostate cancer cases. Total initial costs decreased with age for prostate (P = .0225) and breast (P = .0002) cancers but did not change with degree of comorbidity for any of the three cancers. Total continuing medical care costs increased with stage at diagnosis for colon (P < .0001) and breast (P < .0001) cancer cases but not for prostate cancer cases. Total terminal care costs were similar by stage for all three cancers. Net initial costs differed with stage for all three cancers (P < .05). Net continuing care costs increased with stage (P < .0001) and decreased with age (P < .001) for colon and breast cancers but not for prostate cancer. Net continuing care costs decreased with comorbidity for all three cancers (P = .004, P = .011, and P < .0001 for colon, prostate, and breast cancers, respectively). Among regional stage cancers, continuing care costs decreased with age for colon (P < .0017) and breast (P = .033) cancers but not for prostate cancers. CONCLUSIONS: The results show that total costs vary by stage at diagnosis and age, but the patterns of variation differ for each cancer. Costs of cancer are not simply additive to costs of other conditions. IMPLICATIONS: More needs to be done to explore the reasons and implications of age-related cost differences. Cost-effectiveness analyses of cancer control interventions that shift cancer stage distributions may need to consider both the age and comorbidity of the target populations.

Impairment of long-term potentiation and associative memory in mice that overexpress extracellular superoxide dismutase.

Reactive oxygen species, including superoxide, generally are considered neurotoxic molecules whose effects can be alleviated by antioxidants. Different from this view, we show that scavenging of superoxide with an antioxidant enzyme is associated with deficits in hippocampal long-term potentiation (LTP), a putative neural substrate of memory, and hippocampal-mediated memory function. Using transgenic mice that overexpress extracellular superoxide dismutase (EC-SOD), a superoxide scavenger, we found that LTP was impaired in hippocampal area CA1 despite normal LTP in area CA3. The LTP impairment in area CA1 could be reversed by inhibition of EC-SOD. In addition, we found that EC-SOD transgenic mice exhibited impaired long-term memory of fear conditioning to contextual cues despite exhibiting normal short-term memory of the conditioning experience. These findings strongly suggest that superoxide, rather than being considered exclusively a neurotoxic molecule, should also be considered a signaling molecule necessary for normal neuronal function.

The extracellular signal-regulated kinase cascade is required for NMDA receptor-independent LTP in area CA1 but not area CA3 of the hippocampus.

Activation of extracellular signal-regulated kinase (ERK) has been shown to be necessary for NMDA receptor-dependent long-term potentiation (LTP). We studied the role of ERK in three forms of NMDA receptor-independent LTP: LTP induced by very high-frequency stimulation (200 Hz-LTP), LTP induced by the K(+) channel blocker tetraethylammonium (TEA) (TEA-LTP), and mossy fiber (MF) LTP (MF-LTP). We found that ERK was activated in area CA1 after the induction of both 200 Hz-LTP and TEA-LTP and that this activation required the influx of Ca(2+) through voltage-gated Ca(2+) channels. Inhibition of the ERK signaling cascade with either PD 098059 or U0126 prevented the induction of both 200 Hz-LTP and TEA-LTP in area CA1. In contrast, neither PD 098059 nor U0126 prevented MF-LTP in area CA3 induced by either brief or long trains of high-frequency stimulation. U0126 also did not prevent forskolin-induced potentiation in area CA3. However, incubation of slices with forskolin, an activator of the cAMP-dependent protein kinase (PKA) cascade, did result in increases in active ERK and cAMP response element-binding protein (CREB) phosphorylation in area CA3. The forskolin-induced increase in active ERK was inhibited by U0126, whereas the increase in CREB phosphorylation was not, which suggests that in area CA3 the PKA cascade is not coupled to CREB phosphorylation via ERK. Overall, our observations indicate that activation of the ERK signaling cascade is necessary for NMDA receptor-independent LTP in area CA1 but not in area CA3 and suggest a divergence in the signaling cascades underlying NMDA receptor-independent LTP in these hippocampal subregions.

MAGE-F1, a novel ubiquitously expressed member of the MAGE superfamily.

Most known members of the MAGE superfamily are expressed in tumors, testis and fetal tissues, which has been described as a cancer/testis or "CT" expression pattern. We have identified a novel member of this superfamily, MAGE-F1, which is expressed in all adult and fetal tissues tested. In addition to normal tissues, MAGE-F1 is expressed in many tumor types including ovarian, breast, cervical, melanoma and leukemia. MAGE-F1 is encoded on chromosome 3, identifying a sixth chromosomal location for a MAGE superfamily gene. The coding region of MAGE-F1 is contained within a single exon and includes a microsatellite repeat. Sequence analysis and expression profiles define a new class of ubiquitously expressed MAGE superfamily genes that includes MAGE-F1, MAGE-D1, MAGE-D2/JCL-1 and NDN. The finding that several MAGE genes are ubiquitously expressed suggests a role for MAGE encoded proteins in normal cell physiology. Furthermore, potential cross-reactivity to these ubiquitously expressed MAGE gene products should be considered in the design of MAGE-targeted immunotherapies for cancer.

Breast cancer worry and mammography use by women with and without a family history in a population-based sample.

Worry about breast cancer risk has been found to be a barrier to mammography use by women with a family history of breast cancer in some studies, although worry is generally found to increase mammography use among average risk women. Our study sought to examine the association of worry with mammography use in a population-based sample of women stratified by family history associated risk for breast cancer. A population-based sample of 6512 women completed a telephone interview. Fourteen percent (n = 948) of these reported a family history suggestive of elevated risk, including at least one affected first-degree relative. To examine the effects of worry on mammography use in women, a logistic regression model, including family history associated risk, age, and worry, was tested. Although family history was a significant predictor of mammography use in bivariate examinations, in the multivariate model it was not significant after adjustment for age and worry, which remained statistically significant predictors of mammography (P < 0.05). The association between worry and mammography use was best described by a quadratic term. Interaction terms for family history-associated risk and worry were not statistically significant predictors of mammography use. Worry about breast cancer risk appears to be associated with mammography use in an inverted u-shaped pattern. Women reporting moderate levels of worry were more likely to use mammography annually than those who were either mildly or severely worried. Severe worry may be a barrier to mammography use for all women not only those with a family history.

Ovarian cancer tumor marker behavior in asymptomatic healthy women: implications for screening.

Ovarian cancer screening protocols generally have been limited by inadequate recognition of the normal behavior of tumor markers in women at risk of ovarian cancer. We have characterized the behavior of five serum tumor markers in a large cohort of healthy women and examined the implications for screening. Serial measurements of CA125, HER-2/neu, urinary gonadotropin peptide, lipid-associated sialic acid, and Dianon marker 70/K were obtained during 6 years of follow-up of 1257 healthy women at high risk of ovarian cancer. We analyzed individual-specific tumor marker behavior and explored methods that can exploit this information to develop individual-specific screening rules. These five tumor markers behaved approximately independently. Substantial heterogeneity was observed among women in the behavior of each tumor marker, particularly CA125. Intraclass correlation (ICC), or the proportion of total variability that occurs between individuals, was approximately 0.6 for log-transformed CA125 and urinary gonadotropin peptide, and less than 0.4 for the other markers. This degree of tumor marker heterogeneity among healthy women, and the relative independence of these markers, has important implications for screening and diagnostic tests. Independence of markers results in the clinically useful fact that the combined false positive rate from screening with multiple markers may be estimated by the sum of individual false positive rates. Heterogeneity of tumor marker patterns in healthy women implies that a fixed screening cutoff level is suboptimal to a degree that depends strongly on ICC. Using information on longitudinal measurements and ICC, individual-specific screening rules may be developed with the potential to improve early detection of ovarian cancer.