Detection bias in the diagnostic pursuit of lung cancer

Autopsy studies have shown that lung cancer is often not detected during life and that a correct antemortem diagnosis is made preferentially in patients with pulmonary symptoms, in smokers, and in men. The current research was done as a case-control study to determine whether the autopsy suggestions of detection bias in diagnostic pursuit of lung cancer were confirmed by the way that sputum Papanicolaou smears (Pap smears) were ordered in an inpatient setting. The cases were 385 hospitalized patients in whom sputum Pap tests had been newly performed from October 1977 to September 1980. Each case was matched by age, admission date, and admission diagnosis to a control patient who had not received a Pap test. Excluded from the study were patients in whom sputum Pap tests were obligatory (e.g., those with manifestations of hemoptysis) or unnecessary (e.g., those with a previous diagnosis of lung cancer or multiple previous sputum Pap tests). Demographic data, amount and duration of cigarette smoking, and details of clinical manifestations were extracted from the patients' medical records by research assistants blind to the study hypothesis. Compared with controls, the cases had distinctive elevations in odds ratios for chronic cough, recent cough, male sex, and cigarette smoking, which also showed a distinctive dose-response relation. In multivariate analyses, all four of these "risk factors" for selective ordering of a sputum Pap smear remained independently highly significant. In the extreme category, men who smoked and coughed were 22 times more likely to have a sputum Pap test ordered than were nonsmoking women who did not cough. Clinically, the results suggest that women and nonsmokers may be deprived of appropriate diagnosis and therapy unless a diagnostic workup for lung cancer is guided mainly by radiographic findings and presenting manifestations. Statistically, detection bias has probably led to an excessively elevated magnitude for the cigarette smoking-lung cancer association and to a falsely low estimate of incidence rates in women.     

An experimental inter-expert telepathology network using static imaging

AIMS: To set up a network for remote consultation using static imaging telepathology via Internet connection between pathologists in different European countries, and to collect some numerical and subjective impressions on the usefulness of this form of telepathology. METHODS: A static image remote consultation network between 11 pathologists in nine European countries was set up; all pathologists were equipped with the same telepathology system. The pathologists formed three subject oriented subgroups concerned with prostate, melanoma, and soft tissue sarcoma pathology. Each pathologist sent and received a small number of cases, and data on each case were collected and analysed. The whole experiment was controlled through a World Wide Web site. RESULTS: A total of 56 case consultations on 34 different cases were exchanged. The average case document contained seven images, and contained 1.97 Mbytes of data. For cases in which data were recorded, average case preparation and remote consultation time was 55 minutes and 9.2 minutes, respectively. Transmission times averaged 3.9 minutes. In subjective impressions, reservations were expressed in several cases regarding the confidence that could be given to the diagnosis from the images presented. CONCLUSIONS: Remote consultation by telepathology via the Internet is now technically feasible and reasonably user friendly, but is only suitable as a method of disease diagnosis in some cases.     

Immunosuppressive properties of the Mycoplasma arthritidis T-cell mitogen in vivo: inhibition of proliferative responses to T-cell mitogens.

We have previously shown that Mycoplasma arthritidis produces a soluble T-cell mitogen (MAM) which is active for most mouse strains that express the alpha chain of the I-E molecule (E alpha) encoded within the murine major histocompatibility complex. The lymphocytes from mice injected intravenously with the MAM exhibited a marked decrease in their ability to respond in vitro to MAM, to phytohemagglutinin, or to concanavalin A T-cell mitogens. Suppression could only be induced in MAM-responsive mouse strains and was most marked 1 to 4 days postinjection. Splenic and node cells and, to a lesser extent, thymic cells from MAM-injected mice could inhibit the ability of lymphocytes from normal mice to respond to MAM and lectin mitogens. A minimum of 2.5 x 10(4) viable cells was required for significant transfer of suppression, and no major histocompatibility complex restrictions were seen. Unlike concanavalin A-induced suppressor cells, which consist of a CD4-, CD8+ T-cell subset, suppressor cells induced by MAM were due to a CD4+ CD8- subset. We hypothesize that MAM may play a role in M. arthritidis-mediated disease by both its inflammatory and immunosuppressive properties.     

Growth hormone benefits children with 18q deletions

Most individuals with constitutional deletions of chromosome 18q have developmental delays, dysmyelination of the brain, and growth failure due to growth hormone deficiency. We monitored the effects of growth hormone treatment by evaluating 23 individuals for changes in growth, nonverbal intelligence quotient (nIQ), and quantitative brain MRI changes. Over an average of 37 months, the treated group of 13 children had an average nIQ increase of 17 points, an increase in height standard deviation score of 1.7, and significant change in T1 relaxation times in the caudate and frontal white matter. Cognitive changes of this magnitude are clinically significant and are anticipated to have an effect on the long-term outcomes for the treated individuals.     

Self-reported urogenital symptoms in postmenopausal women: Women's Health Initiative

OBJECTIVE: To examine the prevalence and correlates of self-reported urogenital symptoms (dryness, irritation or itching, discharge, dysuria) among postmenopausal women aged 50-79. DESIGN: A cross-sectional analysis based on n=98,705 women enrolled in the US-based Women's Health Initiative observational study and clinical trials. Urogenital symptoms, symptom severity (mild, moderate, severe), and all covariates were self-reported through questionnaires at enrollment. Prevalence rates of each urogenital symptom were examined and logistic regression was used to identify potential correlates. RESULTS: Prevalence rates for each symptom were: dryness, 27.0%; irritation or itching, 18.6%; discharge, 11.1%; and dysuria, 5.2%. Four factors were correlated with two or more symptoms: Hispanic ethnicity (adjusted odds ratio (AOR)=2.1-3.1 versus white women across all symptoms), obesity (AOR=2.2 severe discharge versus none, AOR=3.6 severe irritation/itching versus none), treated diabetes (pills or shots) compared to no diabetes (AOR=2.4 severe dysuria versus none, AOR=3.2 severe irritation/itching versus none), and vaginal cream HRT/ERT compared to those who never used HRT/ERT (AOR=4.4 severe dryness versus none, AOR=4.6 severe irritation/itching versus none). Factors not associated with the symptoms included sexual activity, age, years since menopause, current smoking, marital status, gravidity, and natural versus surgical menopause. CONCLUSIONS: This is the first report to document urogenital symptoms by race/ethnicity among an exclusively postmenopausal population. We found an elevated prevalence of urogenital symptoms among women who are Hispanic, obese, and/or diabetic. Confirmation of our findings in these subgroups, and, if confirmed, analysis on why these populations are at greater risk, are areas for future research.     

Which treatment for whom for ADHD? Moderators of treatment response in the MTA

Using receiver operating characteristics, the authors examined outcome predictors (variables associated with outcome regardless of treatment) and moderators (variables identifying subgroups with differential treatment effectiveness) in the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (ADHD; MTA). Treatment response was determined using parent- and teacher-reported ADHD and oppositional defiant symptoms, with levels near or within the normal range indicating excellent response. Among 9 baseline child and family characteristics, none predicted but 3 moderated treatment response. In medication management and combined treatments, parental depressive symptoms and severity of child ADHD were associated with decreased rates of excellent response; when these 2 characteristics were present, below-average child IQ was an additional moderator. No predictors or moderators emerged for behavioral and community comparison treatments. The authors discuss conceptual and clinical implications of research on treatment moderators.     

Characterization of a novel leucine-rich repeat protein antigen from group B streptococci that elicits protective immunity

Group B streptococci (GBS) usually behave as commensal organisms that asymptomatically colonize the gastrointestinal and urogenital tracts of adults. However, GBS are also pathogens and the leading bacterial cause of life-threatening invasive disease in neonates. While the events leading to transmission and disease in neonates remain unclear, GBS carriage and level of colonization in the mother have been shown to be significant risk factors associated with invasive infection. Surface antigens represent ideal vaccine targets for eliciting antibodies that can act as opsonins and/or inhibit colonization and invasion. Using a genetic screen for exported proteins in GBS, we identified a gene, designated lrrG, that encodes a novel LPXTG anchored surface antigen containing leucine-rich repeat (LRR) motifs found in bacterial invasins and other members of the LRR protein family. Southern blotting showed that lrrG was present in all GBS strains tested, representing the nine serotypes, and revealed the presence of an lrrG homologue in Streptococcus pyogenes. Recombinant LrrG protein was shown in vitro to adhere to epithelial cells in a dose-dependent manner, suggesting that it may function as an adhesion factor in GBS. More importantly, immunization with recombinant LrrG elicited a strong immunoglobulin G response in CBA/ca mice and protected against lethal challenge with virulent GBS. The data presented in this report suggest that this conserved protein is a highly promising candidate antigen for use in a GBS vaccine.     

Isolation and phenogenetics of a novel circadian rhythm mutant in zebrafish

Widespread use of zebrafish (Danio rerio) in genetic analysis of embryonic development has led to rapid advances in the technology required to generate, map and clone mutated genes. To identify genes involved in the generation and regulation of vertebrate circadian rhythmicity, we screened for dominant mutations that affect the circadian periodicity of larval zebrafish locomotor behavior. In a screen of 6,500 genomes, we recovered 8 homozygous viable, semi-dominant mutants, and describe one of them here. The circadian period of the lager and lime (lag(dg2)) mutant is shortened by 0.7 h in heterozygotes,and 1.3 h in homozygotes. This mutation also shortens the period of the melatonin production rhythm measured from cultured pineal glands, indicating that the mutant gene product affects circadian rhythmicity at the tissue level, as well as at the behavioral level. This mutation also alters the sensitivity of pineal circadian period to temperature, but does not affect phase shifting responses to light. Linkage mapping with microsatellite markers indicates that the lag mutation is on chromosome 7. A zebrafish homolog of period1(per1) is the only known clock gene homolog that maps near the lag locus. However, all sequence variants found in per1 cDNA from lag(dg2) mutants are also present in wild type lines, and we were unable to detect any defect in per1 mRNA splicing, so this mutation may identify a novel clock gene.     

Accelerated elimination of N. brasiliensis from the small intestine after auto-anti-IgE induction.

Immunization of rats with a purified IgE myeloma (IR2) induced an auto-anti-IgE response. Such treatment inhibited total IgE levels in the serum of conventional IgE-producing rats (Marshall & Bell, 1985) and increased the number of mucosal mast cells (MMC) in the intestine. The present study has investigated the ability of auto-anti-IgE induction to influence the course of a Nippostrongylus brasiliensis infection, to modify IgE synthesis, or to affect the number of MMC in the intestine following infection. Auto-anti-IgE induction was found to have a surprising effect on worm elimination. IR2-immunized rats were able to rid themselves of this nematode with an accelerated tempo--a small but significant effect after primary infection, but a substantial enhancement of worm loss after reinfection. Auto-anti-IgE induction was not able to prevent the typical increase in IgE that accompanies an N. brasiliensis infection, nor did it alter the helminth-induced intestinal mastocytosis. When MMC degranulation was measured by assaying the serum levels of a specific rat mast protease (RMCP II) following secondary infection, the amount of RMCP II released was less in auto-anti-IgE-producing rats. These findings have implications for the importance of IgE, MMC and other cells of inflammation in an anti-parasitic response.