Issues in Design and Implementation in an Urban Birth Cohort Study: The Syracuse AUDIT Project

The Syracuse AUDIT (Assessment of Urban Dwellings for Indoor Toxics) project is a birth cohort study of wheezing in the first year of life in a low-income urban setting. Such studies are important because of the documented serious risks to children's health and the lack of attention and published work on asthma development and intervention in communities of this size. We studied 103 infants of mothers with asthma, living predominantly in inner-city households. Our study combines measurements of a large panel of indoor environmental agents, in-home infant assessments, and review of all prenatal and postnatal medical records through the first year of life. We found multiple environmental pollution sources and potential health risks in study homes including high infant exposure to tobacco smoke. The prevalence of maternal smoking during pregnancy was 54%; postnatal environmental tobacco smoke (ETS) exposure was nearly 90%. The majority (73%) of homes showed signs of dampness. Participants' lives were complicated by poverty, unemployment and single-parenthood. Thirty-three percent of fathers were not involved with their children, and 62% of subjects moved at least once during the study period. These socioeconomic issues had an impact on project implementation and led to modification of study eligibility criteria. Extensive outreach, follow up, and relationship-building were required in order to recruit and retain families and resulted in considerable work overload for study staff. Our experiences implementing the project will inform further studies on this and other similar populations. Future reports on this cohort will address the role of multiple environmental variables and their effects on wheezing outcome during the first year of life.Crawford, Hargrave, Liu, Anbar, Hall, Naishadham, Czerwinski, Webster, Lane, and Abraham are with the Department of Pathology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Hunt is with the UNYSPEC Ltd., Baldwinsville, NY, USA.     

Catechol-O-methyltransferase gene polymorphisms in benign prostatic hyperplasia and sporadic prostate cancer.

Various carcinogenic metabolites, including catechol estrogens, play a role in malignant transformation. An enzyme that is capable of neutralizing the genotoxic effects of these compounds is catechol-O-methyltransferase (COMT). A variant form of this enzyme has been shown to reduce its activity by up to 4-fold; thus, we hypothesize that single nucleotide polymorphisms of the COMT gene can be a risk factor for benign prostatic hyperplasia (BPH) and prostate cancer. To test this hypothesis, the genetic distribution of three different COMT polymorphisms at codon 62 (C-->T), codon 72 (G-->T), and codon 158 (G-->A) were analyzed in 131 normal healthy subjects, 134 BPH, and 178 sporadic prostate cancer samples from a Japanese population. Results of these experiments show that the variant genotype at codon 62 (P = 0.060) and codon 158 (P = 0.047) are risk factors for prostate cancer but not BPH when compared with normal controls. Odds ratio (OR) and 95% confidence interval (95% CI) for cancer were 3.24 and 1.38 to 7.61, respectively, for codon 62 T/T genotype when compared with wild type. At codon 158, the A/A variant for cancer had an OR of 3.00 with a 95% CI of 1.38 to 6.54 compared with wild type. Codons 62 and 158 were in linkage disequilibrium (LD), and when compared with the C-G haplotype, other types (C-A, T-G, T-A) were observed to be associated with prostate cancer (P = 0.040) but not BPH. Codon 72 on the other hand, was not in LD with either codon 62 or 158. The homozygous variant on codon 72 was rare in this Japanese population, and the heterozygous G/T at this codon was not associated with either prostate cancer or BPH. When evaluating the risk of COMT polymorphisms with stage or grade of cancer, no associations were observed for any of the genotypes with the exception of a tendency (P = 0.096) for the variant A allele on codon 158 to be correlated with higher stages (> or = T3) of cancer. This is the first report that shows the polymorphisms of COMT to be associated with sporadic prostatic carcinogenesis. These results are important in understanding the role of COMT polymorphisms in the pathogenesis of prostate cancer.     

Hysteroscopic treatment of symptomatic submucous fibroids using a bipolar intrauterine system: a feasibility study

Objective: To determine the feasibility (safety, potential efficacy and cost effectiveness) of a miniature endoscopic bipolar electrosurgical intrauterine system in the treatment of symptomatic submucous fibroids. Study Design: A total of 37 women with symptomatic submucous fibroids were identified on outpatient hysteroscopy. All underwent hysteroscopic excision or ablation using a bipolar intrauterine system (Versapoint™). The main outcomes measures were change in uterine bleeding symptoms measured on a continuous and ordinal scale, patient satisfaction, time of work and use of health service resources at 6 months following treatment. Results: 36/37 (97%) women returned completed outcome questionnaires. The mean amount of abnormal uterine bleeding was reduced at 6 months compared to immediately prior to treatment (P=0.0001). Improvement in bleeding symptoms was reported by 28/36 (78%) women and satisfaction with treatment by 33/36 (92%) women. All procedures were successfully completed, there were no serious operative complications and at 6 months no repeat hysteroscopic procedures were necessary. The mean cost of diagnosis and treatment of submucous fibroids using an endoscopic bipolar intrauterine system was 40% cheaper at 6 months follow-up than a hysterectomy or open myomectomy (£ 1266 versus £ 2123). Conclusion: Hysteroscopic treatment of symptomatic submucous fibroids appears to be safe, efficacious and cost effective. It seems feasible to launch a randomised controlled trial to confirm these provisional results in both the short and longer term.     

Utilizing prognostic and predictive factors in breast cancer

Opinion statement In order to make optimal treatment recommendations for patients with early-stage breast cancer, it is essential to accurately determine the patient’s underlying risk of disease recurrence and choose a therapy to which the individual is most likely to respond. Lymph node status, tumor size, histopathologic features including tumor type and grade, and hormone receptor status are well-accepted prognostic factors related to breast cancer. In addition, hormone receptor status is a very strong predictor of response to hormonal therapy. However, our currently accepted prognostic and predictive factors fall short and there is a critical need to more accurately identify those most likely to require or benefit from particular therapies. Attention has therefore focused on the determination of novel prognostic and predictive factors. The most promising new factor is the level of urokinase plasminogen activator and its inhibitor plasminogen activator inhibitor. Other putative factors include proliferative rate, the presence of lymphatic or vascular invasion, human epidermal growth factor receptor 2 (HER-2/neu or erbB-2) positivity, the presence of micrometastases in lymph nodes or bone marrow, and gene expression profile by microarray analysis, and by RNA-based methodology. Data regarding potential new prognostic factors are constantly emerging. These studies are frequently challenging to interpret as they are often retrospective, based on relatively small numbers of patients, include a mix of treated and untreated women, and often do not control for other known prognostic factors. Therefore, new data must be interpreted with caution.     

Analysis of spatial correlation between 99mTc-Sestamibi uptake and radiographic breast density

Breast scintigraphy is a technique by which the biological properties of breast lesions can be assessed using an injected radiopharmaceutical. It may be particularly useful for women with radiographically dense breasts, in whose mammograms, lesions are often obscured by breast tissue. We are evaluating a dual modality breast scanner developed at the University of Virginia for its ability to distinguish between benign and malignant lesions. The scanner obtains a digital mammogram and a gamma ray emission image in quick succession with the breast held under mild compression, resulting in a fused image in which structures in the digital mammogram can be directly correlated with those in the scintigram. Our experience has shown that radiopharmaceutical uptake by normal breast tissue can sometimes obscure uptake by small lesions. It would therefore be advantageous to correct for this background uptake if possible. One potential way of accomplishing this is to use the information from the digital mammogram to help predict the background radiopharmaceutical distribution. With this in mind, we retrospectively investigated the degree of spatial correlation between the distribution of background activity and the distribution of radiodense breast tissue in normal breasts. Using a histogram-based analysis, we have quantified the degree of correlation in 16 images obtained from a total of 8 patients. We also used the mammographic images to quantify the radiographic density of each breast. Our results suggest that spatial correlation between areas of high radiopharmaceutical uptake and parenchymal density exists in the most dense regions of the breast for either extremely dense or heterogeneously dense breasts. High correlation was also observed for some homogeneously fatty breasts. In the latter case however, variation in breast thickness appeared to be the cause of the increased correlation. Correlation properties are approximately equal in both right and left breasts for a particular patient, except in cases exhibiting focal radiotracer uptake in a lesion. Although our preliminary results suggest that correlation between radiopharmaceutical uptake and parenchymal density exists, the number of cases thus far is too small for definitive conclusions. In addition, the planar nature of the dual modality scans imposes an inherent limitation on our ability to take into account attenuation of the emitted gamma radiation, which thus constitutes an uncontrolled variable in the correlation analysis. In principle, this problem can be eliminated by 3-dimensional imaging.     

Evaluation of the optimal preemptive dose of gabapentin for postoperative pain relief after lumbar diskectomy: a randomized, double-blind, placebo-controlled study

We evaluated the optimal preemptive dose of gabapentin for postoperative pain relief after single-level lumbar diskectomy and its effect on fentanyl consumption during the initial 24 hours in a randomized, double-blinded, placebo-controlled study in 100 patients with American Society of Anesthesiologists physical status I and II. Patients were divided into five groups to receive placebo or gabapentin 300, 600, 900, or 1200 mg 2 hours before surgery. After surgery, patients were transferred to the postanesthesia care unit (PACU). A blinded anesthesiologist recorded the pain scores at time points of 6, 12, 18, and 24 hours in the PACU on a Visual Analog Scale (VAS; 0-10 cm) at rest. Patients received patient-controlled analgesia (fentanyl 1.0 mug/kg on each demand with lockout interval of 10 minutes); total fentanyl consumption during initial 24 hours was recorded. Data were entered into the statistical software package SPSS 9.0 for analysis (one-way analysis of variance and Student-Newman-Keuls test). Patients who received gabapentin 300 mg had significantly lower VAS score at all time points. They consumed less fentanyl (patients who received placebo processed 1217.5 +/- 182.0 versus 987.5 +/- 129.6 mug; P < 0.05). Patients who received gabapentin 600, 900, and 1200 mg had lower VAS scores at all time points than patients who received gabapentin 300 mg (P < 0.05). Increasing the dose of gabapentin from 600 to 1200 mg did not decrease the VAS score, nor did the increasing dose of gabapentin significantly decrease fentanyl consumption (702.5, 635, and 626.5 microg). Thus, gabapentin 600 mg is the optimal dose for postoperative pain relief following lumbar diskectomy.     

Cancer incidence and asbestos in drinking water, Town of Woodstock, New York, 1980-1998

Late in 1985, asbestos contamination was discovered in the public water supply of the Town of Woodstock, Ulster County, New York. Contamination resulted from asbestos-cement pipes installed in the town water system in the mid to late 1950s and the corrosiveness of the local water. The New York State (NYS) Department of Health established the Woodstock Asbestos Exposure Registry (WAER) in 1986 to monitor rates of cancer among individuals who lived on the water supply between 1960 and 1985. Demographic, health, and residential information were collected on 2936 registrants. The follow-up period for observation of cancer was 1980-1998, consistent with the expected lag of 20-30+ years for development of asbestos-related cancers. The NYS Cancer Registry was used to ascertain cancer diagnoses. Standardized incidence ratios (SIRs) for gastrointestinal, respiratory, and total cancers were all approximately 1.00 or less and all 95% confidence intervals (CIs) included 1.00. For individual types of the gastrointestinal cancers, only the SIR for pancreatic cancer was marginally statistically significant at 2.19 (95% CI=1.00-4.16), based on a total of nine observed cases. The excess in pancreatic cancer occurred primarily among men (SIR=3.08; 95% CI=1.13-6.70) and was only slightly elevated among women (SIR=1.39; 95% CI=0.29-4.06). This association may be related to factors other than asbestos exposure such as occupation and lifestyle or to chance. No cases of mesothelioma were observed among WAER participants. There was no increase in incidence by latency or duration of residence on the water supply, but the ability to detect these trends is limited by small numbers and unknown dates of initial exposure. The general pattern of results did not demonstrate a likely link between exposure to asbestos in drinking water and cancer occurrence among participants in the WAER.     

ENPP1/PC-1 K121Q polymorphism and genetic susceptibility to type 2 diabetes

Genetic susceptibility modulates the impact of obesity on risk for type 2 diabetes. The present study evaluates the role of ENPP1 K121Q polymorphism in prediction of type 2 diabetes in three populations that differ in susceptibility to diabetes and environmental exposure. The three cohorts included 679 nonmigrant South Asians living in Chennai, India (223 with type 2 diabetes); 1,083 migrant South Asians living in Dallas, Texas (121 with type 2 diabetes); and 858 nonmigrant Caucasians living in Dallas, Texas (141 with type 2 diabetes). Patients with type 2 diabetes were included in these cohorts if they had diabetes onset before the age of 60 years. The prevalence of subjects carrying the polymorphic ENPP1 121Q allele was 25% in the nondiabetic group and 34% in the diabetic group of South Asians living in Chennai (P = 0.01). The prevalence in the nondiabetic and diabetic groups were 33 and 45% (P = 0.01) for the South Asians living in Dallas and 26 and 39% (P = 0.003) for the Caucasians. Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that ENPP1 121Q predicts genetic susceptibility to type 2 diabetes in both South Asians and Caucasians.     

IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis

Transverse myelitis (TM) is an immune-mediated spinal cord disorder associated with inflammation, demyelination, and axonal damage. We investigated the soluble immune derangements present in TM patients and found that IL-6 levels were selectively and dramatically elevated in the cerebrospinal fluid and directly correlated with markers of tissue injury and sustained clinical disability. IL-6 was necessary and sufficient to mediate cellular injury in spinal cord organotypic tissue culture sections through activation of the JAK/STAT pathway, resulting in increased activity of iNOS and poly(ADP-ribose) polymerase (PARP). Rats intrathecally infused with IL-6 developed progressive weakness and spinal cord inflammation, demyelination, and axonal damage, which were blocked by PARP inhibition. Addition of IL-6 to brain organotypic cultures or into the cerebral ventricles of adult rats did not activate the JAK/STAT pathway, which is potentially due to increased expression of soluble IL-6 receptor in the brain relative to the spinal cord that may antagonize IL-6 signaling in this context. The spatially distinct responses to IL-6 may underlie regional vulnerability of different parts of the CNS to inflammatory injury. The elucidation of this pathway identifies specific therapeutic targets in the management of CNS autoimmune conditions.