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PubMed1972

Quantitation of transplacental haemorrhage.

On four occasions over a period of four years samples of adult blood to which known amounts of fetal blood had been added were distributed to 8-12 different laboratories taking part in clinical trials organized by an M.R.C. Working Party. Estimates were made of the proportion of fetal: adult red cells in the samples after preparing films by the acid-elution method. When the proportion of fetal: adult red cells was less than about 1:10,000, the highest and lowest estimates were separated by a factor of about 10. However, when the number of cells present was between about 1:100 and 1:1,000, most results were between half and twice the true number of cells present.It is pointed out that since fetal red cells are approximately 30% larger than adult red cells, and since only about 90% of fetal cells stain darkly in the acid-elution method, estimates of the proportion of darkly-staining cells in a film underestimate the volume of fetal red cells present by about one-third. A simple formula is proposed which corrects for this factor and which gives an estimate of the total volume of fetal red cells present, deduced from the ratio of fetal: adult red cells and assuming a maternal red cell volume at term of 1,800 ml.A method of screening blood films is suggested which, firstly, endeavours to standardize the density of adult red cells on films, and, secondly, takes into account the Poisson distribution. Thus limits are set for the number of fetal red cells which can be seen in scanning a given number of adult cells before the suspicion is aroused that a transplacental haemorrhage exceeding a certain amount is present.It is emphasized that the density of adult red cells on blood films varies very widely, and unless the cell density and the size of the low-power field are defined the practice of deducing the extent of transplacental haemorrhage from the number of fetal red cells seen per low-power field may lead to large errors.

Blood↗
PubMed1993

Interaction forces between red cells agglutinated by antibody. IV. Time and force dependence of break-up.

We report on an extension of a previously described method to measure the hydrodynamic force to separate doublets of fixed, sphered and swollen red cells cross-linked by antibody (S. P. Tha, J. Shuster, and H. L. Goldsmith. 1986. Biophys. J. 50:1117-1126). With a traveling microtube apparatus, doublets are tracked and videotaped in a slowly accelerating Poiseuille flow in 150-microns-diameter tubes, and the hydrodynamic normal force at break-up, Fn, is computed from the measured doublet velocity and radial position. Previous results showed a large range of Fn, the mean of which increased with [antiserum], and an absence of clustering at discrete values of Fn. Since it was assumed that the cells separate the instant a critical force to break all crossbridges was reached, lack of clustering could have been due to the use of a polyclonal antiserum. We therefore studied the effect of monoclonal IgM or IgA antibody on the distribution of Fn. The results showed that the data are as scattered as ever, with Fn varying from 2 to 200 pN, and exhibit no evidence of clustering. However, the scatter in Fn could be due to the stochastic nature of intercellular bonds (E. Evans, D. Berk, and A. Leung. 1991a. Biophys. J. 59:838-848). We therefore studied the force dependence of the time to break-up under constant shear stress (Fn from 30 to 200 pN), both in Poiseuille and Couette flow, the latter by using a counter-rotating cone and plate rheoscope. When 280 doublets were rapidly accelerated in the traveling microtube and then allowed to coast in steady flow for up to 180 s, 91% survived into the constant force region; 16% of these broke up after time intervals, tP, of 2-30s. Of 340 doublets immediately exposed to constant shear in the rheoscope, 37% broke after time intervals, tc, from < 1 to 10 s. Thus, doublets do indeed break up under a constant shear stress, if given time. The average time to break-up decreased significantly with increasing force, while the fraction of doublets broken up increased. At a given Fn, the fraction of break-ups decreased with increasing [IgM], suggesting that the average number of bonds had also increased. Using a stochastic model of break-up (G. I. Bell. 1978. Science (Washington DC). 200:618-627; E. Evans, D. Berk,and A. Leung. 1991. Biophys. J. 59:838-848) and a Poisson distribution for the number of bonds, Nb, break-up in slowly accelerating Poiseuille flow and in immediate shear application in Couette flow was simulated. In Poiseuille flow, the observed range and scatter in Fn could be reproduced assuming (Nb) > 5. In the rheoscope, the time intervals and number of rotations to break-up, tc, were quite well reproduced assuming (Nb) = 4. The similarity of (Fn) for monoclonal IgM and IgA for doublet break-up under constant slow acceleration is compatible with the conclusion of Evans et al. (1991 a) for normal red cells and Xia et al. (manuscript submitted for publication) for sphered and swollen red cells, that the applied force extracts the antigen from the cell membrane.

Antibodies↗
PubMed2001

Judgement on "hit or non-hit" of CHO cells exposed to accelerated heavy-ions (Fe- or Ar-ions) using division delay and CR-39 plastics as an indicator.

The cell killing effect of ionizing radiation depends on the degree of linear energy transfer (LET). The relative biological effectiveness (RBE) reaches a maximum at LET of around 100-200 keV/micron and decreases at higher levels. The ion clusters produced by high-LET radiation are not uniformly distributed. The incidence of non-hit cell events is higher in high LET irradiation than in the cases of low-LET irradiation. This fact could explain the decrease in the cell killing effect at higher levels of LET irradiation. Since the cell killing effect may be related to the nuclear traversal of heavy-ions, it is necessary to establish methods to distinguish the hit cells from the non-hit cells, especially in case with high LET irradiation. Using time-lapse photography, we first examined the hit events by observing the division delay in the cells caused by high-LET irradiation. In addition, we explored the use of CR-39 plastics to detect the exact position of heavy-ion traversal on the surface of a flask where cells were growing. When Chinese hamster ovary (CHO-K1) cells were exposed to 4 Gy of accelerated Fe-ions (2000 keV/micron) or Ar (1640 keV/micron)-ions, the surviving fraction decreased to about 30% in both cases of irradiation. Eighty percent of the irradiated cells, suffered a division delay in contrast to the remaining 20% of the cells which showed a normal division time (12-13 hrs). The later 20% of the cells is considered to be a population of cells which were not actually traversed by heavy-ions. The difference between the higher values of the surviving fraction (approximately 30%) and the non-hit cell population (20%) indicates that some hit cells can grow even after being hit by heavy-ions. The fraction of recovered cells determined by the time-lapse photography method was 10%, and this value closely correlated with the difference between the surviving fraction and the non-hit cells. We used the Poisson distribution of the hit-events by heavy-ions among the cell population in order to calculate the fraction of cells receiving at least a single-hit in the cell nucleus (130 micron 2 in average size). From this calculation we determined that 80% of the cells had a single hit to their nuclei by a heavy-ion which induced such early cellular responses as division delay. Our finding in the experiments using CR-39 plastics as a detector for hit-sites further supported the idea that the hit lethality of a cell is related to heavy-ion traversal through its nucleus. This study indicates the possible usefulness of both the division delay and CR-39 plastic methods for evaluating the biological effects of heavy-ions, especially when these two methods are combined.

Animals↗
PubMed1996

Coinfection of individual leukocytes with human cytomegalovirus and human immunodeficiency virus is a rare event in vivo.

Infection with the human cytomegalovirus (HCMV) accelerates disease progression in human immunodeficiency virus 1 (HIV-1)-infected individuals. This has been attributed to the transaction of HIV-1 gene expression by HCMV gene products. For transactivation to be effective in vivo both viruses must be present in the same cell. We therefore examined blood samples from 13 HIV-1-infected patients with HCMV viremia for coinfection of individual leukocytes. In four of the patients lymph nodes were also examined. Multiple samples contained defined numbers (between 10 and 1000) of CD4+ lymphocytes or CD14+ monocytes were sorted by a FACS-based automated cell deposition unit. Samples were then analysed by a multiplex nested polymerase chain reaction, which can detect simultaneously HCMV and HIV DNA. The percentage of infected cells was calculated for each virus using the Poisson distribution. Between 0.43% and 6.2% of the CD4+ lymphocytes were infected with HIV and less than 0.15% with HCMV. The level of infection in CD14+ monocytes was always < or = 0.11% for HIV and ranged between < 0.05% and 0.58% for HCMV. Only seven of 1030 sorted samples from blood were positive for both viruses. In lymphnodes, none of the 144 samples tested were double-positive. This clearly shows that coinfection of individual human leukocytes with HIV and HCMV is a very rare event in vivo. Therefore, direct transactivation of HIV by HCMV in coinfected cells obtained from blood and lymphnodes may not explain the effect of HCMV on the prognosis of HIV-infected individuals.

AIDS-Related Opportunistic Infections↗
PubMed1998

Second cancers following in situ carcinoma of the breast.

Carcinoma in situ (CIS) of the breast has increased many-fold in incidence rates and as a proportion of new breast cancers following the introduction of mammographic breast screening. To provide population-based estimates of invasive breast cancer risk following CIS, we linked data on 249 incident primary CIS (median age 53 years) to the Cancer Registry of the Swiss Canton of Vaud (about 600,000 inhabitants) over the period 1977-1994. Women with concurrent invasive cancers of the breast were not included. Standardized incidence ratios (SIR) were determined according to the exact Poisson distribution, with stratification for age and year of diagnosis. A total of 24 cases of breast cancer vs. 3.4 expected [SIR = 7.2, 95% confidence interval (CI): 4.6-10.6], and 7 cases of other neoplasms (except non-melanomatous skin cancer) vs. 6.9 expected (SIR=1.0, 95% CI: 0.4-2.1) were observed. The SIR was 10.4 during the first year, 5.6 between I and 4 years, and 7.7 after > or = 5 years after CIS diagnosis. SIRs were consistent in women below and above age 55 years, but somewhat higher for ductal (SIR=8.6) than lobular (SIR = 4.2) CIS. Six deaths from breast cancer were observed vs. 1.5 expected (standardized mortality ratio=4.0, 95% CI: 1.5-8.7). In 13/19 ductal CIS, but in 2/4 lobular CIS, invasive cancer occurred in the same breast. In most women, CIS and subsequent invasive cancer showed the same morphological (i.e., ductal or lobular) features. The cumulative risk of breast cancer was 16% 10 years after CIS diagnosis, emphasizing the importance of adequate surveillance of women after CIS of the breast.

Adult↗
PubMed1997

Treatment-patient interactions for diagnostics of cross-over trials.

In cross-over trials, various types of responses may be recorded, not all of which can be appropriately modelled by a Normal distribution. Widening the class of models to the generalized linear model family has a number of advantages. An important one is that certain interactions, especially that between patients and treatments, can easily be fitted for frequency and count data. These can be used as diagnostics for the fit of the model used. One handicap has been the frequentist difficulty of comparing the fit of different non-nested models in this family. This can be overcome by the use of a model selection criterion such as the Akaike or Bayesian information criterion. This approach to modelling and diagnostics for cross-over trials is applied to two studies involving small counts of anginal attacks, previously analysed in the literature using classical Normal techniques.

Clinical Trials as Topic↗
PubMed1999

Criticism of a hierarchical model using Bayes factors.

This paper analyses a data file of heart transplant surgeries performed in the United States over a two-year period. A Poisson/gamma exchangeable model is used to learn about the underlying death rates for 94 hospitals. There are concerns about the suitability of this hierarchical model, including the need for a hierarchical structure, the existence of outliers, the choice of prior hyperparameters, the need for a covariate in the model, and the manner in which exchangeability was modelled. Each concern motivates the construction of alternative models and Bayes factors are used to compare the existing model with the alternative models. Graphical displays are used to check the sensitivity of the posterior analysis with respect to model perturbations and plots of Bayes factors are used to criticize these perturbations.

Bayes Theorem↗
PubMed2000

Biases in ecological studies: utility of including within-area distribution of confounders.

This paper is centred on studies commonly known as ecological studies, where one seeks to estimate risks from data aggregated on a geographical basis. The aggregated nature of the data creates difficulties for interpreting, at an individual level, any ecological association found, difficulties which are generically referred to as 'the ecological bias or fallacy'. Here, we address an important component of this bias related to the problem of misspecification in ecological studies. We consider how aggregated level dose-response relationships are derived from integrating individual level ones over the group, and how their correct specification requires, in general, knowledge of the within-group joint distribution of the relevant risk factors, which is rarely available. We discuss in detail the common situation where data on the proportion of persons exposed in each area to several dichotomous risk factors are available. We show that ecological regression estimates of the relative risk for each factor will be improved by including in the regression, besides the linear terms, cross-product terms of the marginal prevalences. Results from a simulation study are discussed and an example concerning the geographical analysis of lung cancer mortality in France is presented.

Adult↗
PubMed1996

Reduced lung cancer mortality in dairy farmers: is endotoxin exposure the key factor?

From two areas in the Province of Padova, we selected 2,283 male farmers who worked either in cattle raising or in crop/orchard cultivation. There were 422 cohort deaths from 1970 to 1992. Using the regional population as a reference, the standardized mortality ratio (SMR) was calculated, with 95% confidence intervals (CI) based on the Poisson distribution. Cancer mortality was significantly reduced among the 1,561 dairy farmers (SMR = 0.65; CI = 0.53-0.81); there was a significant decrease in lung cancer (SMR = 0.49; CI = 0.31-0.74), whereas a significant increase from brain tumors was found (SMR = 2.83; CI = 1.04-6.17). Neither overall cancer mortality nor the lung cancer SMR deviated significantly from unity for the 722 crop/orchard farmers. Among dairy farmers, moreover, lung cancer SMRs showed a significant downward trend across the quartiles of increasing length of work, 0.96 in the first quartile, and 0.48, 0.40, and 0.25 in the second, third, and fourth quartiles, respectively. Moreover, lung cancer risk decreased with increasing farm land area, with SMRs in the quartiles of 0.89, 0.37, 0.41 and 0.19. This decrease cannot be attributed to either a selection (healthy worker effect) or a confounding (lower percentage of smokers) bias. Nor was it due to an artifact introduced by differences in age distribution among the quartiles. Dairy farmers are known to be exposed to higher airborne endotoxin concentrations; reasonably, this cumulative exposure increases further with years of work and area of farm. Endotoxins may have protected the dairy farmers against lung cancer through the tumor necrosis factor produced by alveolar macrophages.

Adolescent↗
PubMed1981

Kinetic analysis of epithelial cell migration in the mouse descending colon.

The kinetics of epithelial cell replacement in the descending colon of the mouse were studied using cell counts and other measurements in mice given a single injection of 3H-thymidine at 10:00 a.m. Cell migration occurs from the base of the crypts in the direction of the colonic lumen. The mean turnover time of epithelial cells as measured after the single injection of 3H-thymidine has been estimated at 4.85 days. Since this figure is in agreement with published data based on continuous infusion of the labeled precursor, it is concluded that the time selected for the analysis provides an index of proliferation which is representative of the mean proliferative activity of the epithelium. If each side of a crypt cut along its axis is referred to as a "crypt column," the mean number of cells per crypt column has been found to be 32.9; after a one-hour pulse labeling starting at 10:00 a.m., the mean number of labeled cells per column was 2.8; and the overall labeling index of the epithelium, 8.6%. The frequency of labeled cells in each cell position along the crypt column varies according to a Poisson distribution with a peak close to position 3. Presumably then, cell proliferation is taking place in a random manner and is, therefore, asynchronous, despite evidence to the contrary in the literature. The kinetic analysis supports the view that cell migration occurs along the crypt column in the direction of the colonic lumen at a velocity averaging 0.28 cell position per hour, or 4.48 microns per hour. The results support the view that vacuolated-columnar, mucous, and caveolated cells migrate jointly; whereas entero-endocrine cells migrate separately from these cell lines, except during the initial stages of the migration.

Animals↗
PubMed2006

Clustered incidence of acute promyelocytic leukemia during gefitinib treatment for non-small-cell lung cancer: experience at a single institution.

Although gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been shown a significant activity for recurrent non-small-cell lung cancer (NSCLC), its long-term adverse effect with its continuous usage has hitherto not been clearly elucidated. Subjects were 108 consecutive NSCLC cases who were treated with gefitinib between November 2001 and December 2004 at our single institution. A crude incidence rate ratio was calculated by ratio of crude incidence rate in our subject to population-based incident rate of all leukemia (ICD: C91-95) in the same region. The 95% confidence intervals (CIs) were calculated based upon a Poisson distribution. Three cases of acute promyelocytic leukemia (APL) occurred during gefitinib treatment, and these patients' past treatment histories are presented herein. No other malignancy was identified. All of the cases were diagnosed at the stage of mild-to-moderate cytopenia, especially thrombocytopenia, without disseminated intravascular coagulation. All presented a normal karyotype with positive PML-RARalpha in RT-PCR, indicating submicroscopic translocation. They responded well to APL treatments, including all-trans-retinoic acid. The crude incident rate ratio was 639.9 (95% confidence interval: 131.6-1,878.9, P < 0.0001) when the APL incidence in this cohort was compared to all leukemia cases in the general population in the same district in Japan. Thus we had three cases of secondary APL patients within the gefitinib-treated NSCLC cohort. Although we cannot exclude an effect of past exposure of other cytotoxic agents and radiotherapy as a cause of APL, APL inducibility of gefitinib should be clarified in the further study.

Adult↗
PubMed2001

Mortality among unionized construction plasterers and cement masons.

BACKGROUND: Plasterers perform a variety of duties including interior and exterior plastering of drywall, cement, stucco, and stone imitation; the preparation, installation, and repair of all interior and exterior insulation systems; and the fireproofing of steel beams and columns. Some of the current potential toxic exposures among plasterers include plaster of Paris, silica, fiberglass, talc, and 1,1,1-trichloroethylene; asbestos had been used by the plasterers in the past. Cement masons, on the other hand, are involved in concrete construction of buildings, bridges, curbs and gutters, sidewalks, highways, streets and roads, floors and pavements and the finishing of same, when necessary, by sandblasting or any other method. Exposures include cement dust, silica, asphalt, and various solvents. METHODS: Proportionate mortality ratios (PMRs) and proportionate cancer mortality ratios (PCMRs) were calculated for 99 causes of death among 12,873 members of the Operative Plasterers' and Cement Masons' International Association who died between 1972 and 1996 using United States age-, race-, and calender-specific death rates. Statistical significance (P value) of results was based upon the Poisson distribution. RESULTS: Among plasterers, statistically significant elevated mortality was observed for asbestosis, where the PMR reached 1,657 (P < 0.01) with eleven observed deaths and less than one death expected, for lung cancer (PCMR = 124, P < 0.01), and for benign neoplasms (PMR = 210, P < 0.05). Among cement masons, statistically significant elevated mortality was observed for cancer of the stomach (PCMR = 133, P < 0.01), benign neoplasms (PMR = 132, P < 0.01), and poisonings (PMR = 159, P < 0.05). Except for poisonings, which were not thought to be occupationally related, all of the statistically significant results occurred among those members who entered the union prior to 1950. However, the risk for lung cancer among plasterers was still elevated among those entering the union after 1970 as was the risk for stomach cancer among cement masons who entered the union after 1950. CONCLUSIONS: The present study suggests that plasterers and cement masons still have elevated risks for certain diseases, especially lung and stomach cancer. Therefore, union members currently living should be screened for asbestos-related diseases and educated about the future risks for these diseases.

Adult↗
PubMed1990

Altered immune status in aluminum reduction plant workers.

From 1978 to 1985, B-cell lymphoma occurred in five employees of an aluminum reduction plant (expected = 0.2; Poisson distribution). As immunodeficiency is a known risk factor for B-cell lymphoma, we did a pilot study to evaluate immune function in apparently healthy plant workers. Twenty-three volunteers were selected for study from 350 workers, representing a range of experience in the potroom and with exposures to strong magnetic fields and volatilized aromatic hydrocarbons. Potroom workers had significantly higher T8 levels (mean = 1,227) than non-potroom workers (mean = 597) (p less than .05, Wilcoxon rank sums) or established normal values (median = 450). T4 levels were higher for potroom workers (mean = 1,017) than for non-potroom workers (mean = 558) or for established norms (median = 756) (p less than .10, Wilcoxon rank sums). Ten of 20 potroom workers had abnormal T4/T8 ratios (less than 0.91) due to disproportionate elevation of the T8 subpopulation. These data suggest an underlying immune alteration in the aluminum workers studied. Further study is needed to assess the implications of abnormal T-cell subsets in a worker population with high rates of lymphoma.

Adult↗
PubMed1993

Cluster of testicular cancer in police officers exposed to hand-held radar.

Within a cohort of 340 police officers, six incident cases of testicular cancer occurred between 1979 and 1991 (O/E 6.9; p < 0.001, Poisson distribution). Occupational use of hand-held radar was the only shared risk factor among all six officers, and all routinely held the radar gun directly in close proximity to their testicles. Health effects of occupational radar use have not been widely studied, and further research into a possible association with testicular cancer is warranted.

Adult↗
PubMedDate not supplied

Aneuploidy and the fragile X syndrome.

The possibility that female carriers of the fragile X gene(s) are at increased risk for nondisjunctional events leading to aneuploid offspring has been suggested by several investigators. To better address this question we analyzed pedigrees of 117 families in which the fragile X syndrome is segregating. The 117 pedigrees, originally collected for segregation analyses, included 236 females with offspring whose carrier status was determined by cytogenetic or pedigree analysis or by analyses using flanking DNA markers. These 236 females have had 931 offspring including one 47,XXY and 6 trisomy 21 individuals (1/155). Statistical analysis suggested that the observed rate of trisomy 21 was significantly higher than expected (Fisher's exact test, p less than or equal to 0.05). Assuming a Poisson distribution to calculate the confidence interval for the observed rate of trisomy 21 individuals, we found that the expected rate of 1.6/1000 in this sample fell outside the 99% confidence limits of our observed rate of 1/155. Additional data from a larger sample are needed to replicate these findings.

Aneuploidy↗
PubMed1995

Type I bipolar disorder associated with a fragile site on chromosome 1.

The objective of this paper is to study the association between chromosomal fragile sites and type I bipolar disorder. This case-control study compares bipolar patients with normal controls. Ten cases of type I bipolar disorder diagnosed according to DSM-III-R criteria and the Composite International Diagnostic Interview (CIDI) were selected from the Escola Paulista affective disorders outpatient clinic and 10 healthy controls (CIDI negative for psychiatric diagnoses) matched for sex and age were drawn from the otorhinolaryngologic outpatient clinic of the same hospital. The cytogenetic analysis was carried out with blood lymphocytes, which were cultured in a folic acid-free medium. A total of 100 mitoses per subject were blindly analyzed to the psychiatric diagnostic assignment, and fragile sites were identified according to a minimum expected frequency of events per band in conformity with a Poisson distribution. A higher frequency of chromosomal lesions for cases than controls was found for the following bands: 1q32, 5q31, and 11q23, the 1q32 being considered a fragile site. Although no evident neuropsychiatric etiological component has been mapped to the 1q32 region so far, this finding may lead to further investigation of a possible linkage between genetic markers of this region and bipolar disorder.

Bipolar Disorder↗
PubMed2005

Risks for severe mental retardation occurring in isolation and with other developmental disabilities.

Individual and maternal characteristics as potential risk factors for having severe mental retardation (SMR) occurring with and without cerebral palsy (CP), epilepsy, or a pervasive developmental disorder (PDD) were explored among a cohort of 119,404 children without Down syndrome born in the California Central Valley in 1992 and 1993. Unadjusted and adjusted relative risks (RRs) and their 95% confidence intervals (CIs) based on the Poisson distribution were used to estimate the risks associated with each individual and maternal factor studied for each SMR diagnostic category. The most notable increased risks for SMR occurring in isolation or with CP or epilepsy was for children born low-birth-weight or preterm who were at a substantially increased risk (RRs 2.6-9.9). In contrast, the risk of SMR occurring with a PDD was the greatest among males compared to females (RR = 3.4, 95% CI 1.5, 7.9), Blacks compared to Whites (RR = 5.1, 95% CI 1.7, 15.5), and Asians compared to Whites (RR = 3.9, 95% CI 1.3, 12.0). Etiologic heterogeneity when SMR occurs with a PDD was suggested.

California↗
PubMed1988

Natural course of joint destruction and fluctuation of serum C1q levels in patients with rheumatoid arthritis.

Using the number of joints with erosion in a total of 68 joints throughout the body, we studied a population of patients with rheumatoid arthritis whose disease duration was 10-15 years. Three groups, each showing a Poisson distribution, were found: the subset with least erosive disease (LES), the subset with more erosive disease (MES), and the subset with mutilating disease (MUD). The mean number of joints with erosion was 10.9 in LES, 32.2 in MES, and 53.5 in MUD. In LES, erosive articular changes were primarily limited to the peripheral smaller joints. In MES, the larger axial joints were also involved. Almost all joints were extensively damaged in MUD. During the early period of disease, differences between the 3 groups were highly significant in the rapidity of carpal bone destruction, as assessed by the yearly reduction of carpal height ratio (P less than 0.001), and in the serum C1q level (P less than 0.001).

Adult↗