Automated image analysis in histopathology: a valuable tool in medical diagnostics

Virtual pathology, the process of assessing digital images of histological slides, is gaining momentum in today's laboratory environment. Indeed, digital image acquisition systems are becoming commonplace, and associated image analysis solutions are viewed by most as the next critical step in automated histological analysis. Here, we document the advances in the technology, with reference to past and current techniques in histological assessment. In addition, the demand for these technologies is analyzed with major players profiled. As there are several image analysis software programs focusing on the quantification of immunohistochemical staining, particular attention is paid to this application in this review. Oncology has been a primary target area for these approaches, with example studies in this therapeutic area being covered here. Toxicology-based image analysis solutions are also profiled as these are steadily increasing in popularity, especially within the pharmaceutical industry. Reinforced by the phenomenal growth of the virtual pathology field, it is envisioned that the market for automated image analysis tools will greatly expand over the next 10 years.     

Validation of a two- to three-dimensional registration algorithm for aligning preoperative CT images and intraoperative fluoroscopy images.

We present a validation of an intensity based two- to three-dimensional image registration algorithm. The algorithm can register a CT volume to a single-plane fluoroscopy image. Four routinely acquired clinical data sets from patients who underwent endovascular treatment for an abdominal aortic aneurysm were used. Each data set was comprised of two intraoperative fluoroscopy images and a preoperative CT image. Regions of interest (ROI) were drawn around each vertebra in the CT and fluoroscopy images. Each CT image ROI was individually registered to the corresponding ROI in the fluoroscopy images. A cross validation approach was used to obtain a measure of registration consistency. Spinal movement between the preoperative and intraoperative scene was accounted for by using two fluoroscopy images. The consistency and robustness of the algorithm when using two similarity measures, pattern intensity and gradient difference, was investigated. Both similarity measures produced similar results. The consistency values were rotational errors below 0.74 degree and in-plane translational errors below 0.90 mm. These errors approximately relate to a two-dimensional projection error of 1.3 mm. The failure rate was less than 8.3% for three of the four data sets. However, for one of the data sets a much larger failure rate (28.5%) occurred.     

Localization of non–N-methyl-D-aspartate glutamate receptors in normal and Alzheimer hippocampal formation

The hippocampi and adjacent temporal cortices of 24 human brains were examined with antibodies to the GluR1, GluR2/3, and GluR4 subunits of the D ,L -α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–preferring glutamate receptor. GluR1 immunoreactivity was most dense in the dentate gyrus, with lower densities in other hippocampal and cortical regions. GluR2/3 immunoreactivity was the most intense of the three antibodies, with high levels throughout most hippocampal subfields, where it was localized to cell bodies, proximal axons, and dendrites. GluR4 immunoreactivity was very sparse in all regions. In Alzheimer's disease brains, the general pattern of staining was similar to that seen in control brains. GluR1 and GluR4 immunoreactivity was seen in some but not all neuritic plaques. All three antibodies recognized some neurons undergoing neurofibrillary degeneration.     

Ultrasonographic dating of pregnancy causes significant errors in Down syndrome risk assessment that may be minimized by use of biparietal diameter-based means.

OBJECTIVES: Gestational dates assessed by ultrasonographic measurement of fetal dimensions are usually quoted in terms of complete weeks because the uncertainty of ultrasonographic measurement is approximately +/- 7 days. This study examines the effect of ultrasonographic dating on Down syndrome risk assessment. STUDY DESIGN: The effect of small changes in measured biparietal diameter resulting in a change in estimated gestational week and the benefits of a more precise measure of fetal gestational age (raw biparietal diameter) are examined mathematically. RESULTS: If maternal serum alpha-fetoprotein and human chorionic gonadotropin are used to assess Down syndrome risk, risks assessed with ultrasonographically determined dates may be less than or equal to 45% too high for fetuses with biparietal diameter at the lowest end of the size band and less than or equal to 22% too low with biparietal diameter at the top of the size band. If the results for maternal serum alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol are used, these figures become less than or equal to 150% and less than or equal to 60%, respectively. CONCLUSION: If ultrasonography is used to assess gestational age, the raw biparietal diameter and not the estimated week of gestation must be used to derive means for calculation of multiples of the mean.     

Health impacts of family planning

Among the many effects of family planning is the influence ithas on mortality and morbidity in women and children throughthe mechanism of changing the number and spacing of children.There is a complex set of relationships between mother's age,parity, birth spacing and infant and child mortality and morbidity.Much effort has been put into untangling this web in the hopeof identifying clear causal connections, but for the most parton the basis of inadequate data. Rather than attempt to establishthe relative importance of child spacing as a cause of decreasesin mortality, this paper takes as its starting point that thereis a connection, and presents some possible causal mechanismswhich explain how short birth intervals and child mortalitycould be related. In addition the most frequently cited hypotheses-maternaldepletion and sibling competition-a third is examined-birthcrowding which, it is suggested, influences the pattern of thetransmission of infectious diseases and, in turn, mortality. In the field of maternal mortality, the data which could beused to quantify the benefits of family planning are in evenshorter supply; however, the causal connections are rather moreeasily identified. The final section combines parity-specificdata on maternal mortality with evidence of changes in fertilitypatterns brought about by family planning to assess how successfulwe can hope to be in reducing through birth control the numberof women who die in childbirth.     

Embryo-fetal developmental and reproductive toxicology of vinyl chloride in rats.

Vinyl chloride (VC) exposure is primarily via inhalation in the workplace. The primary target organ of VC toxicity is the liver and occupational exposure to VC leads to hepatic angiosarcoma. However, based on epidemiological studies, researchers have been unable to ascertain the effect of occupational VC exposure on embryo-fetal development or reproductive function. A limited number of animal studies available in the literature have examined the effect of VC on embryo-fetal development, however, there are no published studies on the effect of VC exposure on reproductive capability. The current study was designed to assess the potential maternal and/or embryo-fetal developmental and 2-generation reproductive toxicity of inhaled VC in CD(R) Sprague-Dawley rats at exposure levels of 0, 10, 100, and 1100 ppm. In the embryo-fetal/developmental toxicity study, the female rats were exposed to VC daily from gestation day (GD) 6 through 19. In the reproductive toxicity study, the F(0) generation male and female rats were exposed to VC for a 10-week premating and 3-week mating periods. The F(0) generation male rats were exposed to VC until terminal euthanasia. The F(0) generation female rats were exposed from GD 0 through GD 20 and lactation day (LD) 4 through LD 25. Our results indicate that up to 1100 ppm VC exposure did not adversely affect embryo-fetal developmental or reproductive capability over 2 generations in rats. The primary target organ of VC, the liver, was affected as evidenced by an increase in liver weight and/or histologically identified cellular alterations, such as centrilobular hypertrophy at 100 and 1000 ppm. Based on the results of these studies, the no observed adverse effect level (NOAEL) for embryo-fetal/development is 1100 ppm, and the NOAEL for reproduction is 1100 ppm. The results from the current studies, which are a more comprehensive embryo-fetal/developmental and reproduction study, may be incorporated into future risk assessments of occupational exposure to VC where concerns regarding the effects of VC exposure remain.     

The effect of lithium therapy on arginine vasopressin secretion and thirst in man

Lithium therapy is known to reduce the renal responsiveness to arginine vasopressin (AVP: the antidiuretic hormone in man) and a proportion of treated patients develop polyuria and polydipsia. In this study seven nonpolyuric female patients receiving lithium treatment for an affective disorder (lithium group) were age-matched with seven healthy females (control group). The mean response of plasma AVP to osmotic stimulation was significantly enhanced in the lithium group but the mean osmotic threshold for AVP release was unchanged. Thirst appreciation in the lithium group commenced and increased overall at an osmotic stimulus 5 mmol/kg less than the control group. It is suggested that primary thirst does play a role in the expression of lithium-induced polyuria.