Associative Classification of Mammograms using Weighted Rules.

In this paper, we present a novel method for the classification of mammograms using a unique weighted association rule based classifier. Images are preprocessed to reveal regions of interest. Texture components are extracted from segmented parts of the image and discretized for rule discovery. Association rules are derived between various texture components extracted from segments of images, and employed for classification based on their intra- and inter-class dependencies. These rules are then employed for the classification of a commonly used mammography dataset, and rigorous experimentation is performed to evaluate the rules' efficacy under different classification scenarios. The experimental results show that this method works well for such datasets, incurring accuracies as high as 89%, which surpasses the accuracy rates of other rule based classification techniques.

Can a herpes simplex virus type 1 neuroinvasive score be correlated to other risk factors in Alzheimer's disease?

Herpes simplex virus type 1 (HSV-1) is latent in the nervous system of most humans. Ball [Can J Neurol Sci 9 (1982) 303] first suggested the hypothesis that HSV-1 could be involved in the pathogenesis of Alzheimer's Disease (AD) by noting that regions of the brain particularly and earliest affected in AD were the same as those most damaged during HSV encephalitis. Data from Itzhaki's research suggests that HSV-1 in the brain and the carriage of an apolipoprotein E allele 4 (ApoE e4) together confer risk for AD [J Pathol 97 (2002) 395], [Mol Chem Neuropathol 28 (1996) 135], [Alzheimer's Rep 1 (1998) 173], [Biochem Soc Trans 26 (1998) 273]. Of the two other studies based on Itzhaki's findings, one showed similar results [Lancet 349 (1997) 1102], and the other showed a similar trend [Lancet 351 (1998) 1330], [Lancet 352 (1998) 1312]. To further examine the role of HSV-1 in the etiology of AD, we have formulated a Neuroinvasive Score that quantifies the presence and viral load of HSV-1 in eight brain regions. These regions are: entorhinal cortex, hippocampus, pons, cerebellum, and neocortex (temporal, parietal, occipital, and frontal). We hypothesize that the Neuroinvasive Score that encompasses the presence, amount, and extent of HSV-1 spreading (neuroinvasiveness), will correlate with the genetic risk factor, ApoE e4, in the assessment of autopsy samples from AD patients. If the neuroinvasive score can be directly correlated to the different stages of AD (mild, moderate, severe), this will strengthen the hypothesis that HSV-1 is involved in AD and that ApoE e4 also confers risk for the development and progression of AD.

Thrombotic thrombocytopenic purpura. Potential benefit of splenectomy after plasma exchange.

Two patients with thrombotic thrombocytopenic purpura (TTP) were treated with a combination of antiplatelet drugs, corticosteroids, and plasma exchange. There was immediate clinical and laboratory improvement in both patients. However, the improvement did not persist following plasma exchange, even with infusions of fresh frozen plasma. Splenectomy was performed on both patients with subsequent sustained remission of the disease. Platelet counts returned to normal within eight days (case 1) and five days (case 2). Follow-up at eight months in one patient and at four months in the other disclosed normal laboratory values with no evidence of recurrent TTP. These cases suggest that in addition to other therapies, splenectomy may be beneficial in some patients.

Effect of growth factors on collagen lattice contraction by human keratocytes.

A three-dimensional gel contraction model was used to evaluate interactions between human keratocytes and different kinds of collagen in the presence or absence of various growth factors. Bovine collagen type I or human placental copolymerized collagen type I/III was used to create the lattices. Normal keratocytes from neonatal, aged, and insulin-dependent diabetic donors, as well as abnormal keratocytes from a donor with macular corneal dystrophy, were cultured. Growth factors included epidermal growth factor (EGF), basic fibroblastic growth factor (FGF), insulin-like growth factor (IGF-I), and platelet-derived growth factor homodimer beta beta (PDGF). Gel area and optical transmittance were determined from computerized measurements. Dose-response experiments (0.01-100 ng/ml) demonstrated that PDGF at 10 ng/ml (P less than 0.005) and EGF at 1 and 10 ng/ml (P less than 0.0001) were the most effective in promoting gel contraction, compared to IGF-I and FGF. Comparison of cell strains revealed different dose-response profiles. Cells from insulin-dependent diabetics and cells from a donor with macular dystrophy contracted lattices more rapidly than cells from normal neonates (P less than 0.0001). Lattices of copolymerized human collagen type III/I demonstrated significantly reduced contraction rates (P less than 0.0001) and increased optical transmittance, compared to bovine collagen type I lattices. Ultrastructural studies revealed that keratocytes extend processes to form a network within the collagen lattice. Specialized intercellular junctional complexes were observed by transmission electron microscopy. This model provides a useful in vitro corneal stroma-equivalent for the study of keratocyte, extracellular matrix, and growth factor interactions.

Automated keratoconus screening with corneal topography analysis.

PURPOSE: Although visual inspection of corneal topography maps by trained experts can be powerful, this method is inherently subjective. Quantitative classification methods that can detect and classify abnormal topographic patterns would be useful. An automated system was developed to differentiate keratoconus patterns from other conditions using computer-assisted videokeratoscopy. METHODS: This system combined a classification tree with a linear discriminant function derived from discriminant analysis of eight indices obtained from TMS-1 videokeratoscope data. One hundred corneas with a variety of diagnoses (keratoconus, normal, keratoplasty, epikeratophakia, excimer laser photorefractive keratectomy, radical keratotomy, contact lens-induced warpage, and others) were used for training, and a validation set of 100 additional corneas was used to evaluate the results. RESULTS: In the training set, all 22 cases of clinically diagnosed keratoconus were detected with three-false-positive cases (sensitivity 100%, specificity 96%, and accuracy 97%). With the validation set, 25 out of 28 keratoconus cases were detected with one false-positive case, which was a transplanted cornea (sensitivity 89%, specificity 99%, and accuracy 96%). CONCLUSIONS: This system can be used as a screening procedure to distinguish clinical keratoconus from other corneal topographies. This quantitative classification method may also aid in refining the clinical interpretation of topographic maps.

Flow cytometry measurements of the DNA content of corneal epithelial cells during wound healing.

This study presents the first application of flow cytometry (FCM) techniques to the assessment of cell cycle dynamics in the corneal epithelium after experimental wounding. Anterior keratectomies 6 mm in diameter were created in the central corneas of albino rabbits. The authors sampled the epithelial tissue obtained outside the wound at 12-hr intervals until wound closure at 72 hr. Regenerated epithelium from the surface of the wounded area was collected at 78 hr. The percentages of nuclei in the G0/G1 (growth), S (DNA synthesis), and G2/M (tetraploid/mitosis) phases were determined by FCM. An increase in the percentage of nuclei in the G2/M phase at 36 hr was seen, compared with cell populations in samples from unwounded control corneas. The authors found an increase in mitotic activity in the corneal epithelium during the period of cell migration before wound closure.

Cold stress-induced recurrences of herpetic keratitis in the squirrel monkey.

PURPOSE: Models of recurrent herpetic keratitis that depend on tissue damage or immunosuppression have been described. The authors report a model that depends only on minimal temperature stress to produce clinical recurrences in a small primate. METHODS: Squirrel monkeys (Saimiri sciureus) infected by the ocular route with the Rodanus strain of herpesvirus type 1 (HSV-1) were exposed to temperatures approximately 5 degrees C lower than the usual ambient temperature for periods as short as 12 hours. RESULTS: The corneas showed more or larger lesions typical of recurrent herpetic keratitis than are usually seen in these animals under normal conditions. Statistical analysis showed that there were significantly higher frequencies of epithelial keratitis at 18 degrees C and 20 degrees C (P < 0.0001). CONCLUSIONS: A minimal temperature change produced significant recurrences in this small animal within a short time. Tissues were not damaged to produce the recurrences. This approach may provide an efficient primate model for rapid testing of drugs to prevent clinical recurrence of ocular herpetic keratitis.

Histochemical distribution of carbonic anhydrase in rat and rabbit lacrimal gland.

PURPOSE: The purpose of this study was to examine the histochemical distribution of carbonic anhydrase (CA) in lacrimal glands from rats and rabbits; and to determine if age- and/or sex-related differences exist in the amount and distribution of CA in the rat lacrimal gland. METHODS: Lacrimal glands from young (3-12 wk) and aged (2-2.5 yr), male and female F344 rats and male rabbits were fixed in 1% paraformaldehyde and embedded in glycolmethacrylate. CA histochemistry was performed on 2-microns sections. The distribution of CA activity was determined by morphometric analysis. RESULTS: In rat lacrimal gland, CA activity was distributed in a discontinuous, mosaic fashion among the acinar cells. In tissue from young males and females as well as from aged females, about 10% of the acinar tissue displayed CA activity. Significantly more activity was present in tissue from aged male rats. CA was present in the ductal lumina, suggesting that it is a secretory product of the acinar cells. In rabbits, CA activity was associated with the basolateral membranes of the terminal acinar cells only. CONCLUSIONS: In rat, the presence of CA activity in certain acinar cells and in ductal lumina suggests that CA is actively secreted by the lacrimal gland. An age-related increase in the amount of CA activity in the male glands exists that may be under gender-specific hormonal influences. In the rabbit lacrimal gland, the membrane-associated CA found uniquely with the terminal acinar cells suggests that these cells have special transport functions associated with the primary secretion of lacrimal fluid.

Posterior scleral thickness in perfusion-fixed normal and early-glaucoma monkey eyes.

PURPOSE: To characterize posterior scleral thickness in the normal monkey eye and to assess the effects of acute (15- to 80-minute) and short-term chronic (3- to 7-week) intraocular pressure (IOP) elevations. METHODS: Both eyes of four normal monkeys (both eyes normal) and four monkeys with early glaucoma (one eye normal and one eye with induced chronic elevation of IOP) were cannulated. In each monkey, IOP was set to 10 mm Hg in the normal eye and 30 or 45 mm Hg in the contralateral eye (normal or early glaucoma) for 15 to 80 minutes. All eight monkeys were perfusion fixed, yielding eight low IOP-normal eyes, four high IOP-normal eyes, and four high IOP-early glaucoma eyes. Posterior scleral thickness was measured histomorphometrically at 15 measurement points within each eye, and the data were grouped by region: foveal, midposterior, posterior-equatorial, and equatorial. RESULTS: Overall, posterior scleral thickness was significantly different in the various regions and among the treatment groups (P < 0.0001). In the low IOP-normal eyes, the posterior sclera was thickest in the foveal region (307 microm) and thinner in the midposterior (199 microm), posterior-equatorial (133 microm), and equatorial (179 microm) regions. In the high IOP-normal and high IOP-early glaucoma eyes, the posterior sclera was thinner both overall and within specific regions, compared with the low IOP-normal eyes. CONCLUSIONS: The posterior sclera in the perfusion-fixed normal monkey eye thins progressively from the fovea to the equator and is thinnest just posterior to the equator. Acute and short-term chronic IOP elevations cause regional thinning within the posterior sclera of some monkey eyes, which significantly increases stresses in the scleral wall.

EGF cell surface receptor quantitation on ocular cells by an immunocytochemical flow cytometry technique.

A method is presented for the rapid flow cytometric determination of epidermal growth factor (EGF) receptor densities on the surface of cultured ocular cells. The technique uses a biotinylated monoclonal antibody directed against the EGF receptor in conjunction with a streptavidin-bound fluorochrome and requires the specific fluorescence per cell to be measured as a function of ligand and receptor concentration. Because the measurement is noninvasive and restricted to cell surface-bound material, the cells can be kept in a physiologic environment, even at the moment of assay. Calculated receptor densities ranged from 5142/cell (infant human corneal endothelium) to 35,678/cell (infant human keratocytes) to greater than 5 x 10(5)/cell for an A431 control cell line. Species and donor age differences were noted, as was transient receptor downregulation after EGF administration. Flow cytometry represents a valuable time saving procedure for large scale applications while providing the same level of sensitivity as standard radioimmunoassays. This technique is applicable to quantitation of other growth factor cell surface receptors and could greatly expand the use of flow cytometry in the research laboratory.

Simple clinical variables are markers of the propensity for readmission in patients hospitalized with heart failure.

In a consecutive cohort of patients hospitalized for decompensated heart failure, we found that chronic obstructive pulmonary disease and history of hospitalization for any cause in the preceding 6 months were the strongest correlates of early readmission. Based on these findings, we propose a simple risk stratification system to classify patients who are hospitalized for heart failure as low, medium, or high risk for early readmission.

Effect of 9-(4-hydroxybutyl)-N2-phenylguanine (HBPG), a thymidine kinase inhibitor, on clinical recurrences of ocular herpetic keratitis in squirrel monkeys.

9-(4-Hydroxybutyl)-N2-phenylguanine (HBPG) is a new viral thymidine kinase inhibitor that we tested for the ability to prevent recurrences of herpetic keratitis. Eighteen squirrel monkeys (Saimiri scuireus) were infected in both corneas with the Rodanus strain of herpes simplex virus type 1 (HSV-1). All corneas showed typical dendritic keratitis 3 days after infection, followed by spontaneous healing. On day 21, the monkeys were randomized into two coded groups and ocular examinations were begun. One group received intraperitoneal (i.p.) injections of HBPG, 150 mg/kg, in a corn oil suspension every 8 h, and the other group received i.p. injections of the corn oil vehicle only. On day 22, recurrences were induced by reducing the temperature of the room in the late afternoon so that a low of 18 degrees C was achieved during the night. After the morning treatment, room temperature was raised to the normal ambient temperature (24-27 degrees C), and treatment was discontinued. Treatment was reinstituted on day 27, the room temperature was lowered again on day 28, and treatment was again discontinued as before. Third and fourth cycles of treatment and cold stress were begun on days 34 and 69. Ocular examinations were continued until day 73, at which point the code was broken. We found that the HBPG treatment significantly reduced the number of corneas with recurrences during the treatment periods, compared with recurrences in untreated, cold-stressed animals (P = 0.01).

Suppression of ocular herpes recurrences by a thymidine kinase inhibitor in squirrel monkeys.

5'-Ethynylthymidine, an inhibitor of viral thymidine kinase (TK), was given intraperitoneally to squirrel monkeys previously infected by the ocular route with Rodanus strain herpes simplex virus. Spontaneous ocular recurrences were reduced during therapy, compared to saline-treated controls. This is the first in vivo demonstration that a viral TK inhibitor can reduce recurrences of HSV-1. Similar benefit would be expected for HSV-2 and perhaps VZV (varicella zoster virus).

Trifluridine, cidofovir, and penciclovir in the treatment of experimental herpetic keratitis.

OBJECTIVE: To compare trifluridine eyedrops, cidofovir eyedrops, and penciclovir ophthalmic ointment for the treatment of herpes simplex virus type 1 keratitis. METHODS: New Zealand white rabbits were infected with the McKrae strain of herpes simplex virus type 1. Three days after viral inoculation, the rabbits were randomly assigned to treatment with 1% trifluridine, 0.2% cidofovir, 3% penciclovir ointment, or phosphate-buffered saline (for control) on various schedules. The severity of keratitis was graded in a masked manner. RESULTS: Treatment with any of the antiviral drugs resulted in significantly less severe keratitis than treatment with phosphate-buffered saline. There was no statistically significant difference between eyes given trifluridine 2, 4, or 7 times a day and eyes given cidofovir 2 times a day (P=.06, P=.43, and P=.19, respectively, using the F test of the analysis of variance). Cidofovir given twice a day was significantly more effective than penciclovir given either 2 or 4 times a day (P<.001 and P=.002, respectively). Even with once-a-day dosage, all 3 drugs were significantly more effective than phosphate-buffered saline (P<.001 for all). There was no significant difference between once-a-day trifluridine and cidofovir treatments (P=.17). Trifluridine administered 5 times a day was as effective as 1% cidofovir. A similar degree of punctate keratitis was seen after 4 to 5 days in eyes treated with trifluridine at the highest frequency, 1% cidofovir, or penciclovir ointment. CONCLUSION: Trifluridine treatment was highly effective in this rabbit model, even when given only once a day. Treatment with cidofovir was as effective as that with trifluridine. CLINICAL RELEVANCE: Cidofovir and penciclovir treatments may prove to be effective against epithelial keratitis. Clinical trials of trifluridine, cidofovir, and penciclovir with lower treatment frequencies appear to be warranted.

Corneal thickness measurements with the Topcon SP-2000P specular microscope and an ultrasound pachymeter.

OBJECTIVE: To compare the reproducibility of measurements obtained with a new pachymetry instrument, the Topcon specular microscope (Topcon SP-2000P; Topcon America Corp, Paramus, NJ), with those obtained by ultrasound pachymetry. METHODS: Corneal thickness was measured in 40 eyes of 40 patients 3 times each with the Topcon SP-2000P and an ultrasound pachymeter (DGH 500, DGH Technology Inc, Exton, Pa) by 2 separate investigators. Comparisons included average thickness as measured by each instrument, average thickness for each instrument as measured by each investigator, and differences in thickness due to corneal abnormalities. RESULTS: Mean corneal thickness measured by the Topcon instrument was significantly less (32 microm; P<.001) than the mean value obtained with the ultrasound pachymeter. Similarly, mean values obtained with the 2 instruments by the 2 investigators were significantly different (P<.001 and .008 for investigators 1 and 2, respectively), with the Topcon value less than the ultrasound value in both cases. Both instruments detected abnormalities in corneal thickness equally well. However, the measurements obtained with the Topcon instrument by the 2 investigators were more consistent (no significant difference [P=.32]) than those obtained with the ultrasound unit (difference was significant [P=.02]). CONCLUSIONS: The new noncontact Topcon specular microscope provides measurements of corneal thickness that are somewhat less than those of ultrasound pachymetry, but that seem to be more consistent from one operator to another, possibly as a result of the elimination of observer bias induced by probe placement required by the ultrasound unit. This consistency may be important in the comparison of measurements by different operators over time in patients being followed up after refractive surgery or other therapeutic interventions.

Cidofovir and experimental herpetic stromal disease.

OBJECTIVE: To compare topical cidofovir with topical trifluridine for the prevention and treatment of herpes simplex type 1 stromal keratitis in rabbits. METHODS: The RE strain of herpes simplex virus 1 was injected into the central stroma of both eyes of New Zealand white rabbits. Two to 3 days after virus inoculation, the rabbits were randomized to treatment groups of 10 each and treated with 1% trifluridine administered 5 or 7 times a day, 1%, 0.5%, or 0.2% cidofovir administered twice a day, fluorometholone administered twice a day, or balanced salt solution (BSS) administered twice a day (control) until day 21 after injection. The treated corneas were examined 3 times a week and the severity of stromal keratitis was graded in a masked fashion. To evaluate the ability of cidofovir to treat established stromal disease, groups of 10 rabbits each were inoculated with herpes simplex virus and treated with 1% cidofovir twice a day, 1% trifluridine 5 times a day, fluorometholone twice a day, or BSS twice a day beginning on day 7 after virus inoculation through day 21. RESULTS: Treatment with 0.2% cidofovir twice a day was not effective in preventing the appearance of stromal disease (P = .89), whereas treatment with 0.5% (P<.001) or 1% (P<.001) cidofovir twice a day or 1% trifluridine 5 times a day (P<.001) or 7 times a day (P = .006) significantly reduced the appearance of stromal keratitis on the 8 evaluation days, compared with BSS treatment (F test analysis of variance). There was no difference between the eyes treated with 0.5% cidofovir twice a day and those treated with 1% trifluridine 5 times a day. Treatment with 1% cidofovir was not effective in treating established stromal disease. CONCLUSIONS: Cidofovir and trifluridine are highly effective in preventing the appearance of herpetic stromal disease. Cidofovir is as effective as, but no more effective than, trifluridine in this model. Neither cidofovir nor trifluridine benefits established stromal disease, however. CLINICAL RELEVANCE: Cidofovir is a new, potent antiviral that seems similar in efficacy to trifluridine and is effective in the prevention of the development of stromal herpes, but is not effective in the treatment of established stromal disease in which hypersensitivity predominates.

Accuracy and precision of the Tono-Pen in measuring intraocular pressure after keratoplasty and epikeratophakia and in scarred corneas.

Intraocular pressure measurements with the Goldmann and Schiotz tonometers are unreliable when the cornea is irregular due to disease or surgery. The Tono-Pen (Oculab, Glendale, Calif) is an electronic applanation tonometer based on the same principle as the MacKay-Marg tonometer. We measured intraocular pressure in 37 eyes with irregular corneas, in 50 eyes that had recently undergone penetrating keratoplasty, in 16 eyes that had undergone epikeratophakia, and in 12 eyes with normal corneas with both the MacKay-Marg and Tono-Pen tonometers. The same two instruments were used, and the sequence of measurement was randomized. Analysis of variance demonstrated no significant difference between measurements obtained with the two tonometers in any of the groups. The data suggest that the Tono-Pen is as accurate as the MacKay-Marg tonometer in those situations where the Goldmann tonometer is inaccurate.

Effects of scleral reinforcement on the elongation of growing cat eyes.

OBJECTIVE: We investigated the effect of scleral reinforcement on ocular elongation in the rapidly growing eyes of juvenile cats. METHODS: Bands made from donor sclera or expanded polytetrafluoroethylene were used to reinforce one eye of each animal; contralateral eyes underwent sham surgery. RESULTS: During 5 months of follow-up, normal intraocular pressures implied normal functioning of angle structures. A-scan on the central axis showed no difference in globe lengths. Direct physical measurements of the posterior aspect of the globe at enucleation revealed significant decreases in off-center lengthening where reinforcement was present compared with unreinforced areas in the same eyes and in the contralateral unbanded eyes. Venous beading in fundus photographs of three eyes suggested impairment of venous outflow. CONCLUSIONS: Scleral reinforcement appears to control expansion of the growing cat eye to a limited extent, but the effects on vision and retinal perfusion require further investigation.

Optisol corneal storage medium.

Optisol is an investigational, intermediate-term corneal storage medium containing chondroitin sulfate and dextran to enhance corneal dehydration during storage. We used scanning electron microscopy to grade endothelial cell morphologic characteristics in terms of cell shape, cell borders, cell swelling, and apical holes in pairs of corneas stored in Optisol and Dexsol. Optisolstored corneas showed significantly fewer morphologic changes after 14 days at 4 degrees C than did Dexsol-stored corneas. No significant differences were seen after 1 to 4 days at 26 degrees C. Temperature-reversal analysis showed no significant change in corneal thickness with warming after 2-week storage at 4 degrees C in either medium, although Optisol-stored corneas were significantly thinner than those stored in Dexsol at all times. The results of scanning electron microscopy suggest that preservation at refrigerator temperature for 2 weeks in Optisol is superior to preservation in Dexsol. Both media may be useful in preserving endothelial structure for limited periods at room temperature, which could provide a measure of safety in shipping or storage where refrigeration is unreliable.

PMMA model of steep central islands induced by excimer laser photorefractive keratectomy.

We designed a polymethyl methacrylate (PMMA) model of refractive steep central islands (CIs) induced by PRK. A standardized photorefractive ablation procedure was performed using seven different excimer lasers on test PMMA specimens including 70 flat plates and 98 convex contact lenses. The resulting surface was analyzed by high-resolution confocal microscopy and computerized videokeratoscopy using both TMS-1 and CAS-2000 systems. A total of 50 (54.9%) CIs were observed using computerized videokeratoscopy. The rate of occurrence of CIs was significantly reduced by shock wave absorption (P = 0.0001), aspiration of fumes (P = 0.0044), and smaller diameter ablation (P = 0.0296). The diameter of the CIIs was significantly increased for broad-beam mode ablation (P = 0.016) and for larger ablation zones, (P = 0.042). The refractive power of CIs was significantly increased in the absence of a shock wave absorption system (P = 0.001). Only 20 (40%) of the CIs detected by the TMS-1 device were identified on CAS-2000 at a 0.5 diopter (D) scale resolution level. Shock wave induced deformation and subsequent dynamic alteration of convection forces applied to emitted particles may be the primary mechanism underlying the formation of CIs after PRK, regardless of any biological response of the ablated tissue. Reported rates and characteristics of CIs may largely depend upon the specific design of videokeratoscopes.