Reliable feature selection for automated angle closure glaucoma mechanism detection.

Glaucoma is an eye disease where a loss of vision occurs as a result of progressive optic nerve damage usually associates with high intraocular pressure. A subtype of glaucoma called primary angle-closure glaucoma (PACG) has been observed to be the result of one or more mechanisms such as Pupil block, Plateau iris, Peripheral iris roll, and Lens in the anterior segment of the eye. Reliable features in anterior segment images are important for determining the specific mechanisms involved in PACG. In this paper, first the discriminant features are selected by several feature selection algorithms in the context of PACG detection based on anterior segment optical coherence tomography (AS-OCT) images, and then a novel criteria is proposed to further select more reliable features. Our approach is based on selecting the top-ranked features in each algorithm and its rank combination for selection of the best features. Compared with the features selected by the individual feature selection methods, the features selected by our method achieves the best performance in terms of the accuracy of classification of the four PACG mechanisms by using AdaBoost classifier.

Multiple myeloma--presenting as acute kidney injury.

BACKGROUND: Multiple myeloma (MM) is a commonly encountered hematological malignancy with significant renal involvement and often presents as renal failure. The aim of the present study is to analyze clinical spectrum of acute renal failure (ARF) in patients with MM. MATERIAL AND METHODS: We analyzed 26 (males 24; females 2) patients of multiple myeloma who were referred for evaluation of ARF between July 1994 - June 2007. The referral diagnosis did not include MM in majority 23 (88%) of the patients. Multiple myeloma was diagnosed by at least two of the four features; (1) lytic bone lesions, (2) serum or urine monoclonal peak, (3) Bence Jones proteinuria and (4) more than 20% plama cells in marrow aspirate. RESULTS: Multiple myeloma contributes 1.93% of total ARF cases (26/1342) over a period of thirteen years. Mean age of patients was 59.3 +/- 7.4 years. The clinical manifestations of myeloma included; anemia (100%), Bence Jones proteinuria (80%), "M" peak in serum electrophoresis (69%), lytic bone lesions (62%), "M" peak in urine electrophoresis (54%), body pain (58%), plasma cells more than 20% in bone marrow aspirate (38%). Oliguric ARF was seen in 73% patients. The precipitating factors of ARF identified were; hypercalcemia (31%); infection (23%); volume depletion (19%); and NSAIDs in (15%). Dialysis support was needed in 77% of the patients because of severe renal failure at presentation with mean serum creatinine of 9.05 +/- 2.84 mg%. Seventeen patients completed chemotherapy, seven last to follow up and two patients died. Ten (38.5%) patients had complete recovery of renal function; three patients had partial recovery and off dialysis and four patients remained dialysis dependent. Remission of myeloma was achieved in nine of seventeen patients treated with chemotherapy Renal biopsy finding in nine patients revealed-cast nephropathy in (4), amyloidosis in (3), proliferative glomerulonephritis in (1) and cast nephropathy with chronic interstitial nephritis and plasma cell infiltration in one patient. CONCLUSION: Acute reversible renal failure is a common complication in MM, multiple myeloma should be considered as cause a cause of unexplained ARF in middle aged and elderly patients.

PCA-based localization approach for segmentation of optic disc.

PURPOSE: The optic disc is the origin of the optic nerve, where the axons of retinal ganglion cells join together. The size, shape and contour of optic disc are used for classification and identification of retinal diseases. Automatic detection of eye disease requires development of an efficient algorithm. This paper proposes an efficient method for optic disc segmentation and detection for the diagnosis of retinal diseases. METHODS: The methodology involves optic disc localization, blood vessel inpainting and optic disc segmentation. Localization is based on principal component analysis, and segmentation is based on Markov random field segmentation. In order to get reasonable background images, blood vessel inpainting is done before segmentation. RESULTS: The proposed method tested with two standard databases MESSIDOR and DRIVE, and achieved an average overlapping score of 92.41, 92.17%, respectively; also validation experiments were done with one local database from Venu Eye Hospital, New Delhi, and obtained an average overlapping score of 91%. CONCLUSION: An efficient algorithm is developed for detecting optic disc using principal component analysis-based localization and Markov random field segmentation. The comparison with alternative method yielded results that demonstrate the superiority of the proposed algorithm for optic disc detection.

Effect of 9-benzyl-9-deazaguanine, a potent inhibitor of purine nucleoside phosphorylase, on the cytotoxicity and metabolism of 6-thio-2'-deoxyguanosine.

6-Thio-2'-deoxyguanosine (T-dGuo) has been reported to be both phosphorylated by deoxycytidine kinase and converted to 6-thioguanine by purine nucleoside phosphorylase (PNP). Combination of T-dGuo with an inhibitor of PNP would be expected to generate the 5'-triphosphate of T-dGuo and limit or prevent the formation of 6-thioguanosine triphosphate. Because the incorporation of 6-thioguanine into DNA is believed to be primarily responsible for the antitumor activity of the thiopurines, this treatment might result in enhanced activity against certain tumors, particularly those of T-cell origin. We have evaluated the metabolic basis of this strategy by examining the effects of 9-benzyl-9-deazaguanine (BDG), a potent inhibitor of PNP, on the metabolism of T-dGuo in CEM cells. The concentration of T-dGuo required to inhibit cell growth by 50% was approximately 50-fold greater in the presence of 8.0 microM BDG than in its absence. As expected, the addition of BDG to cells treated with T-dGuo prevented the metabolism of T-dGuo to 6-thio-guanine-containing ribo-nucleotides, but, unexpectedly, no 6-thio-2'-deoxyguanosine 5'-triphosphate was detected. In cells treated with T-dGuo plus BDG, the major phosphorylated metabolite was T-dGMP. These results indicated that even in the absence of PNP activity, T-dGuo cannot be phosphorylated directly to 6-thio-2'-deoxyguanosine 5'-triphosphate due to the inability of guanylate kinase to utilize T-dGMP as a substrate.

Enhancement and bias removal of optical coherence tomography images: An iterative approach with adaptive bilateral filtering.

Optical coherence tomography (OCT) has continually evolved and expanded as one of the most valuable routine tests in ophthalmology. However, noise (speckle) in the acquired images causes quality degradation of OCT images and makes it difficult to analyze the acquired images. In this paper, an iterative approach based on bilateral filtering is proposed for speckle reduction in multiframe OCT data. Gamma noise model is assumed for the observed OCT image. First, the adaptive version of the conventional bilateral filter is applied to enhance the multiframe OCT data and then the bias due to noise is reduced from each of the filtered frames. These unbiased filtered frames are then refined using an iterative approach. Finally, these refined frames are averaged to produce the denoised OCT image. Experimental results on phantom images and real OCT retinal images demonstrate the effectiveness of the proposed filter.

Structure-based design of inhibitors of purine nucleoside phosphorylase. 5. 9-Deazahypoxanthines.

The synthesis and evaluation as inhibitors of purine nucleoside phosphorylase of six 9-deazahypoxanthines (2a-f) are reported. In contrast to reports in the literature of other hypoxanthine-guanine analog pairs, these inhibitors (2a-f) are equipotent with the corresponding 9-deazaguanines.

Structure-based design of inhibitors of purine nucleoside phosphorylase. 3. 9-Arylmethyl derivatives of 9-deazaguanine substituted on the methylene group.

X-ray crystallography and computer-assisted molecular modeling (CAMM) studies aided in the design of a potent series of mammalian purine nucleoside phosphorylase (PNP) inhibitors. Enhanced potency was achieved by designing substituted 9-(arylmethyl)-9-deazaguanine analogs that interact favorably with all three of the binding subsites of the PNP active site, namely the purine binding site, the hydrophobic pocket, and the phosphate binding site. The most potent PNP inhibitor prepared during our investigation, (S)-9-[1-(3-chlorophenyl)-2-carboxyethyl]-9-deazaguanine (18b), was shown to have an IC50 of 6 nM, whereas the corresponding (R)-isomer was 30-fold less potent.

Structure-based design of inhibitors of purine nucleoside phosphorylase. 2. 9-Alicyclic and 9-heteroalicyclic derivatives of 9-deazaguanine.

Alicyclic and heteroalicyclic derivatives of 9-deazaguanine (2-amino-1,5-dihydro-4H-pyrrolo[3,2-d] [pyrimidin-4-one) are, with one exception, potent inhibitors of purine nucleoside phosphorylase (PNP) equaling the corresponding 9-arylmethyl derivatives previously investigated. The mode of binding of these compounds to PNP was determined by X-ray crystallography.

Structure-based design of inhibitors of purine nucleoside phosphorylase. 1. 9-(arylmethyl) derivatives of 9-deazaguanine.

Purine nucleoside phosphorylase (PNP, EC 2.4.2.1) is a salvage enzyme important to the T-cell-mediated part of the immune system and as such is an important therapeutic target. This paper describes the design, synthesis, and enzymatic evaluation of potent, competitive inhibitors of PNP. Potential inhibitors were designed using the three-dimensional structure of the enzyme in an iterative process that involved interactive computer graphics to model the native enzyme and complexes of it with the inhibitors, Monte Carlo-based conformational searching, and energy minimization. Studies of the enzyme/inhibitor complexes were used to determine priorities of the synthetic efforts. The resulting compounds were then evaluated by determination of their IC50 values and by X-ray diffraction analysis using difference Fourier maps. In this manner, we have developed a series of 9-(arylmethyl)-9-deazapurines (2-amino-7-(arylmethyl)-4H-pyrrolo[3,2-d]-pyrimidin-4-ones) that are potent, membrane-permeable inhibitors of the enzyme. The IC50 values of these compounds range from 17 to 270 nM (in 1 mM phosphate), with 9-(3,4-dichlorobenzyl)-9-deazaguanine being the most potent inhibitor. X-ray analysis explained the role of the aryl groups and revealed the rearrangement of hydrogen bonds in the binding of the 9-deazaguanines in the active site of PNP relative to the binding of the 8-aminoguanines that results in more potent inhibition of the enzyme.

Intratumor heterogeneity of biomarker expression in breast carcinomas.

Small biopsy samples are used increasingly to assess the biomarker expression for prognostic information and for monitoring therapeutic responses prior to and during neoadjuvant therapy. The issue of intratumor heterogeneity of expression of biomarkers, however, has raised questions about the validity of the assessment of biomarker expression based on limited tissue samples. We examined immunohistochemically the expression of HER-2neu (p185erbB-2), epidermal growth factor receptor (EGFR), Bcl-2, p53, and proliferating cell nuclear antigen (PCNA) in 30 breast carcinomas using archived, paraffin embedded tissue and determined the extent of intratumor heterogeneity. Each section was divided into four randomly oriented discrete regions, each containing a portion of the infiltrating carcinoma. For each tumor, the entire lesion and four regions were analyzed for the expression of these markers. Scores of both membrane and cytoplasmic staining of HER-2neu and EGFR, scores of cytoplasmic staining of Bcl-2, and scores of nuclear staining of both p53 and PCNA were recorded. The intensity of staining and the proportion of immunostained cells were determined. A semiquantitative immunoscore was calculated by determining the sum of the products of the intensity and corresponding proportion of stained tumor cells. We analyzed both invasive (IDC) and in situ (DCIS) carcinomas. The Wilcoxon signed-rank test was used for paired comparisons between overall and regional immunoscores and between overall and regional percentages of stained cells. Spearman's correlation coefficients were used to assess the level of agreement of overall biomarker expression with each of the regions. Generalized linear models were used to assess overall and pair-wise differences in the absolute values of percent changes between overall and regional expression of biomarkers. For IDCs, there were no statistically significant differences in the expression of the biomarkers in terms of either the percentage of cells staining or the immunoscores when comparing the entire tumor with each region except for the lower EGFR expression of arbitrarily selected region 1 and lower p53 expression of region 1 compared to that of the entire tumor section. For DCIS, there were no statistically significant differences in the expression of the biomarkers between the entire tumor and each region except in PCNA of region 2 compared to that of entire tumor section. Positive correlation of immunoscores was observed between the entire tumor and each region as well as across all four regions for IDC. Similar observations were noted with DCIS except for HER-2neu and PCNA. No statistically significant differences were observed in the absolute values of percent changes of biomarker expression between overall and the four regions for both DCIS and IDC. Therefore, no significant intratumor heterogeneity in the expression of HER-2neu, Bcl-2, and PCNA was observed in IDC. Minor regional variations were observed for EGFR and p53 in IDC. Similarly, no significant regional variation in the expression of markers was observed in DCIS except for PCNA.

An expert support system for breast cancer diagnosis using color wavelet features.

Breast cancer diagnosis can be done through the pathologic assessments of breast tissue samples such as core needle biopsy technique. The result of analysis on this sample by pathologist is crucial for breast cancer patient. In this paper, nucleus of tissue samples are investigated after decomposition by means of the Log-Gabor wavelet on HSV color domain and an algorithm is developed to compute the color wavelet features. These features are used for breast cancer diagnosis using Support Vector Machine (SVM) classifier algorithm. The ability of properly trained SVM is to correctly classify patterns and make them particularly suitable for use in an expert system that aids in the diagnosis of cancer tissue samples. The results are compared with other multivariate classifiers such as Naïves Bayes classifier and Artificial Neural Network. The overall accuracy of the proposed method using SVM classifier will be further useful for automation in cancer diagnosis.

Synthesis of two diastereoisomeric p-nitrophenyl phosphodiesters of 2',3'-secouridine and their affinity for phosphodiesterases.

The synthesis of the p-nitrophenyl esters of the 5'- and 3'-phosphates of the nucleoside analogue 2',3'-secouridine are described. Unlike the corresponding diesters of thymidine, these two compounds are diastereoisomers. Their affinity for phosphodiesterases types I and II were investigated. Both analogues were hydrolysed very slowly by snake venom phosphodiesterase but their affinity for the enzyme was similar to that of the p-nitrophenyl ester of thymidine 5'-monophosphate of which they were both competitive inhibitors with Ki approximately Km. Neither compound was hydrolysed by spleen phosphodiesterase but both competitively inhibited the p-nitrophenyl ester of thymidine 3'-monophosphate, with Ki's slightly higher than the Km. Although for each enzyme the Ki of the correct analogue phosphodiester (i.e. the 5'-derivative for snake venom and the 3'-derivative for spleen) was the lower, the absolute specificity seen for the normal substrates had been lost.

Prevalence and intensity of infections of Ascaris lumbricoides and Trichuris trichiura and associated socio-demographic variables in four rural Honduran communities.

Between January and March 1998, a cross-sectional survey was carried out in four rural communities in Honduras, Central America. We examined the prevalence and intensity of Ascaris lumbricoides and Trichuris trichiura infections among 240 fecal specimens, and the association between selected socio-demographic variables and infection for 62 households. The overall prevalence of A. lumbricoides and T. trichiura was 45% (95% CI 39.0-51.9) and 38% (95% CI 31.8-44.4) respectively. The most intense infections for Ascaris and Trichuris were found in children aged 2-12 years old. By univariate analysis variables associated with infections of A. lumbricoides were: number of children 2-5 years old (p=0.001), level of formal education of respondents (p=0.01), reported site of defecation of children in households (p=0.02), households with children who had a recent history of diarrhea (p=0.002), and the location of households (p=0.03). Variables associated with both A. lumbricoides and T. trichiura infection included: number of children 6-14 years old (p=0.01, p=0.04, respectively), ownership of a latrine (p=0.04, p=0.03, respectively) and coinfection with either helminth (p=0.001, p=0.001, respectively). By multivariate analysis the number of children 2-5 years living in the household, (p=0.01, odds ratio (OR)=22.2), children with a recent history of diarrhea (p=0.0, OR=39.8), and infection of household members with T. trichiura (p=0.02, OR=16.0) were associated with A. lumbricoides infection. The number of children 6-14 years old in the household was associated with both A. lumbricoides and T. trichiura infection (p=0.04, p=0.01, OR=19.2, OR=5.2, respectively).

Cost analysis of computer-aided endoscopic sinus surgery.

Functional endoscopic sinus surgery' (FESS) is a common otolaryngologic procedure, with over 250,000 operations performed annually. Computerized surgical navigation systems are available to assist the rhinologic surgeon in the complex dissection required for FESS. Our objective was to determine whether this system provided quantifiable benefits in FESS. We retrospectively reviewed 203 patients with chronic sinusitis who underwent endoscopic sinus surgery, and divided them into two groups based on whether or not computerized surgical navigation was used. There was no statistically significant difference between the two groups in terms of surgery duration, extent of surgery, percent of complementary procedures, percent of supplementary procedures, complexity of surgery, and percent revision surgery. Computer-assisted surgery (CAS) was 6.7% more expensive than sinus surgery without computerized surgical navigation (p = 0.01). However, the intangible benefits of CAS may outweigh the added expense. (American

Molecular interaction of nonsteroidal compounds with uterine progesterone receptor (Part I).

Progesterone-receptor binding affinity of some nonsteroidal molecules was assessed by competitive protein binding assay in rabbit as well as human uterine cytosol in vitro. Of 40 compounds belonging to 5 different series tested, 3-(p-anisoyl)-2-chloro-6, 7-dimethoxy-quinoline exhibited around 50% inhibition whereas 2-(p-anisoyl) naphthalene and 3-substituted phenyl-1-(3-(2-chloro-6, 7-dialkoxy) quinolinyl)prop-2-en-1-one showed around 20% inhibition in 3H-progesterone binding for rabbit and human uterine progesterone receptor.

Purine nucleoside phosphorylase inhibitors: biochemical and pharmacological studies with 9-benzyl-9-deazaguanine and related compounds.

Certain derivatives of 9-deazaguanine that contain arylmethyl, heteroarylmethyl or cycloalkylmethyl groups at the 9-position are potent inhibitors of purine nucleoside phosphorylase (PNP, E.C. 2.4.2.1). To determine whether these agents can produce metabolically significant inhibition of PNP in cells and in animals, the authors performed pharmacological studies with a representative member of the series, 9-benzyl-9-deazaguanine (BzDAG). BzDAG was a potent inhibitor of PNP from calf spleen (Ki = 12 nM). It was also an effective inhibitor of PNP in cells and in animals as shown by the findings that it 1) inhibited the conversion of inosine to nucleotides in L1210 cells in culture at concentrations that had little effect on the utilization of hypoxanthine; 2) potentiated the toxicity of deoxyguanosine to CCRF-CEM cells in culture; 3) increased the pools of deoxy GTP in CCRF-CEM, Molt-3 and Molt-4 cells that had been treated with deoxyguanosine; 4) prevented the toxicity of 6-thioguanosine to HEp-2 cells in culture; 5) increased the plasma levels of endogenous inosine in rats; and 6) increased the plasma levels of 2',3'-dideoxyinosine in rats that had received BzDAG and dideoxyinosine in combination. Pharmacokinetic analysis of BzDAG in the rat showed it to be 48% orally bioavailable (at a dose of 5 mg/kg). About 95% of BzDAG was protein bound. After i.v. administration of BzDAG (5 mg/kg), more than 50% of the erythrocyte PNP was inhibited for 40 min. These results indicate that the 9-substituted-9-deazaguanines are potent orally active PNP inhibitors and are therefore of potential clinical interest as immunosuppressive and anti-inflammatory agents.

The Arthus reaction in rodents: species-specific requirement of complement.

We induced reverse passive Arthus (RPA) reactions in the skin of rodents and found that the contribution of complement to immune complex-mediated inflammation is species specific. Complement was found to be necessary in rats and guinea pigs but not in C57BL/6J mice. In rats, within 4 h after initiation of an RPA reaction, serum alternative pathway hemolytic titers decreased significantly below basal levels, whereas classical pathway titers were unchanged. Thus the dermal reaction proceeds coincident with systemic activation of complement. The serine protease inhibitor BCX 1470, which blocks the esterolytic and hemolytic activities of the complement enzymes Cls and factor D in vitro, also blocked development of RPA-induced edema in the rat. These data support the proposal that complement-mediated processes are of major importance in the Arthus reaction in rats and guinea pigs, and suggest that BCX 1470 will be useful as an anti-inflammatory agent in diseases where complement activation is known to be detrimental.

Response to salvage treatment in recurrent ovarian cancer treated initially with paclitaxel and platinum-based combination regimens.

OBJECTIVE: The aim of this study was to evaluate the response to salvage treatment in recurrent ovarian cancer treated initially with paclitaxel-based chemotherapy. METHODS: A retrospective review of patients with recurrent ovarian cancer treated with surgical debulking and paclitaxel-based chemotherapy was performed. All cases received second-line treatment with a response evaluated by clinical or surgical means. Data analysis was conducted using the SAS statistical package. RESULTS: Fifty cases of advanced stage disease were available for review. Patients received paclitaxel and cisplatin or carboplatin with a 72.0% response rate. The median time to recurrence after primary treatment was 6 months. Second-line treatment included cisplatin or carboplatin (50%), Taxol (10%), or lutetium (22%), an intraperitoneal radiolabeled monoclonal antibody targeted to TAG-72. A 52.0% clinical response to salvage treatment was detected. With a median follow-up of 7 months, 68.0% of patients had experienced recurrence or progression of their disease. The median time to second recurrence was 5 months. Cases sensitive to initial paclitaxel-containing chemotherapy responded to any of the salvage treatments more frequently than chemotherapy-resistant tumors (88.5% versus 11.5%, P < 0.05). CONCLUSIONS: Recurrent ovarian cancer patients initially treated with paclitaxel-based chemotherapy frequently responded to salvage treatment. However, the duration of response was brief, and hospitalization for treatment-related side-effects was common. Tumor response to initial paclitaxel/platinum treatment was predictive of future response to second-line agents. Current salvage therapies appear to provide little benefit in cases of tumors resistant to primary chemotherapy.

Prevalence and intensity of infections of Ascaris lumbricoides and Trichuris trichiura and associated socio-demographic variables in four rural Honduran communities

Between January and March 1998, a cross-sectional survey was carried out in four rural communities in Honduras, Central America. We examined the prevalence and intensity of Ascaris lumbricoides and Trichuris trichiura infections among 240 fecal specimens, and the association between selected socio-demographic variables and infection for 62 households. The overall prevalence of A. lumbricoides and T. trichiura was 45 percent (95 percent CI 39.0-51.9) and 38 percent (95 percent CI 31.8-44.4) respectively. The most intense infections for Ascaris and Trichuris were found in children aged 2-12 years old. By univariate analysis variables associated with infections of A. lumbricoides were: number of children 2-5 years old (p=0.001), level of formal education of respondents (p=0.01), reported site of defecation of children in households (p=0.02), households with children who had a recent history of diarrhea (p=0.002), and the location of households (p=0.03). Variables associated with both A. lumbricoides and T. trichiura infection included: number of children 6-14 years old (p=0.01, p=0.04, respectively), ownership of a latrine (p=0.04, p=0.03, respectively) and coinfection with either helminth (p=0.001, p=0.001, respectively). By multivariate analysis the number of children 2-5 years living in the household, (p=0.01, odds ratio (OR)=22.2), children with a recent history of diarrhea (p=0.0, OR=39.8), and infection of household members with T. trichiura (p=0.02, OR=16.0) were associated with A. lumbricoides infection. The number of children 6-14 years old in the household was associated with both A. lumbricoides and T. trichiura infection (p=0.04, p=0.01, OR=19.2, OR=5.2, respectively)