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We evaluated the in vivo responses to chloroquine (CQ), the first line antimalarial, and to sulfadoxine-pyrimethamine (SP), the most readily available and affordable alternative treatment, in children under 5 with acute uncomplicated Plasmodium falciparum malaria in seven sites of Democratic Republic of Congo (DRC) between May 2000 and November 2001, using the standard 14-day WHO protocol. In the CQ group, the overall treatment failure rate was 45.4% (95% CI: 40.1-50.8) of 350 infections successfully tested; in the SP group it was 7.5% (95% CI: 5.0-11.0) of 333 infections. Of 191 patients who had an adequate clinical response (ACR) in the CQ group, 127 (66.5%; range: 62.5-71.4) still had parasitaemia on day 14. In the SP group, only 21 (6.8%; range: 2.2-12.8) of 308 patients with an ACR were still parasitaemic on day 14. Using pooled data from three rural sites, haematological recovery was better in the SP group (mean of haematocrit difference between days 14 and 0 among anaemic children: 4.7 vs. 3.2; P < 0.01, Wilcoxon test). These findings suggest that CQ is no longer effective in DRC and that SP may be a good alternative for its replacement as first line antimalarial treatment. The Ministry of Health (MOH) therefore now recommends SP as the first line antimalarial drug in DRC, as an interim step, 18 months after launching the first study. Additional studies are needed to select alternative therapies that might replace SP or improve its efficacy, should it prove ineffective in the future.

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The mode of transmission of Helicobacter pylori is unknown. Since viable bacteria have been shown to be excreted in feces from infected individuals and houseflies habitually develop and feed on excrement, we hypothesized that flies ingest and harbor H. pylori and, in turn, contaminate the human environment. This study examined the possible vector potential of houseflies (Musca domestica) for H. pylori. Caged houseflies were exposed to freshly grown H. pylori on agar plates. After a 6-h feeding period, the plates were removed and were replaced with sterile petri dishes containing a droplet of sterile brucella broth. At regular intervals, small numbers of houseflies were removed for microbiological and histological analysis, and the petri dishes were replaced with fresh sterile plates with fresh drops of brucella broth. The flies' bodies, the flies' dissected alimentary tracts, and excreta on the petri dishes were cultured for H. pylori, whose identity was confirmed by the urease, catalase, and oxidase reactions and Gram staining. In contrast to control flies, viable H. pylori could be isolated from external surfaces for up to 12 h and from gut and excreta for as long as 30 h after the initial feeding period. After 30 h other gram-negative bacteria overgrew the cultures of samples from all locations tested, rendering the selective culture of H. pylori colonies impossible. Histological analysis revealed Helicobacter-like organisms in the gut lumen and attached to intestinal epithelial cells. We conclude that houseflies can harbor viable H. pylori on their bodies and in their intestinal tracts. They are also able to disseminate viable H. pylori in excreta, and they may therefore present a significant reservoir and be a vector in the transmission of H. pylori.

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The feasibility of using most comfortable loudness (MCL) as a real-world measure of speech attenuation introduced by hearing protection devices (HPDs) was studied. The authors compared three insert HPDs and an earmuff under three test conditions: (a) monaural earphone listening, (b) binaural earphone listening, and (c) sound field listening. The earmuff was used only in the sound-field condition. In addition, three sets of fitting instructions were utilized. Twelve normal hearing subjects participated. Results indicate that MCL shift can be used as a simple measure of speech attenuation provided by HPDs. The observed MCL shifts were affected by the fitting instruction but not by the listening condition. Findings support the notion that MCL-based tests of speech attenuation by HPDs can be conducted reliably both in sound field and under earphones and may be a simple and valid tool for assessing changes in speech audibility due to the wearing of HPDs.

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The human glutathione transferases (GSTs) are a multigene family of detoxication enzymes with patterns of expression that are both tissue specific and genetically determined. Changes in the levels of one or more GST isoenzymes have been associated with the development of anticancer drug resistance in cultured cell lines. In this study, total GST activity and GST isoenzyme composition have been determined for 45 primary human breast carcinomas using a 1-chloro-2,4-dinitrobenzene substrate assay and Western blotting, respectively. The GST activity ranged from 5-208 mU/mg protein with a mean of 67 mU/mg protein (+/- 44 SD). GST-pi) isoenzyme protein was detectable on Western blots in 44 of 45 samples. Mu Class GST protein was detected in 18 of 38 samples and undetectable in 20 of the 38 samples tested. By polymerase chain reaction analysis of genomic DNA, the absence of mu class GST in breast tumors was determined to be due to the deletion of the gene for GST-mu in the DNA of those tumors. None of the 43 primary human breast cancer samples tested contained detectable alpha class GST protein. Neither the total GST activity of tumor samples, the quantity of GST-pi protein, nor the presence or absence of mu class GST correlated with other factors known to be of prognostic significance including tumor size, nodal status, estrogen receptor protein positivity, or progesterone receptor protein positivity. Substantial differences exist among primary breast carcinomas in both the amount of GST activity and GST isoenzyme composition. However, these are not tightly linked either to tumor stage or to hormone receptor status. Whether the levels of these enzymes are independent predictors of either risk of recurrence or response to anticancer therapy has yet to be tested directly.

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This study evaluates the effects of potential risk factors for benign breast disease (BBD) with special attention to the histologic and mammographic specificity of the effects. Cases were 172 women with BBD that underwent biopsy; controls were 134 women free of breast signs or symptoms. All cases and controls had undergone mammography. For all types of BBD combined, parity, use of oral contraceptives, and use of exogenous estrogen after menopause were strongly protective, whereas obesity and early menarche were weakly protective. Family history of breast cancer was virtually unrelated to BBD. The protective effect of parity was stronger for BBD with intralobular or extralobular fibrosis, and with mammographic homogeneous density or large nodular densities, than it was for BBD without these characteristics. Similar relations with the histologic and mammographic features were observed for obesity. These findings suggest that some risk factors for BBD have effects that are related to specific features of its morphology.

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The 193 nm argon fluoride excimer laser was used to ablate a 6 mm diameter area of the central rabbit cornea under various conditions of power, beam configuration and exposure time. High repetition rates or prolonged exposures produced charring and prevented rapid epithelial wound closure. Endothelial vacuolization, reduction in density, and displacement of cell material into Descemet's layer resulted in these experiments. A beam of low and uniform power intensity (40 pulses per second, 100 seconds at 23 mJ/cm2) reduced stromal damage, cellular infiltration, and epithelial irregularities including punctate staining and cell exfoliation. Epithelial rehealing occurred within two days. Basal lamina and hemidesmosomes were reformed by one week. Endothelial damage was not detected. Excimer laser ablation may allow removal of superficial dystrophies or scars, followed by rapid healing from normal corneal reparative processes.

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Prosthetic posterior chamber intraocular lenses can abrade the iris pigmented epithelium, resulting in pigment dispersion, callus formation, and iris adhesions. To evaluate iris abrasion from intraocular lens materials, we developed an in vitro test and studied three materials: polymethylmethacrylate (PMMA), silicone, and PMMA surface-modified by covalent binding of a hydrophilic polymer (surface-modified PMMA). Each lens was rubbed 1,000 times on the posterior iris of pigmented rabbits using a total force of 0.5 gram. Scanning electron micrographs of the abraded irides were scored using a subjective, nonparametric numerical scale. Polymethyl-methacrylate lenses removed iris epithelium completely, exposing underlying connective tissue. Silicone lenses damaged an area longer and narrower than the PMMA lens and also exposed connective tissue. Surface-modified PMMA lenses caused only slight surface damage, including flattening or breaking of protruding suspensory ligaments. The test conditions used cannot precisely mimic prolonged lens implantation in living subjects. Nevertheless, the results indicate that iris-lens interaction may be reduced in vivo by using a surface-modified PMMA lens. This hypothesis should be further verified by animal implantation studies.

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A monoclonal antibody that recognizes the carboxyl terminus of substance P was used to localize tachykinin-like immunoreactivity in neurons of area 17 of the adult monkey cerebral cortex. Tachykinin immunostaining was examined in normal monkeys, in monkeys receiving monocular injections of the sodium channel blocker TTX for 10 or 15 d, and in monkeys from which the crystalline lens of one eye had been removed 3 or 6 months prior to death. The immunocytochemical staining in each monkey was compared with the histochemical staining for the mitochondrial enzyme cytochrome oxidase (CO). These forms of monocular deprivation produce the most profound changes in the staining of layers II-III and IVC. In layers II-III of normal monkeys, tachykinin-immunoreactive somata are uniformly distributed by immunostained puncta are densely packed in rows of patches that correspond to the rows of CO-stained patches. Following monocular TTX injections, both the patches of CO staining in the deprived-eye columns and the corresponding patches of intense tachykinin immunostaining shrink. Quantitative analyses indicate the numerical density of immunostained somata is reduced by 50% within the deprived-eye rows of patches and is also reduced within regions surrounding the patches in both sets of ocular dominance columns. Following the removal of the lens from one eye, the CO-stained patches and the immunostained patches in one set of rows shrink and the density of immunostained somata in these rows is reduced by 60%. In the alternating rows, the CO staining between patches increases so that many of the patches fuse to form long, continuous bands. Patches of immunostained puncta also enlarge and fuse; the density of immunostained somata in these rows of enlarged patches is approximately 30% greater than normal. In layer IVC of normal monkeys, the CO staining and the tachykinin immunostaining are relatively uniform. Following monocular TTX injections the CO staining and the tachykinin immunostaining are greatly reduced in columns dominated by the injected eye, corresponding to an 80% reduction in the numerical density of immunoreactive somata. By contrast, the CO staining in layer IVC of aphakic monkeys is changed only slightly from normal and the tachykinin immunostaining appears normal. The changes in the density of immunostained somata in both layers II-III and in IVC occur even through the total density of thionin-stained neurons remains normal.(ABSTRACT TRUNCATED AT 400 WORDS)

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Fibronectin is an extracellular structural protein with the unique ability to bind to both cells and collagen. It plays a major role in the development of the cornea. The universal appearance of fibronectin within 8 hours of corneal wounding has promoted major interest in its wound healing properties. The early clinical evidence for fibronectin treatment of recurrent corneal erosion and certain forms of keratitis sicca is strong. The current major problem preventing commercial use is the antigenic nature of fibronectin derived from separate species. Human pooled fibronectin has been suggested as a commercial source of this ubiquitously occurring protein.

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Mammograms and histologic slides of a group of 320 women who had breast symptoms and a biopsy without cancer being found were reviewed. The mammographic features assessed were the parenchymal pattern and extent of nodular and homogeneous densities. In addition to the pathologic diagnosis, the histologic features assessed included epithelial hyperplasia and atypia, intralobular fibrosis, and extralobular fibrosis. Among premenopausal women, those with marked intralobular fibrosis were more likely to have large (3+ mm) nodular densities on the mammogram. Among postmenopausal women, epithelial hyperplasia or atypia was related to having nodular densities in at least 40% of the breast volume. In both groups, marked extralobular fibrosis was related to the presence of homogeneous density on the mammogram. We conclude that mammographic nodular densities may be an expression of lobular characteristics, whereas homogeneous density may reflect extralobular connective tissue changes.

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Polyvinylpyrrolidone-iodine (PVP-I) is a biocompatible broad spectrum antimicrobial that is widely used as an ophthalmic pre-operative prepping agent. In order to determine if PVP-I is safe for treating corneal ulcers and conjunctivitis, we evaluated the ocular toxicity of frequent dosing in a rabbit model. We evaluated ocular irritation in 18 rabbits according to the McDonald-Shadduck method. Concentrations of 0.5% PVP-I or less were practically non-irritating when administered six times per day. We evaluated corneal epithelial wound healing in 16 rabbits with standardized abrasions. Concentrations of 0.33% PVP-I showed epithelial healing comparable to gentamicin treated eyes and untreated controls. Concentrations of 0.5% PVP-I delayed epithelial healing by one day. Because of its broad spectrum and apparently low toxicity, PVP-I may be a useful treatment for corneal ulcers, keratitis and conjunctivitis.

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Two monoclonal antikeratin antibodies, AE1 and AE3, were used in indirect immunocytochemistry to examine keratin expression in normal, benign proliferative, and malignant human breast epithelium. Both antibodies reacted strongly with most luminal cells in ducts and acini of normal gland. While AE1 did not stain myoepithelium, AE3 recognized myoepithelial cells of ducts but not acini, implying a cytoskeletal difference between the myoepithelium of these two components. Moreover, the antibodies reacted differently with the myoepithelium of intracanalicular as compared with pericanalicular types of fibroadenomas. Tumour cells of infiltrating ductal carcinomas with a prominent intraductal component stained more homogeneously with AE1 and AE3 than those without intraductal growth. The results provide evidence for two phenotypes of myoepithelial cells and for the presence of cryptic keratin epitopes in human breast epithelial cells. The finding that neither AE1 nor AE3 is a universal detector of these cells has important clinical and experimental implications.

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Corneal wound healing and the many factors which may promote or prevent it are of concern to both clinicians and researchers. Ophthalmologists are often confronted with corneal dystrophies and problematic injuries resulting in persistent and recurrent epithelial erosion and with permanent endothelial loss. Scientists have long noted that corneal epithelial and endothelial cell layers are among the most simple and accessible for experimental manipulation and non-invasive study in both animal and human models. Healing epithelium provides a classical model of cell locomotion over a surface, while endothelial cell viability and function is of fundamental importance to maintenance of corneal clarity and vision during the aging process as well as after disease, surgery, or laser treatment. Growth factors can now be produced homogeneously by genetic engineering, increasing the potential of commercial development for purposes such as corneal wound healing. This article reviews some known properties of growth factors whose effects have been at least partially characterized in corneal tissues.

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Lenticular autofluorescence in a diabetic population was quantitated by scanning ocular fluorophotometry. Measurements were made through the lens along the optical axis. The profile of the scan from front to rear was characterized by anterior and posterior juxtacortical peaks and a central plateau. Maximum fluorescence values were compared with those of nondiabetic control subjects. Fluorescence increased linearly with age in both populations, but was significantly higher in the diabetic population of all ages. Posterior to anterior fluorescence peak ratios decreased as a parabolic function of age in both populations, but peak ratios were lower in the diabetic population. We conclude that in vivo measurements of lens autofluorescence correlate with premature lenticular senescence in diabetes.

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We quantitated blue-green light transmission and autofluorescence of the human crystalline lens in vivo, using an automated scanning fluorophotometer (Fluorotron) coupled with a lens system designed for high resolution of the ocular anterior segment. Lenses were scanned through the dilated pupil along the optical axis, generating a fluorescence profile consisting of anterior and posterior juxtacortical peaks and a central plateau. Fluorescence increased linearly with increasing age. We calculated percent transmission of excitation (410-500 nm) and emission (510-670 nm) as the ratio of posterior to anterior juxtacortical peaks. Light transmission decreased as a parabolic function of age and was correlated with both fluorescence increase and observed lens brunescence.

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This article reviews the objectives which must be considered in producing optimal formulations for topical ophthalmic use. The effects of preservatives, vehicles, and adjunct agents are described. Anatomical considerations which impact bioavailability of the drug at the desired target site are discussed in detail. Model systems that can aid in determining the best formulations for preclinical and clinical testing are also reviewed. The long term objective of this review is the development of formulations for optimal efficacy and safety, considering all the requirements of the patient.

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Bactericidal levels of gentamicin were obtained in vitreous humor by iontophoresis of antibiotic directly through the sclera. A silicone rubber tube of small diameter filled with gentamicin sulfate formed the electrode. A two milliampere current applied for three minutes to each of four perilimbal sites introduced gentamicin sufficient to maintain therapeutic levels for more than 24 hours. The proportion of drug reaching vitreous versus aqueous humor was dependent on electrode position relative to retina and pars plana. An endogenous antibacterial agent was apparently released during iontophoretic stimulation and interfered with the bacterial growth inhibition assay. Ketoconazole, a water-insoluble antifungal agent, has also been introduced successfully into vitreous humor by anodal iontophoresis after protonation in weak acid.

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