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The objective of this study was to identify sources and linkages among methicillin-resistant Staphylococcus aureus infections using whole-genome sequencing (WGS).A total of 56 samples were obtained from all patients with a confirmed MRSA infection over 6 months at University of Florida-Health Jacksonville. Samples were cultured and sequenced; data was analyzed on an automated cloud-based platform. Genetic Clusters were defined as40 single nucleotide polymorphisms. Temporal Clusters were defined as ≥5 MRSA cases over 3 days.We found 7 Genetic Clusters comprising 15 samples. Four Genetic Clusters contained patients with non-overlapping stays (3-10 weeks apart), 3 of which contained patients who shared the same Unit. We also found 5 Temporal Clusters comprising 23 samples, although none of the samples were genetically related.Results showed that temporal clustering may be a poor indicator of genetic linkage. Shared epidemiological characteristics between patients in Genetic Clusters may point toward previously unidentified hospital sources. Repeated observation of related strains is also consistent with ongoing MRSA transmission within the surrounding high-risk community.WGS is a valuable tool for hospital infection prevention and control.

The Rakai Community Cohort Study in south central Uganda has surveyed people aged 15–49 since 1994. Antiretroviral therapy (ART) was introduced in 2004. HIV p24 and gp41 subtype distribution and viral diversity were studied from blood samples collected at three surveys in 1994–1995, 2002–2003, and 2008–2009, which were compared with a new survey round from 2011 to 2012. These included 1364 HIV+ individuals. For both p24 and gp41 domains, the genetic diversity within subtypes A and D was significantly increasing in the pre-ART era and decreased between the last two survey rounds in the ART era (p

Objective:To determine the prevalence of low scores for two neuropsychological tests with five total scores that evaluate learning and memory functions.Method:N = 5402 healthy adults from 11 countries in Latin America and the commonwealth of Puerto Rico were administered the Rey–Osterrieth Complex Figure (ROCF) and the Hopkins Verbal Learning Test (HVLT-R). Two-thirds of the participants were women, and the average age was 53.5 ± 20.0 years. Z-scores were calculated for ROCF Copy and Memory scores and HVLT-R Total Recall, Delayed Recall, and Recognition scores, adjusting for age, age2, sex, education, and interaction variables if significant for the given country. Each Z-score was converted to a percentile for each of the five subtest scores. Each participant was categorized based on his/her number of low scoring tests in specific percentile cutoff groups (25th, 16th, 10th, 5th, and 2nd).Results:Between 57.3% (El Salvador) and 64.6% (Bolivia) of the sample scored below the 25th percentile on at least one of the five scores. Between 27.1% (El Salvador) and 33.9% (Puerto Rico) scored below the 10th percentile on at least one of the five subtests. Between 5.9% (Chile, El Salvador, Peru) and 10.3% (Argentina) scored below the 2nd percentile on at least one of the five scores.Conclusions:Results are consistent with other studies that found that low scores are common when multiple neuropsychological outcomes are evaluated in healthy individuals. Clinicians should consider the higher probability of low scores when evaluating learning and memory using various sets of scores to reduce false-positive diagnoses of cognitive deficits.

To determine if there is a relationship among isometric hip strength, hip kinematics, and peak gluteal muscle forces in cross-country runners during running.Cross Sectional.University Biomechanics Laboratory.Forty-six NCAA Division III collegiate cross-country runners (18 males, 28 females).Pearson correlation coefficients were used to describe relationships among isometric hip strength, hip kinematics, and peak gluteal muscle forces during the stance phase of running. Strength of correlations were interpreted as little to no relationship (r 0.25), fair relationship (0.25 ≤ r 0.5), moderate relationship (0.5 ≤ r 0.75), and strong relationship (r ≥ 0.75). Correlations were considered significant if p 0.05.Little to no relationships were found among isometric hip strength and gluteal muscle forces during running (r 0.25). A fair relationship was present between prone external rotation isometric hip strength and peak hip adduction (0.25r 0.5). Little to no relationship was shown between gluteus medius force and hip internal rotation. Moderate relationships were present among peak gluteus medius and minimus muscle forces and peak hip adduction (0.5r 0.75).Isometric hip strength does not appear to be related to gluteal muscle forces and hip kinematics during the stance phase of running while gluteal muscle force was moderately related to hip adduction. Factors other than strength may be related to muscle force production and hip kinematics during running.

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare disease associated with congenital or acquired genetic abnormalities that result in uncontrolled complement activation, leading to thrombotic microangiopathy and kidney failure. Until recently, the only treatment was plasma exchange or plasma infusion (PE/PI), but 60% of patients died or had permanent kidney damage despite treatment. Eculizumab, a complement inhibitor, has shown promising results in aHUS. However, data are mainly extracted from case reports or studies of heterogeneous cohorts, and no direct comparison with PE/PI is available. Methods: An observational retrospective study of adult, dialysis-dependent aHUS patients with acute kidney injury (AKI) who were treated with either PE/PI alone or with second-line eculizumab in our center. We compared the effect of PE/PI and eculizumab on kidney function, hypertension, proteinuria, hematologic values, relapse, and death. Results: Thirty-one patients were included (females, 18; sporadic aHUS, 29; mean age, 46 ± 20 years). Twenty-six patients were treated with PE/PI alone, and 5 were deemed to be plasma-resistant and received eculizumab after stopping PE/PI. Among patients receiving eculizumab, 80% attained complete recovery of kidney function, 100% stopped dialysis, 20% had decreased proteinuria, and no patient relapsed (vs. 38.5, 50, 15.4, and 11.5%, respectively, of patients receiving only PE/PI). At 1-year of follow-up, no deaths had occurred in either group. Conclusion: Eculizumab shows greater efficacy than PE/PI alone for the treatment of adult aHUS patients with AKI. Prospective studies and meta-analyses are warranted to confirm our findings and set guidelines for treatment, monitoring, and maintenance.

Background:First metatarsal protrusion distance (MPD) has been commonly studied as a characteristic of hallux valgus deformity. To date, the majority of investigations have used radiographic methods, with most reporting first metatarsal (ray) protrusion to be associated with deformity. As an alternative, this study used a three-dimensional (3-D) image acquisition and data analysis method to quantify MPD.Methods:Magnetic resonance images were acquired in weightbearing on 29 women (19 with hallux valgus; 10 controls). After the 3-D images were reconstructed into virtual bone models, two examiners measured MPD in relation to the navicular. In addition to a reliability analysis, a t test assessed for group differences in demographics, foot posture (hallux valgus, intermetatarsal angles), and MPD.Results:Group demographics were not different, while measures of hallux valgus and intermetatarsal angles were different (P < 0.01) between groups. The measurement of MPD was highly reliable (ICC 0.99; SEM 0.78 mm). Metatarsal protrusion averaged approximately –2.0 mm in both groups. There was no statistical group difference (P = 0.89) in MPD.Conclusions:The reconstructed image datasets captured the 3-D spatial relationship of the anatomy. Measurements of MPD were reliable. The first ray measured 2 mm shorter than the second ray in both the hallux valgus and control groups. Though unexpected, this result may prompt future study of the pathokinematics associated with hallux valgus that include the quantification of metatarsal protrusion with 3-D methods, instead of relying solely on single-plane radiograph reports.

Objective To generate normative data for the Rey-Osterrieth Complex Figure (ROCF) in Spanish-speaking pediatric populations. Method The sample consisted of 4,373 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the ROCF as part of a larger neuropsychological battery. The ROCF copy and immediate recall (3 minutes) scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. Results The final multiple linear regression models showed main effect for age on copy and immediate recall scores, such that scores increased linearly as a function of age. Age2 affected ROCF copy score for all countries, except Puerto Rico; and ROCF immediate recall scores for all countries, except Chile, Guatemala, Honduras, Paraguay, and Puerto Rico. Models indicated that children whose parent(s) had a MLPE >12 years obtained higher scores compared to children whose parent(s) had a MLPE≤12 years for Chile, Puerto Rico, and Spain in the ROCF copy, and Paraguay and Spain for the ROCF immediate recall. Sex affected ROCF copy and immediate recall score for Chile and Puerto Rico with girls scoring higher than boys. Conclusions This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate approach to interpret the ROCF Test in pediatric populations.

OBJECTIVE: To generate normative data for the Trail Making Test (TMT) in Spanish-speaking pediatric populations. METHOD: The sample consisted of 3,337 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the TMT as part of a larger neuropsychological battery. The TMT-A and TMT-B scores were normed using multiple linear regressions and standard deviations of residual values. Age, age 2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. RESULTS: The final multiple linear regression models showed main effects for age on both scores, such that as children needed less time to complete the test while they become older. TMT-A scores were affected by age 2 for all countries except, Cuba, Guatemala, and Puerto. TMT-B scores were affected by age 2 for all countries except, Guatemala and Puerto Rico. Models indicated that children whose parent(s) had a MLPE >12 years of education needed less time to complete the test compared to children whose parent(s) had a MLPE ≤12 years for Mexico and Paraguay in TMT-A scores; and Ecuador, Mexico, Paraguay, and Spain for TMT-B scores. Sex affected TMT-A scores for Chile, Cuba, Mexico, and Peru, in that boys needed less time to complete the test than girls. Sex did not affect TMT-B scores. CONCLUSIONS: This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate approach to interpret the TMT in pediatric populations. © 2017 - IOS Press and the authors. All rights reserved.

Objective To generate normative data for the verbal fluency tests (VFT-letter M, fruits, and occupations categories) in Spanish-speaking adult populations, with country-specific adjustments for age, education, and sex when appropriate. Method The sample consisted of 3,977 healthy adults from 11 countries in Latin America (Argentina, Bolivia, Chile, Cuba, El Salvador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico; sample size per country ranged between n = 184 and n = 1,300). Each participant was administered the VFT as part of a larger neuropsychological battery. Scores for letter M, fruits, and occupations categories were normed using multiple linear regressions. The country-specific regression models included age, age2, education, education2, and sex as predictors. Results The final multiple linear regression models showed that age affected the performance on these tests but not uniformly. For example, M letter scores decrease linearly with age except for Argentina, Guatemala, and Mexico, in which quadratic age effect was found. Scores also increase linearly as a function of education but not in all countries. For example, a quadratic education effect was found for the fruits category in Bolivia, Honduras, and Paraguay. Sex had a significant impact on the M letter category fluency in Guatemala, fruits category in Guatemala and Peru, and occupations' category in Mexico. Conclusions This study presents verbal fluency test normative data across 11 countries in Latin America. These norms are expected to be useful for neuropsychologists of these countries. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Hepatitis-C Virus (HCV) sequences are often used to establish networks of people who inject drugs (PWID). However, the degree to which within-host evolutionary dynamics affect those inferences has not been carefully studied. Here, we analyzed 702 longitudinally-sampled HCV E1 sequences from 88 HCV+ people who inject drugs (PWID) in the Baltimore Before and After Acute Study of Hepatitis (BBAASH) cohort. Individuals were tested for HCV RNA over multiple visits to the clinic, and the HCV E1 gene was sequenced for HCV+ samples. Genetic clustering was performed on the full set of sequences using a 3% genetic distance threshold to define epidemiological linkage. Maximum-likelihood (ML) phylogenies were inferred to assess evolutionary relationships. We found 22 clusters containing sequences sampled over five or more years (long-term clusters, LTC), of which 17 had >1 subject. In six of the multi-subject LTC, one subject had a sequence sampled >3 years earlier or later than the next-closest subject in the cluster (time-gap LTC). ML trees showed that, in three of the time-gap LTC, two subjects had identical sequences despite 7–10 years separating the sampling times. In four of the time-gap LTC for whom additional data were available, the subject with the later detected shared variant had both different variants and visits with no detectable HCV RNA (RNA-) prior to the appearance of the shared variant. In the subject with the earlier detection of the shared variant, different variants and RNA- visits were also detected in multiple cases subsequent to appearance of the shared variant. Complex patterns of shared viral variation among PWID reflect on-going re-infection, multiple transmission partners, and/or inconsistent detection of viral variants. Our results suggest that transmission events are currently underestimated by analysis of sequences at a single point in time.

HIV-1 Nef is a flexible, multifunctional protein with several cellular targets that is required for pathogenicity of the virus. This protein maintains a high degree of genetic variation among intra- and inter-host isolates. HIV Nef is relevant to HIV-associated neurological diseases (HAND) in patients treated with combined anti-retroviral therapy because of the protein’s role in promoting survival and migration of infected brain macrophages. In this study, we analyzed 2,020 HIV Nef sequences derived from 22 different tissues and 31 subjects using a novel computational approach. This approach combines statistical regression and evolved neural networks (ENNs) to classify brain sequences based on the physical and chemical characteristics of functional Nef domains. Based on training, testing, and validation data, the method successfully classified brain Nef sequences at 84.5% and provided informative features for further examination. These included physicochemical features associated with the Src-homology-3 binding domain, the Nef loop (including the AP-2 Binding region), and a cytokine binding domain. Non-brain sequences from patients with HIV-associated neurological disease were frequently classified as brain, suggesting that the approach could indicate neurological-risk using blood-derived virus or for the development of biomarkers for use in assay systems aimed at drug efficacy studies for the treatment of HIV-associated neurological diseases.

Objective To generate normative data for the Stroop Word-Color Interference test in Spanish-speaking pediatric populations. Method The sample consisted of 4,373 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the Stroop Word-Color Interference test as part of a larger neuropsychological battery. The Stroop Word, Stroop Color, Stroop Word-Color, and Stroop Interference scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. Results The final multiple linear regression models showed main effects for age on all scores, except on Stroop Interference for Guatemala, such that scores increased linearly as a function of age. Age2 affected Stroop Word scores for all countries, Stroop Color scores for Ecuador, Mexico, Peru, and Spain; Stroop Word-Color scores for Ecuador, Mexico, and Paraguay; and Stroop Interference scores for Cuba, Guatemala, and Spain. MLPE affected Stroop Word scores for Chile, Mexico, and Puerto Rico; Stroop Color scores for Mexico, Puerto Rico, and Spain; Stroop Word-Color scores for Ecuador, Guatemala, Mexico, Puerto Rico and Spain; and Stroop-Interference scores for Ecuador, Mexico, and Spain. Sex affected Stroop Word scores for Spain, Stroop Color scores for Mexico, and Stroop Interference for Honduras. Conclusions This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate approach to interpret the Stroop Word-Color Interference test in pediatric populations.

In this study, we employed proteomics to identify mechanisms of posttranslational regulation on cell survival signaling proteins. We focused on Cu-Zn superoxide dismutase (SOD1), which protects cells from oxidative stress. We found that acylation of K122 on SOD1, while not impacting SOD1 catalytic activity, suppressed the ability of SOD1 to inhibit mitochondrial metabolism at respiratory complex I. We found that deacylase depletion increased K122 acylation on SOD1, which blocked the suppression of respiration in a K122-dependent manner. In addition, we found that acyl-mimicking mutations at K122 decreased SOD1 accumulation in mitochondria, initially hinting that SOD1 may inhibit respiration directly within the intermembrane space (IMS). However, surprisingly, we found that forcing the K122 acyl mutants into the mitochondria with an IMS-targeting tag did not recover their ability to suppress respiration. Moreover, we found that suppressing or boosting respiration levels toggled SOD1 in or out of the mitochondria, respectively. These findings place SOD1-mediated inhibition of respiration upstream of its mitochondrial localization. Lastly, deletion-rescue experiments show that a respiration-defective mutant of SOD1 is also impaired in its ability to rescue cells from toxicity caused by SOD1 deletion. Together, these data suggest a previously unknown interplay between SOD1 acylation, metabolic regulation, and SOD1-mediated cell survival.

OBJECTIVE: To generate normative data for the Modified Wisconsin Card Sorting Test (M-WCST) in Spanish-speaking pediatric populations. METHOD: The sample consisted of 4,373 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the M-WCST as part of a larger neuropsychological battery. Number of categories, perseverative errors, and total error scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. RESULTS: The final multiple linear regression models indicated main effects for age on all scores, such that the number of categories correct increased and total number of perseverative errors and total number of errors decrease linearly as a function of age. Age2 had a significant effect in Chile, Cuba, Ecuador, and Spain for numbers of categories; a significant effect for number of perseverative errors in Chile, Cuba, Mexico, and Spain; and a significant effect for number of total errors in Chile, Cuba, Peru, and Spain. Models showed an effect for MLPE in Cuba (total errors), Ecuador (categories and total errors), Mexico (all scores), Paraguay (perseverative errors and total error), and Spain (categories and total errors). Sex affected number of total errors for Ecuador. CONCLUSIONS: This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate way to interpret the M-WCST with pediatric populations.

Objective To generate normative data for the Symbol Digit Modalities Test (SDMT) in Spanish-speaking pediatric populations. Method The sample consisted of 4,373 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the SDMT as part of a larger neuropsychological battery. SDMT scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. Results The final multiple linear regression models showed main effects for age in all countries, such that score increased linearly as a function of age. In addition, age2 had a significant effect in all countries, except in Honduras and Puerto Rico. Models indicated that children whose parent(s) had a MLPE >12 years of education obtained higher score compared to children whose parent(s) had a MLPE ≤12 years for Chile, Guatemala, Mexico, and Spain. Sex affected SDMT score for Paraguay and Spain. Conclusions This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate interpretation of the SDMT with pediatric populations.

Background and Purpose— Evidence suggests the potential to improve motor status in patients with stroke by modifying brain catecholaminergic tone. The current study hypothesized that increased dopaminergic tone via the dopamine agonist ropinirole, when combined with physiotherapy (PT), would significantly and safely increase gait velocity. Methods— Patients with moderate motor deficits due to stroke 1 to 12 months prior were randomized (double blinded) to 9 weeks of immediate-release ropinirole or placebo, each with PT, and followed up for 3 additional weeks. Drug dose (0.25 to 4 mg once daily) was titrated weekly, as tolerated. The primary end point was gait velocity during the 12 weeks of study participation. Results— Patients in the ropinirole+PT group averaged 2.4 mg/d by end of week 9, although the target dose was at least 3 mg/d. Ropinirole+PT was generally safe and well tolerated, including no drug-related serious adverse events. Across all 33 enrollees, significant gains were found over time for gait velocity and for most secondary end points. However, gains did not differ by treatment assignment. PT and occupational therapy were commonly prescribed outside of the trial, although the extent of these was not correlated with study outcomes. Conclusions— At doses achieved in this trial, increased dopaminergic tone via ropinirole+PT was generally well tolerated but did not show any improvement over and above the effects of PT alone.

During the late nineteenth and early twentieth centuries, there was one kind of female orgasm and it was clitoral; there was also only one kind of healthy sexual instinct for a woman and it was for penetrative sex with her husband. When a woman behaved outside of this normality-by masturbating or by not responding to her husband's affections-her sexual instinct was seen as disordered. If healthy women, then, were believed only to be sexual within the marital embrace, what better way to explain these errant behaviors than by blaming the clitoris, an organ seen as key to female sexual instinct? Doctors corrected a clitoris in an unhealthy state using one of four surgeries-removing smegma or adhesions between the clitoris and its hood, removing the hood (circumcision), or removing the clitoris (clitoridectomy)-in order to correct a woman's sexual instinct in an unhealthy state. Their approach to clitoral surgery, at least as revealed in published medical works, was a cautious one that respected the importance of clitoral stimulation for healthy sexuality while simultaneously recognizing its role as cause and symptom in cases of insanity that were tied to masturbation.

Rationale:Macrophagesarebelievedtoplay acentralrole inemphysema based largely on data from mouse models. However, the relevance of these models to smoking-related lung disease in humans is uncertain. Objectives: We sought to comprehensively characterize the effects of smoking on gene expression in human alveolar macrophages and to compare these with effects seen in transgenic mouse models of emphysema. Methods: We used DNA microarrays with genomewide coverage to analyze alveolar macrophages from 15 smokers, 15 nonsmokers, and 15 subjects with asthma (disease control). Selected gene expression changes were validated by polymerase chain reaction and ELISA. Expression changes were compared with those identified by microarray analysis of interleukin-13–overexpressing and integrin6–deficient mice, which both develop emphysema. Measurements and Main Results: All 15 smokers shared a common pattern of macrophage gene expression that distinguished them from nonsmokers, a finding not observed in subjects with asthma. We identified 110 genes as differentially expressed in smokers despite using conservative statistical methods. Matrix metalloproteinase 12, a proteinase that plays a critical role in mouse models, was the third most highly induced gene in smokers (ninefold, p 0.0001). However, most changes in smokers were not reflected in mouse models. One such finding was increased osteopontin expression in smokers (fourfold, p 0.006), which was confirmed at the protein level and correlated with the degree of airway obstruction. Conclusions: Smoking induces a remarkably consistent and distinctive pattern of alveolar macrophage activation. These studies identify aspects of mouse models that are directly relevant to human smokers and also reveal novel potential mediators of smokingrelated diseases.

Background Asthma functional genomics studies are challenging because it is difficult to relate gene expression changes to specific disease mechanisms or pathophysiologic features. Use of simplified model systems might help to address this problem. One such model is the IL-13/Epi (IL-13–overexpressing transgenic mice with STAT6 expression limited to epithelial cells) focused transgenic mouse, which isolates the effects of a single mediator, IL-13, on a single cell type, the airway epithelial cell. These mice develop airway hyperreactivity and mucus overproduction but not airway inflammation. Objective To identify how effects of IL-13 on airway epithelial cells contribute to gene expression changes in murine asthma models and determine whether similar changes are seen in people with asthma. Methods We analyzed gene expression in ovalbumin allergic mice, IL-13–overexpressing mice, and IL-13/Epi mice with microarrays. We analyzed the expression of human orthologues of genes identified in the mouse studies in airway epithelial cells from subjects with asthma and control subjects. Results In comparison with the other 2 models, IL-13/Epi mice had a remarkably small subset of gene expression changes. Human orthologues of some genes identified as increased in the mouse models were more highly expressed in airway epithelial cells from subjects with asthma than in controls. These included calcium-activated chloride channel 1, 15-lipoxygenase, trefoil factor 2, and intelectin. Conclusion The combination of focused transgenic models, DNA microarray analyses, and translational studies provides a powerful approach for analyzing the contributions of specific mediators and cell types and for focusing attention on a limited number of genes associated with specific pathophysiologic aspects of asthma.

Microarrays can be produced by deposition (or spotting) of DNA or by in situ synthesis of oligonucleotides on a solid substrate. Spotted cDNA arrays are typically produced by depositing PCR amplicons, made from cDNA clones, on modified glass slides (Schena et al. 1996). In general, PCR amplicons are several hundred to a few thousand base pairs, and one amplicon (or sometimes a few different amplicons) are used to probe each gene. These arrays can be produced by individual investigators or core facilities, or can be purchased commercially. Production of microarrays by in situ synthesis requires more sophisticated and costly equipment, and these arrays are generally produced commercially. One widely used implementation of this technology is the Affymetrix short oligonucleotide array (GeneChip). Here, photolithography and solid-phase chemistry are used to produce high-density arrays of 25-mer oligonucleotides (Lockhart et al. 1996). Each perfect-match oligonucleotide is paired with a mismatched oligonucleotide, and several (11–20) pairs of 25-mers are used for each gene. Various approaches have been used to verify the accuracy of microarray data. Microarray assay technology can be calibrated by spiking known quantities of one or several RNA transcripts into test samples. Alternatively, independent methods including Northern blotting or quantitative PCR can be used to verify array measurements (Yuen et al. 2002). Results from both approaches indicate that spotted cDNA arrays and short oligonucleotide arrays accurately quantify gene expression in many cases. However, some exceptions have been noted, and these approaches typically only evaluate measurements of a very small fraction of the thousands of genes represented on modern microarrays. Other investigators have compared the performance of spotted cDNA arrays and Affymetrix 25-mer arrays across a larger set of genes. Kuo et al. (2002) reported that measurements of gene expression by spotted cDNA arrays and Affymetrix 25-mer arrays showed little correlation. However, this comparison involved data generated by two different groups using RNA samples generated independently from the same set of cell lines, and therefore it is not clear whether the lack of correlation is attributable to the difference in array type. Li et al. (2002) used both commercial cDNA arrays and Affymetrix GeneChips to analyze gene expression changes induced by tert-butylhydroxyquinone treatment of human neuroblastoma cells. They concluded that there were very substantial discrepancies between the two array types, and that the cDNA arrays often failed to detect differences in gene expression. Kothapalli et al. (2002) also used both of these array types to analyze gene expression in peripheral blood mononuclear cells from normal and leukemic subjects, and found substantial discrepancies. These discrepancies have been attributed to several factors, including nonspecific hybridization and misidentification of cDNA probes. Thus, the small number of reports that directly address this issue do not provide clear support for the idea that there is good agreement between gene expression measurements made with spotted cDNA arrays and in situ-synthesized short oligonucleotide arrays. Spotted long oligonucleotide arrays were recently introduced as an alternative to spotted cDNA arrays and in situ-synthesized oligonucleotide arrays (Kane et al. 2000). Spotted oligonucleotide arrays are produced by deposition (or `spotting') of solutions containing synthetic oligonucleotides, typically 40–90 bases long, on a solid substrate. These arrays can be produced and used with methods identical or very similar to those used for spotted cDNA arrays. Although large sets of oligonucleotide probes and arrays made from long oligonucleotide probes are now available from various suppliers, there are as yet few published reports involving the evaluation or application of these arrays. However, strong support for the utility of long oligonucleotide probes comes from a study of 60-mer oligonucleotide arrays fabricated by an ink-jet oligonucleotide synthesizer (Hughes et al. 2001). Results obtained with this type of array correlated well with results obtained using yeast cDNA arrays, and human ink-jet 60-mer arrays were able to identify 20 of 23 human genes that had been found to be upregulated by at least threefold following retinoic acid-induced differentiation of NB4 cells, in two previous studies performed using cDNA arrays and Affymetrix GeneChips. To evaluate the performance of spotted oligonucleotide arrays, we used these arrays to compare gene expression in two dissimilar RNA samples. We expected that this would result in a large number of differentially expressed genes, which would allow us to draw meaningful conclusions about how well measurements made using different array types were correlated across a large set of genes. We produced arrays using two large commercially available collections of ∼70-mer oligonucleotide probes for thousands of genes (generally one probe per gene). We analyzed gene expression in the two RNA samples using these two types of spotted long oligonucleotide arrays as well as Affymetrix 25-mer arrays. We were able to compare measurements for 7344 genes represented on all three arrays, and found strong correlations between relative expression measurements made using these three different array types.

Assessing validity and reliability of end points used in docosahexanoic and arachidonic acids (DHA and ARA) infant formula supplementation trials as an example for addressing the impact of end-point selection and critical need for well-defined, reliable and validated clinical outcome assessments for neurocognitive assessment in neonates and infants. We searched eight electronic databases and reviewed all randomized, controlled human trials using DHA/ARA supplements with neurodevelopment clinical outcomes. We systematically evaluated the validity and reliability of end-point measures based on the criteria for studying nutritional additives recommended by the Institute of Medicine, criteria described in the Food and Drug Administration guidance for clinical outcome assessment, development and literature review. We identified 29 articles that met the selection criteria. The end points that were used for neurodevelopment measures in 23 out of 29 original short-term studies included the Bayley Scale of Infant Development (BSID)-I and -II (n=12), Brunet-Lezine test (n=2), videotape infant's movements (n=1), record time to milestones including sitting, crawling, standing and walking (n=1), problem-solving test (n=2), brainstem auditory-evoked potential (n=1), Touwen examination (n=1), Fagan test of infant intelligence (n=2) and visual habituation protocol (n=1). None of these end points have a long-term predictive property for neurocognitive assessment. Compared with standard infant formula, the beneficial effects of DHA/ARA supplementation on neurodevelopment were reported in 2 out of 12 studies using BSID vs 8 out of 11 studies using other end-point measures. In addition, 6 out of 29 long-term follow-up studies used the end points including Stanford–Binet IQ test (n=1), Wechsler Preschool and Primary Scale of Intelligence (n=4) and Bracken Basic Concept Scale (n=1), which are generally scales of intellectual ability and typically do not change substantively in the short term. None of these long-term follow-up studies demonstrated beneficial effects of DHA/ARA supplementation on neurodevelopment. The choice of end-point measures affects the outcomes of DHA/ARA-supplemented infant formula trials. Available data are currently inadequate to conclude that DHA/ARA supplementation has a clinically meaningful beneficial effect upon neurological development. Although BSID is validated to assess early developmental delays, it is not designed to predict long-term neurocognitive outcome. A well-defined, valid and reliable clinical outcome assessment that measures neurocognitive function in neonates and infants is essential to provide the scientific evidence required for future clinical trials.

We sought to explore the relationship between the diagnosis of hypertension and obstructive sleep apnea (OSA) in a Hispanic population, describe the effect of continuous positive airway pressure (CPAP) on blood pressure regulation, and assess the effect of CPAP on quality of life.A retrospective, recall interview study.Patients enrolled at the Home Oxygen Program of the San Juan V.A. Medical Center with the diagnosis of OSA and treatment with CPAP.The Calgary Sleep Apnea Quality of Life Index was administered to all patients after informed consent. Information regarding co-morbid conditions and fluctuations in blood pressure and anthropometric variables were obtained on a follow-up evaluation.After excluding for the use of antihypertensive medications, weight, and age, a 10% decrease in mean arterial pressure (MAP) from 100 mm Hg to 92 mm Hg was observed in an average of 40 months of therapy (p0.05). With the Calgary Quality of Life Index, 67% of the patients reported an extreme improvement in their quality of life. Compliance with CPAP therapy correlated with improved quality of life (r = 0.33, p0.015).In this pilot study, there appears to be a correlation between our intervention and decline of blood pressure, independent of body weight, age, or medication usage. CPAP treatment is an effective modality in improving symptoms and quality of life.

We have performed a phase II study to evaluate the activity and toxicity of ifosfamide and cisplatin as first-line treatment for advanced ovarian cancer. Patients were treated with cisplatin 100 mg/m 2 on day 1 and ifosfamide 5 g/m 2 in 18-hr continuous infusion on day 1 or 1.5 g/m 2 bolus on days 1–5. Between August 1988 and March 1990, 30 women were entered in the trial, 26 of them with measurable disease. The overall clinical response rate was 69% (95% CI: 48–85%), including 34.6% complete responses (95% CI:17–55%). Reassessment laparotomy was performed in 12 cases, and 4 (33%) exhibited a pathologic complete response. For all patients, the median duration of progression-free survival was 14 months, and the median overall survival was 25 months. There were no major differences in the response rate or survival between the two ifosfamide administration modalities. Relevant toxicities were grade IV hematologic toxicity in 11/30 patients and grade IV renal toxicity in 2/30 patients. A patient with grade IV encephalopathy developed a trauma-related cerebral hemorrhage and died 2 months later. The combination of ifosfamide and cisplatin is active in first-line therapy in advanced ovarian cancer, although it does not seem to improve the efficacy or toxicity profile of conventional combinations.

Polymorphic expression of arylamine N-acetyltransferase (EC 2.3.1.5) may be a differential risk factor in metabolic activation of arylamine carcinogens and susceptibility to cancers related to arylamine exposures. Human epidemiological studies suggest that rapid acetylator phenotype may be associated with higher incidences of colorectal cancer. We used restriction fragment length polymorphism analysis to determine acetylator genotypes of 44 subjects with colorectal cancer and 28 non-cancer subjects of similar ethnic background (i.e., approximately 25% Black and 75% White). The polymorphic N-acetyltransferase gene (NAT2) was amplified by the polymerase chain reaction from DNA templates derived from human colons of colorectal and non-cancer subjects. No significant differences inNAT2 allelic frequencies (i.e., WT, M1, M2, M3 alleles) or in acetylator genotypes were found between the colorectal cancer and non-cancer groups. No significant differences inNAT2 allelic frequencies were observed between Whites and Blacks or between males and females. Cytosolic preparations from the human colons were tested for expression of arylamine N-acetyltransferase activity. Although N-acetyltransferase activity was expressed for each of the arylamines tested (i.e., p-aminobenzoic acid, 4-aminobiphenyl, 2-aminofluorene, β-naphthylamine), no correlation was observed between acetylator genotype and expression of human colon arylamine N-acetyltransferase activity. Similarly, no correlation was observed between subject age and expression of human colon arylamine N-acetyltransferase activity. These results suggest that arylamine N-acetyltransferase activity expressed in human colon is catalyzed predominantly by NAT1, an arylamine N-acetyltransferase that is not regulated byNAT2 acetylator genotype. The ability to determine acetylator genotype from DNA derived from human surgical samples should facilitate further epidemiological studies to assess the role of acetylator genotype in various cancers.

Purpose Patients with advanced gastric or gastroesophageal adenocarcinoma need more efficacious and safer treatments than established today. S-1, a contemporary oral fluoropyrimidine, can provide that advantage. Patients and Methods This study was conducted in 24 countries and 146 centers. One thousand fifty-three patients were stratified (center, number of metastatic sites, prior adjuvant therapy, and measurable cancer) and randomly assigned. Patients received either S-1 at 50 mg/m2 divided in two daily doses for 21 days and cisplatin at 75 mg/m2 intravenously on day 1, repeated every 28 days (527 patients) or infusional fluorouracil at 1,000 mg/m2/24 hours for 120 hours and cisplatin at 100 mg/m2 intravenously on day 1, repeated every 28 days (526 patients). The primary end point was superiority in overall survival (OS) from cisplatin/S-1 compared with cisplatin/infusional fluorouracil in patients with advanced, untreated gastric, or gastroesophageal adenocarcinoma. The secondary end points were response rate, progression-free survival, time to treatment failure, and safety. Results The median OS was 8.6 months in the cisplatin/S-1 arm and 7.9 months in the cisplatin/infusional fluorouracil arm (HR, 0.92; 95% CI, 0.80 to 1.05; P = .20). Significant safety advantages were observed in the cisplatin/S-1 arm compared with the cisplatin/infusional fluorouracil arm for the rates of grade 3/4 neutropenia (32.3% v 63.6%), complicated neutropenia (5.0% v 14.4%), stomatitis (1.3% v 13.6%), hypokalemia (3.6% v 10.8%), and treatment-related deaths (2.5% v 4.9%; P < .05). Conclusion Cisplatin/S-1 did not prolong OS of patients with advanced gastric or gastroesophageal adenocarcinoma compared with cisplatin/infusional fluorouracil, but it did result in a significantly improved safety profile.

Cerebral control of foot movements has received limited study. Functional MRI compared slow with rapid foot movement, and right (dominant) with left foot movement. Brain activation during right, as compared with left, foot movement was larger, with higher amplitude task-related motor cortex signal change, and higher laterality index. Brain activation during fast, as compared with slow, foot movement was larger in cortical and cerebellar areas but smaller in deep gray areas. Some principles of cerebral control of hand movement extend to foot, but exceptions found include that dominant foot movement showed greater activation than did nondominant, and faster foot movements activated bilateral deep gray matter structures less than did slower. Results might have utility in trials of restorative therapies.

A cross sectional study was conducted from 2002-2004 to record the evolution of HIV-1 infection in Puerto Rico by monitoring the expression of antiretroviral resistance-associated mutations.Samples were analyzed by using the TRUGENE HIV-1 Genotyping Kit and the OpenGene DNA Sequencing System.Mutations in the HIV-1 virus were detected in 92.7% of men and 94.8% of women. Of these, 75.1% of men and 72.4% of women had HIV-1 with resistance to at least one medication. The average number of HIV mutations was 6.1 in men and 5.3 in women. In 2002 and 2003, strains were most frequently resistant to the antiretroviral drugs zalcitabine, lamivudine and didanosine, while in 2004, strains were most frequently resistant to zalcitabine, lamivudine, and efavirenz. The most prevalent mutations in the reverse transcriptase gene were M184V, K103N, T215Y, and M41L. The most prevalent mutations in the protease gene were L63P, M361, L90M, A71V, and L101.Significant differences between men and women were recorded in the levels of HIV-1 expressed mutations and resistance. When comparing these results with data from 2000 and 2001, results indicate that expression of resistant mutations has remained constant.

Overproduction of mucus is a central feature of asthma. The cytokine, IL-13, epidermal growth factor receptor (EGFR), and transcription factor, FOXA2, have each been implicated in mucus production, but the mechanistic relationships between these molecules are not yet well understood. To address this, we established a primary normal human bronchial epithelial cell culture system with IL-13-induced mucus production and gene transcript expression changes similar to those seen in vivo in mice. IL-13 did not stimulate release of the EGFR ligand, transforming growth factor (TGF)-alpha. However, there was constitutive release of TGF-alpha from normal human bronchial epithelial cells, and inhibition of TGF-alpha or EGFR reduced both constitutive and IL-13-induced mucin production. Microarray analysis revealed that IL-13 and the EGFR pathway appear to have almost completely independent effects on transcript expression. IL-13 induced a relatively small set of transcripts, including several novel transcripts that might play a role in pathogenesis of allergic airway disease. In contrast, EGFR activity had extensive effects, including altered expression of many transcripts associated with cell metabolism, survival, transcription, and differentiation. One of the few common effects of IL-13 and EGFR signaling was decreased expression of FOXA2, which is known to prevent mucus production. We conclude that the IL-13 and EGFR pathways make critical but quite distinct contributions to gene regulation in airway epithelial cells, and that both pathways affect expression of the key transcription factor, FOXA2, a known regulator of mucus production.

The cell adhesion molecule integrin alpha 4 beta 7 helps direct the migration of blood lymphocytes to the intestine and associated lymphoid tissues. We hypothesized that beta 7+ and beta 7- blood memory T helper cells differ in their expression of genes that play a role in the adhesion or migration of T cells.RNA was prepared from beta 7+ and beta 7- CD4+ CD45RA- blood T cells from nine normal human subjects and analyzed using oligonucleotide microarrays. Of 21357 genes represented on the arrays, 16 were more highly expressed in beta 7+ cells and 18 were more highly expressed in beta 7- cells (/=1.5 fold difference and adjusted P0.05). Several of the differentially expressed transcripts encode proteins with established or putative roles in lymphocyte adhesion and chemotaxis, including the chemokine receptors CCR9 and CCR10, the integrin alpha 4 subunit, L-selectin, KLRB1 (CD161), NT5E (CD73), LGALS1 and LGALS2 (galectin-1 and -2), and RGS1. Flow cytometry was used to determine whether differences in levels of transcripts encoding cell surface proteins were associated with differential expression of those proteins. Using this approach, we found that surface expression of KLRB1, LAIR1, and NT5E proteins was higher on beta 7+ memory/effector T cells than on beta 7- cells.Memory/effector T cells that express integrin beta 7 have a distinct pattern of expression of a set of gene transcripts. Several of these molecules can affect cell adhesion or chemotaxis and are therefore likely to modulate the complex multistep process that regulates trafficking of CD4+ memory T cell subsets with different homing behaviors.

Musculoskeletal complaints are common in patients with HIV and appear to increase in frequency with disease progression. Various forms of musculoskeletal manifestations are discussed, including arthritis, myositis, and osteomyelitis. The most common forms of musculoskeletal disease that occur in HIV patients are arthralgias and frank arthritis. A table provides selected features of musculoskeletal manifestations in HIV disease.

A novel lipodystrophy syndrome characterized by insulin resistance, hypertriglyceridemia, and fat redistribution has recently been described in human immunodeficiency virus (HIV)-infected men and women. Women with the HIV lipodystrophy syndrome exhibit a marked increase in waist-to-hip ratio and truncal adiposity; however, it is unknown whether androgen levels are increased in these patients. In this study, we assessed androgen levels in female patients with clinical lipodystrophy based on evidence of significant fat redistribution in the trunk, extremities, neck and/or face (LIPO: n = 9; age, 35.7+/-1.7 yr; BMI, 24.7+/-0.8 kg/m2) in comparison with age- and BMI-matched nonlipodystrophic HIV-infected females (NONLIPO: n = 14; age, 37.6+/-1.1 yr; BMI, 23.4+/-0.6 kg/m2) and healthy non-HIV-infected control subjects (C: n = 16; age, 35.8+/-0.9 yr; BMI, 23.1+/-0.4 kg/m2). Fasting insulin, lipid levels, virologic parameters, and regional body composition using dual energy x-ray absorptiometry were also assessed. Total testosterone [ LIPO, 33+/-6 ng/dL (1.1+/-0.2 nmol/L); NONLIPO, 17+/-2 ng/dL (0.6+/-0.1 nmol/L); C, 23+/-2 ng/dL (0.8+/-0.1 nmol/L); P0.05 LIPO vs. C and LIPO vs. NONLIPO] and free testosterone determined by equilibrium dialysis [LIPO, 4.5+/-0.9 pg/mL (16+/-3 pmol/L); NONLIPO, 1.7+/-0.2 pg/mL (6+/-1 pmol/L); C, 2.4+/-0.2 pg/mL (8+/-1 pmol/L); P0.05 LIPO vs. C and LIPO vs. NONLIPO] were increased in the lipodystrophic patients. Sex hormone-binding globulin levels were not significantly different between LIPO and C, but were significantly lower in the LIPO vs. NONLIPO patients (LIPO 84+/-7 vs. NONLIPO 149+/-17 nmol/L, P0.05). The LH/FSH ratio was significantly increased in the LIPO group compared with the NONLIPO and C subjects (LIPO, 2.0+/-0.6; NONLIPO, 1.1+/-0.1; C, 0.8+/-0.1; P0.05 LIPO vs. NONLIPO and LIPO vs. C). Body fat distribution was significantly different between LIPO and C subjects. Trunk to extremity fat ratio (1.46+/-0.17 vs. 0.75+/-0.05, LIPO vs. C, P0.05) was increased and extremity to total fat ratio decreased (0.40+/-0.03 vs. 0.55+/-0.01, LIPO vs. C, P0.05). In contrast, fat distribution was not different in the NONLIPO group vs. control subjects. Among the HIV-infected patients, free testosterone correlated with percent truncal fat (trunk fat/trunk mass) (r = 0.43, P = 0.04). These data suggest that hyperandrogenemia is another potentially important feature of the HIV-lipodystrophy syndrome in women. Additional studies are necessary to determine the clinical significance of increased androgen levels and the relationship of hyperandrogenism to fat redistribution and insulin resistance in this population of patients.

PURPOSE Standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy repeated at 3-week intervals is difficult to deliver in elderly patients with non-Hodgkin's lymphoma (NHL). The use of hemopoietic growth factors may decrease the hematologic toxicity of chemotherapy and allow the delivery of full-dose CHOP. PATIENTS AND METHODS We conducted a phase II trial with the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to CHOP chemotherapy in NHL patients older than 60 years of age. Twenty-six previously untreated patients were assessable; median age was 67 years (range, 61 to 84 years). CHOP included cyclophosphamide 750 mg/m2 intravenously day 1; doxorubicin 50 mg/m2 intravenously day 1; vincristine 1.4 mg/m2 (2 mg total dose) intravenously day 1; and prednisone 100 mg orally days 1 through 5. GM-CSF 5 microg/kg was administered subcutaneously on days 4 through 13. Cycles were repeated every 21 days for six cycles. Results were analyzed for the total group and for two age subgroups: 61 to 69 years (n = 15) and 70 years or older (n = 11). RESULTS Sixteen patients (62%) achieved a complete response (CR), four patients (15%) achieved a partial response (PR), and six patients (23%) did not respond to therapy. After a median follow-up of 41 months, the median progression-free and overall survival were 19 and 30 months, respectively. Twenty patients completed six cycles. One hundred thirty-eight of the 156 planned cycles were delivered (88%). The relative dose-intensity was 95%. The chemotherapy-induced toxicity was important. Absolute neutrophil count was less than 500/mL in 43% of the cycles, platelet nadir was less than 20,000/mL in 19%, and febrile neutropenia occurred in 21%. There were no grades 3 to 4 mucositis. Treatment-related death occurred in two patients, and was associated with neutropenic septic shock. The toxicity related to GM-CSF was mild hypotension after the cytokine was administered in 7% of cycles. When the results of the study were analyzed by age subgroups, we observed that whereas response and median survival were similar in patients aged 61 to 69 years or 70 years or older, there were significant differences in dose delivery and toxicity. Chemotherapy was delivered in 86 of 90 planned cycles in patients aged 61 to 69 years, but in only 52 of 72 planned cycles in patients aged 70 to 84 years (P = .00008). Absolute neutrophil count was less than 500/mL in 24% of cycles in patients aged 61 to 69 years and 73% of cycles in patients aged 70 years or older (P = .00001). The platelet nadir of less than 20,000/mL occurred in 5% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Fever and neutropenia occurred in 8% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Mucositis (grades 1 to 2) occurred in 21% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P = .006). CONCLUSION CHOP chemotherapy plus GM-CSF is an active regimen in elderly patients with NHL. Despite cytokine support, the toxicity of the regimen is elevated. We have identified two age subgroups (61 to 69 and > or = 70 years) that do not differ in treatment efficacy but show large differences in treatment-related toxicity.

Based on previous reports suggesting that an intravenous (i.v.) continuous infusion of alkylating agents produced a significant response rate in acute lymphoblastic leukemia (ALL), a phase I trial of ifosfamide/mesna (IFO/MES) was conducted in 11 adult patients with relapsed ALL. IFO/MES were administered as a 24-h i.v. continuous infusion in doses ranging from 5 g/m2 to 9 g/m2; the courses of treatment were repeated every 3 weeks. Patients were examined for toxicity after every cycle and responses were carefully defined and evaluated. All 11 admitted patients were evaluable for toxicity and response. Myelosuppression was the dose limiting effect and it was dose-related. Microscopic and/of macroscopic hematuria was detected in four (11%) out of 36 cycles administered. Ifosfamide produced a positive biological response with a preliminary response rate of 45.4%. Ifosfamide/mesna in a 24-h i.v. continuous infusion appears to be tolerated and produces a biological response in ALL. We recommend that phase II studies of this drug schedule be conducted at the initial dose of 7 g/m2 repeated every 3 weeks and combined with other antileukemic agents.

The efficacy and safety of a 10-day course of ceftibuten oral suspension (9 mg/kg once daily) were compared with those of penicillin V (25 mg/kg/day in 3 divided doses) in children 3 to 18 years old treated for symptomatic pharyngitis and scarlet fever caused by group A beta-hemolytic streptococci (Streptococcus pyogenes). The study was prospective, randomized, multicenter and investigator-blinded; patients were randomized in a 2:1 ratio (ceftibuten:penicillin V). Overall clinical success (cure/improvement) at the primary end point of treatment (5 to 7 days posttherapy) was achieved in 97% (285 of 294) of ceftibuten-treated patients vs. 89% (117 of 132) of penicillin V-treated patients (P0.01). Elimination of infecting streptococci 5 to 7 days posttherapy was achieved in 91% (267 of 294) of ceftibuten-treated patients vs 80% (105 of 132) of penicillin V-treated patients (P0.01). A significant rise in anti-streptolysin O or anti-DNase B was observed in approximately 30% of patients in both treatment groups. No patient developed rheumatic fever or nephritis. Treatment-related adverse events were similar between the two groups; mild vomiting (2%) was most frequently reported. These data suggest that once daily ceftibuten is as safe as and more effective than three times daily penicillin V for the treatment of group A beta-hemolytic streptococcal pharyngitis.

Pulmonary complications of alpha 1-antitrypsin deficiency are most commonly manifested by panlobular emphysema. This report describes histologically proven bronchiectasis in a 21 year old man with massive haemoptysis and homozygous deficiency of alpha 1-antitrypsin. Neither panlobular emphysema nor cirrhosis of the liver were present. Bronchiectasis must be considered part of the spectrum of the pulmonary pathology that may be encountered in individuals with alpha 1-antitrypsin deficiency.

This is the first time, to our knowledge, that evidence is presented showing that a polyantigenic immunomodulator (PAI), acting as a biological response modifier, can either induce or suppress HIV expression depending on the viral load of infected PBMC. PAI consists of a mixture of inactivated bacteria with influenza virus vaccine. PBMC from HIV-infected patients (asymptomatic, age 22-36, symptomatic, age 30-59 and pediatric,2 years old) were co-cultured with PHA-stimulated PBMC from uninfected individuals in medium containing IL-2 and PAI. Parallel co-cultures were carried out in a PAI-free medium. Cultures were fed with PHA-stimulated PBMC from uninfected donors on a weekly basis. HIV-p24 ag and cytokine profiles (IL-1 beta, IL-2, IL-4, IFN-gamma and TNF-alpha) were determined on supernatants on day 14. Peripheral blood samples from each patient were evaluated at the beginning of the experiment as to total CD3, total CD19, CD3/CD4, CD3/CD8, CD16/CD56, CD8/HLA-DR and CD8/CD38 markers through flow cytometry. PAI was able to induce viral expression (up to 11,881 pg/ml of p24 antigen) in cultures showing a low (less than 16 pg/ml) or no viral titer. In contrast, in those cultures with high viral titer (10(2)-10(5) pg/ml), a substantial reduction on the titer was observed upon exposure to PAI. PAI was able to induce the production of IFN-gamma and TNF-alpha while that of IL-4 and IL-1 beta was reduced. The predominant cell type detected in the blood samples of the studied subjects were CD8+, CD8+/CD38+ or CD8+/HLA-DR+.(ABSTRACT TRUNCATED AT 250 WORDS)

Parietal cell secretion of acid requires the coordinated fusion of H(+)-K(+)-adenosinetriphosphatase (ATPase)-containing tubulovesicles with a secretory canalicular target membrane. We have previously reported the presence of rab2 on parietal cell tubulovesicles (L. H. Tang, S. A. Stoch, I. M. Modlin, and J. R. Goldenring. Biochem. J. 285: 715-719, 1992). Since 60% of the small GTP-binding protein sequences obtained from parietal cells were > 95% homologous with human rab11 (J. R. Goldenring, K. R. Shen, H. D. Vaughan, and I.M. Modlin. J. Biol. Chem. 268: 18419-18422, 1993), we sought to study rab11 in gastric parietal cells. A complete rab11 sequence was obtained, and the deduced amino acid sequence of rabbit rab11 was identical to that for human. Rab11 mRNA was present throughout the gastrointestinal mucosa. mRNA for both rab11 and rab2 were enriched in isolated parietal cells compared with chief cells. A polyclonal antiserum against rab11 labeled a single 25-kDa band in isolated parietal cells. Immunostaining of rat fundic tissue demonstrated prominent staining of parietal cells. Rab11 staining cosegregated with alpha-H(+)-K(+)-ATPase staining in enriched preparations of rabbit parietal cell tubulovesicles. These results suggest that rab11 is enriched in parietal cells and is associated with intracellular tubulovesicles.

Eleven patients with diagnosis of possible neurocistycercosis were studied in our Department since 1986. All of them were adults. Eight were Bolivian citizens. The commonest neurological clinical manifestation were seizures and/or headache. Brain CT scans showed cystic lesions and calcifications in 5 patients, only calcifications in 3, enlarged ventricles in 2 and an isolated frontal cystic lesion in 1. Six out of 7 patients who were submitted to spinal fluid ELISA test showed positive response for cysticercosis. Patients were put on praziquantel (50 mg/Kg/d) or albendazol (15 mg/Kg/d) with good outcome for all them. Surgery was carried on for treatment of enlarged ventricles (2 patients) and for a like-expansive lesion (1 patient). The aim of this work is to underscore the fact that in Buenos Aires city, which previously was not within the endemic latin american area for cysticercosis, is now possible to find patients with the neurological manifestations of this parasitosis, most probably due to migration of people coming from the north provinces or from countries situated at its border where the disease is endemic.

This article describes a collaborative effort between specialty areas at a large urban medical center to develop a comprehensive liver transplant educational program. The historical overview, needs assessment, and program planning are discussed. The implementation, planning, and evaluation phases are examined. The process presented here can serve as a framework for clinical educators confronted with major new initiatives.

Respiratory syncytial virus (RSV)-infected cotton rats (Sigmadon hispidus) and owl monkeys (Aotus trivirgatus) showed significant reductions in RSV shedding from their respiratory tracts following parenteral therapy with human intravenous immunoglobulin (IVIG) containing high titers of RSV-neutralizing antibody. Because this therapy was well tolerated and appeared safe, a double-blind, placebo-controlled IVIG immunotherapy pilot study was performed on 35 hospitalized, RSV-infected infants and children. The treatment was well tolerated and resulted in significant reductions in nasal RSV shedding and in improvements in transcutaneous oximetry readings. However, the mean duration of hospitalization was not reduced by IVIG treatment. Followup to date has revealed no harmful effects resulting from immunotherapy of RSV infections. These studies appear to refute the hypothesis that passively acquired antibody may exacerbate RSV bronchiolitis or pneumonia in infants. Studies with larger numbers of seriously ill children will be required to determine if immunoglobulin G immunotherapy of RSV infections in infants is of clinical value.

Middle ear exudate was obtained by myringotomy or aspiration from 625 suburban children, aged 1 month to 12 years, who had acute otitis media; bacterial pathogens were isolated from 71%. Haemophilus species were isolated from 212 (29%), and Streptococcus pneumoniae from 205 (28%). From 1975 to August 1977, the number of Haemophilus isolates found to be resistant to ampicillin has appreciably increased. Currently, 8% of all cases of acute otitis media in the Washington, DC, area are due to H influenzae resistant to ampicillin. Thirty-one of 35 patients with resistant H influenzae otitis were treated with an erythromycin/sulfisoxazole combination with an impressive clinical response. Twenty-six of these 31 cases had failed to have H influenzae eradicated by an average of ten days of oral ampicillin in recommended doses.

The respiratory syncytial virus (RSV) is a common cause of bronchiolitis and pneumonia in infants and young children. Throughout the world annual RSV epidemics result in numerous hospitalizations, substantial morbidity and some mortality. Until the recent introduction of ribavirin only supportive therapy has been available for treating these infections. The development of animal models of RSV infection and the observation that some lots of immunoglobulin prepared for intravenous administration contained substantial RSV-neutralization antibody titers, prompted a series of studies examining the safety and efficacy of immunoglobulin prepared for intravenous administration in the prophylaxis and treatment of RSV infections. This discussion will review our published, or soon to be published, studies on the use of Sandoglobulin for both immunoprophylaxis and immunotherapy of RSV infections in cotton rats. It will summarize studies utilizing both parenteral and topical (tracheal) Sandoglobulin therapy for RSV infections in owl monkeys. Finally the results of a small double blind trial of parenteral albumin or Sandoglobulin in the therapy of RSV bronchiolitis and/or pneumonia in hospitalized children will be reviewed. The data show that immunoprophylaxis and immunotherapy of RSV infections in laboratory animals was well-tolerated, was safe and induced highly significant reductions in RSV shedding from the lower respiratory tract. Further, immunotherapy of RSV infections in children was also well-tolerated, induced no short or long term evidence of toxicity or injury and caused significant improvements in oxygenation and reductions in RSV shed from the respiratory tract.(ABSTRACT TRUNCATED AT 250 WORDS)