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The present article is a case study of a Polish biopharmaceutical company, “Pure Biologics”. The company was founded in 2010 by a group of scientists and, over the last nine years, grew substantially from just a few individuals to nearly one hundred professionals. Initially, a privately-funded civil partnership, Pure Biologics, has been transformed into a publicly-traded company. Such a transformation has been possible not only because of the expertise and growing experience of corporate management, but also the specific economic environment and substantial public funding dedicated to innovative Small and Medium Enterprises (SMEs).

Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. In the past various classification systems for HLDs have been used, based on imaging findings, clinical manifestation, and organelle-specific disorders. Here we present a molecular insight into HLDs based on a defect in specific gene engaged in myelination. We discuss recent findings on pathogenesis, clinical presentation, and imaging related to these disorders. We focus on HLDs that are in use in differential diagnostics of Pelizaeus-Merzbacher disease (PMD), with a special emphasis on Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition with delayed myelination due to thyroid transport disturbances. On the background of previously published patients we describe a proband initially considered as presenting with a severe PMD, whose diagnosis of AHDS due to a novel nonsense SLC16A2 mutation unraveled two previously undiagnosed generations of affected males who died in infancy from unexplained reasons. Since AHDS is found to be a relatively frequent cause of X-linked intellectual disability, we emphasize the need for determining the whole thyroid profile especially in hypotonic males with a delay of psychomotor development.

Background Current color vision (CV) tests used for aviation screening in the U.S. Army only provide pass-fail results, and previous studies have shown variable sensitivity and specificity. The purpose of this study was to evaluate seven CV tests to determine an optimal CV test screener that potentially could be implemented by the U.S. Army. Methods There were 133 subjects [65 Color Vision Deficits (CVD), 68 Color Vision Normal (CVN)] who performed all of the tests in one setting. CVD and CVN determination was initially assessed with the Oculus anomaloscope. Each test was administered monocularly and according to the test protocol. The main outcome measures were test sensitivity, specificity, and administration time (automated tests). Results Three of the four Pseudoisochromatic Plate (PIP) tests had a sensitivity/specificity > 0.90 OD/OS, whereas the FALANT tests had a sensitivity/specificity > 0.80 OD/OS. The Cone Contrast Test (CCT) demonstrated sensitivity/specificity > 0.90 OD/OS, whereas the Color Assessment and Diagnosis (CAD) test demonstrated sensitivity/specificity > 0.85 OD/OS. Comparison with the anomaloscope ("gold standard") revealed no significant difference of sensitivity and specificity OD/OS with the CCT, Dvorine PIP, and PIPC tests. Finally, the CCT administration time was significantly faster than the CAD test. Discussion The current U.S. Army CV screening tests demonstrated good sensitivity and specificity, as did the automated tests. In addition, some current PIP tests (Dvorine, PIPC), and the CCT performed no worse statistically than the anomaloscope with regard to sensitivity/specificity. The CCT letter presentation is randomized and results would not be confounded by potential memorization, or fading, of book plates.

BACKGROUND: Currently, Army aircrews needing refractive correction are issued the HGU-4/P aviator spectacles. However, a recently published survey found dissatisfaction with the current spectacle frame. The Aircrew Flight Frame (AFF) has been used by the Air Force for over 14 yr, with the AFF-OP (Operational) style used the longest. The purpose of this study was to evaluate AFF-OP performance and compatibility among U.S. Army aircrew under operational conditions. METHODS: At 1-, 6-, and 12-wk intervals, 73 Army aircrew members wore the AFF-OP eyewear and completed a Likert scale survey. There were 14 outcome measures surveyed, with the main outcome measure being frame preference. RESULTS: The AFF-OP was preferred significantly more than the HGU-4/P spectacle. Overall, 94% of aircrew responses preferred the AFF-OP and the three highest subjective reasons for AFF-OP preference were: 1) comfort around the ears without helmet or headset; 2) comfort around the ears with helmet or headset; and 3) the effect on ear cup seal. There were no statistically significant differences in responses over the three surveyed time intervals. DISCUSSION: Army aviation aircrew preferred the AFF-OP over the current HGU-4/P spectacles. Two of the top three highest subjective reasons for AFF-OP preference coincided with two of the top three operational eyewear problems reported in the recently published survey. If Army aircrew do not wear their issued eyewear, they may purchase their own frame "out of pocket." However, this can lead to use of a frame that has not been tested for compatibility and may compromise performance of aircrew life support equipment. Walsh DV, Jurek GM, Capo-Aponte JE, Riggs DW, Ramiccio JA. Assessment of an alternative army aircrew eyewear. Aerosp Med Hum Perform. 2015; 86(12):1014-1019. Language: en

UNLABELLED: The purpose of this study was to determine whether repetitive exposure to low-level blasts during military breacher training produces acute and cumulative damage to the ocular tissues or visual system. The effects of low-level blast exposure on high-contrast visual acuity, contrast sensitivity, oculomotor function, color vision, visual field (VF), pupillary light reflex, corneal endothelial cell density (ECD), macular thickness, retinal nerve fiber layer thickness, and cup-to-disc ratio were assessed using a battery of standard clinical ophthalmic tests administered 10 times over a 2-year period. Data from nine breacher instructors (Cadre) were compared with data from four breacher engineers (CONTROL). The Cadre group showed higher vertical deviation at near than the CONTROL group over time. The VF mean deviation on the left eye that tended to be worse in the Cadre group was worse throughout the study, suggesting a decrease in VF sensitivity (Cadre: -0.20 +/- 0.15 dB; CONTROL: 1.05 +/- 0.15 dB; p = 0.03). The Cadre group had a reduced ECD (right eye: Cadre 2,502 cells/mm(2) vs CONTROL 2,808 cells/mm(2), p = 0.05; left eye: Cadre 2,558 cells/mm(2) vs CONTROL 2,892 cells/mm(2), p = 0.04). These results suggest that even low-level primary blast has the potential to produce occult eye injury. Language: en

Przemysław M Jurek,* Konrad Zabłocki,* Urszula Waśko, Maciej P Mazurek, Jacek Otlewski, Filip Jeleń Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Poland *These authors contributed equally to this work Abstract: Compounds that recognize and strongly bind to molecular targets are one of the cornerstones of modern pharmaceutics. Work has been ongoing for the past 25 years on the therapeutic use of aptamers, nucleic acid molecules, whose three-dimensional structure is the result of interactions between complementary base pairs. The aptamers selection methods allow the oligonucleotides which bind the molecular target in its native environment to be quickly isolated from a large library of random oligonucleotides. The possibilities presented for aptamers in the field of targeted therapy require the application of effective carriers to counter the renal clearance effect and/or functional cargo to exert therapeutic action if the aptamer is only used as a targeting moiety. Lately, a material gaining ground in biomedical research is iron oxide particles, which exhibit a superparamagnetic characteristic at nanoscale levels. This allows the iron oxide nanoparticles to convert external magnetic energy into heat, a mechanism known as hyperthermy, and efficiently supports conventional oncological treatment. In this study, we describe an experimentally confirmed functional model of targeted anticancer hyperthermia therapy. Using the systematic evolution of ligands by exponential enrichment technique, we selected a DNA aptamer that specifically binds to the extracellular domain of recombinant fibroblast growth factor receptor type-1 (FGFR1) with a nanomolar dissociation constant. The chosen target plays an important role in many crucial cellular processes and is also considered a candidate protein that is involved in tumor initiation, survival and progression. Next, we combined the selected aptamer with iron oxide nanoparticles to produce aptamer superparamagnetic conjugates (ASCs). Finally, we found that targeted ASCs selectively destroy FGFR1-overexpressing human osteosarcoma cells U2OS upon magnetic field irradiation. Keywords: aptamers, targeted hyperthermia, nanoparticles, iron oxide magnetic nanoparticles, targeted cancer therapy

Aptamers emerged over 20 years ago as a class of nucleic acids able to recognize specific targets. Today, aptamer-related studies constitute a large and important field of biotechnology. Functional oligonucleotides have proved to be a versatile tool in biomedical research due to the ease of synthesis, a wide range of potentially recognized molecular targets and the simplicity of selection. Similarly to antibodies, aptamers can be used to detect or isolate specific molecules, as well as to act as targeting and therapeutic agents. In this review we present different approaches to aptamer application in nanobiotechnology, diagnostics and medicine.

Purpose Birth certificates are a convenient source of population data for epidemiologic studies. It is well documented, however, that birth certificate data can be highly inaccurate. Nonetheless, studies based on birth certificates are routinely analyzed without accounting for sources of data errors. We focused on the association between maternal cigarette smoking and cleft lip and palate based on birth certificate data. Methods We adjusted odds ratio estimates simultaneously for exposure and outcome misclassification. We also calculated odds ratios adjusted for exposure misclassification only and outcome misclassification only. Results Adjustment for both maternal smoking during pregnancy and clefting resulted in adjusted odds ratios that ranged from less than 1.0 to much greater than the unadjusted estimate of 1.16, with most adjusted estimates outside of the 95% confidence limits (1.01, 1.33). Conclusions Because of the potentially large impact of birth certificate classification errors, we suggest that inferences from these or similar records employ quantitative methods for incorporating uncertainties caused by data errors.

Assessment of whether pesticide exposure is associated with neurodevelopmental outcomes in children can best be addressed with a systematic review of both the human and animal peer-reviewed literature. This review analyzed epidemiologic studies testing the hypothesis that exposure to pesticides during pregnancy and/or early childhood is associated with neurodevelopmental outcomes in children. Studies that directly queried pesticide exposure (e.g., via questionnaire or interview) or measured pesticide or metabolite levels in biological specimens from study participants (e.g., blood, urine, etc.) or their immediate environment (e.g., personal air monitoring, home dust samples, etc.) were eligible for inclusion. Consistency, strength of association, and dose response were key elements of the framework utilized for evaluating epidemiologic studies. As a whole, the epidemiologic studies did not strongly implicate any particular pesticide as being causally related to adverse neurodevelopmental outcomes in infants and children. A few associations were unique for a health outcome and specific pesticide, and alternative hypotheses could not be ruled out. Our survey of the in vivo peer-reviewed published mammalian literature focused on effects of the specific active ingredient of pesticides on functional neurodevelopmental endpoints (i.e., behavior, neuropharmacology and neuropathology). In most cases, effects were noted at dose levels within the same order of magnitude or higher compared to the point of departure used for chronic risk assessments in the United States. Thus, although the published animal studies may have characterized potential neurodevelopmental outcomes using endpoints not required by guideline studies, the effects were generally observed at or above effect levels measured in repeated-dose toxicology studies submitted to the U.S. Environmental Protection Agency (EPA). Suggestions for improved exposure assessment in epidemiology studies and more effective and tiered approaches in animal testing are discussed.

BACKGROUND Apache pilots needing refractive correction are issued modified HGU-4/P aviator spectacles. However, a recently published survey found field of view (FOV) dissatisfaction with the current spectacles when sighting in with a Helmet Display Unit (HDU). A current Air Force flight frame was modified in-lab and the purpose of this study was to evaluate the FOV with the current Apache flight frame vs. the modified flight frame. METHODS Recruited were 21 Apache pilots to assess FOV under three conditions: 1) wearing the current Apache frame; 2) wearing the modified Apache frame; and 3) wearing no frame. The main outcome measure was total FOV of four quadrants tested: superior left (45°); superior right (135°); inferior right (225°); and inferior left (315°). RESULTS No significant differences in FOV were seen between the two frames tested while wearing the current Apache helmet (P = 0.33) and the new Apache helmet (P = 0.64). However, there were significant differences in FOV between the no frame condition and the two frame conditions tested with both helmets (P < 0.001). DISCUSSION No significant differences in FOV were seen between the two frames tested while wearing either Apache helmet. However, with both helmets there were significant differences in FOV between the no frame condition and the two frame conditions tested. This suggests that wearing no eyewear is still optimal in integrating the HDU device. With advances in contact lens technology, future research can study the viability of the latest generation of multifocal contact lenses with Apache aviators. Walsh DV, Jurek GM, McLean WE, Statz JK, Allen RL, Riggs DW. Assessment of a prototype Apache flight eyewear. Aerosp Med Hum Perform. 2016; 87(9):800-805.

The World Trade Centre (WTC) disaster occurred on September 11, 2001 and resulted in 2,876 immediate deaths and approximately 6,000 injuries. Shortly after the disaster, the WTC medical screening program (MSP) was started for the responders. The program was initially designed as a one-time medical screening, but evolved into a longitudinal medical monitoring program allowing researchers to investigate a wide range of health outcomes. There have now been more than 2,000 WTC scientific publications, but none that have formally investigated potential impacts of biases that may have arisen from the challenging conditions under which the studies were designed and data collected. We conducted a systematic assessment of the potential impacts of biases on health effects studies of the WTC MSP. Systematic review of the published studies was supplemented with targeted analyses of the primary data collected from WTC responders to identify and evaluate biases in qualitative and quantitative approaches. Several potential biases were identified using questionnaire data collected by WTC MSP. Selection bias likely occurred at least through self-selection into the WTC MSP. Loss to follow-up and non-random sampling due to differential recruiting strategies across study periods also likely occurred. Significant exposure misclassification may have occurred through use of self-reported information without validation from objective real-time exposure assessment. For some health outcomes, misclassifications may have occurred due to low inter-rater reliability during clinical diagnosis of health conditions, as well by changes over time in which health conditions were recognised as WTC-related. A quantitative analysis estimated the magnitude of the impact of these biases. Implementing a disaster based epidemiologic surveillance faces many challenges; among them is designing health surveillance in ways that increase reliability and reduce potential biases. Our study aimed to strengthen future disaster epidemiology studies by learning from the challenges of data collection and analysis for the WTC MSP.

We have studied a solid-to-plasma transition by irradiating Al foils with the FLASH free electron laser at intensities up to 10(16) W/cm(2). Intense XUV self-emission shows spectral features that are consistent with emission from regions of high density, which go beyond single inner-shell photoionization of solids. Characteristic features of intrashell transitions allowed us to identify Auger heating of the electrons in the conduction band occurring immediately after the absorption of the XUV laser energy as the dominant mechanism. A simple model of a multicharge state inverse Auger effect is proposed to explain the target emission when the conduction band at solid density becomes more atomiclike as energy is transferred from the electrons to the ions. This allows one to determine, independent of plasma simulations, the electron temperature and density just after the decay of crystalline order and to characterize the early time evolution.

Purpose When learning bias analysis, epidemiologists are taught to quantitatively adjust for multiple biases by correcting study results in the reverse order of the error sequence. To understand the error sequence for a particular study, one must carefully examine the health study's epidemiologic data-generating process. In this article, we describe the unique data-generating process of a man-made disaster epidemiologic study. Methods We described the data-generating process and conducted a bias analysis for a study associating September 11, 2001 dust cloud exposure and self-reported newly physician-diagnosed asthma among rescue-recovery workers and volunteers. We adjusted an odds ratio (OR) estimate for the combined effect of missing data, outcome misclassification, and nonparticipation. Results Under our assumptions about systematic error, the ORs adjusted for all three biases ranged from 1.33 to 3.84. Most of the adjusted estimates were greater than the observed OR of 1.77 and were outside the 95% confidence limits (1.55, 2.01). Conclusions Man-made disasters present some situations that are not observed in other areas of epidemiology. Future epidemiologic studies of disasters could benefit from a proactive approach that focuses on the technical aspect of data collection and gathers information on bias parameters to provide more meaningful interpretations of results.

Purpose: Bedside newborn hearing screening is highly successful in identifying deaf or hard-of-hearing infants. However, newborn hearing screening protocols have high loss to follow-up rates. We propose that bloodspot-based genetic testing for GJB2 alleles can provide a means for rapid confirmation in a subset of infants who fail bedside newborn hearing screening. Methods: We performed a case-control study comparing the prevalence of common GJB2 mutations from deidentified bloodspots designated as “refer” by newborn hearing screening and contemporaneously selected randomly chosen controls designated as “pass.” Between March 2006 and December 2007, 2354 spots were analyzed for common alleles, c.35delG, c.167delT, c.235delC, and p.V37I in GJB2 with a subset reanalyzed by conventional Sanger sequencing to search for additional alleles. Results: The prevalence of biallelic GJB2 mutations in bloodspots from infants who referred by newborn hearing screening is approximately 1 in 50 (23/1177). In contrast, one bloodspot from an infant who passed newborn hearing screening was identified to harbor biallelic GJB2 mutations. Conclusions: These findings show that when a newborn refers by newborn hearing screening, there is a significant chance that GJB2-related hearing loss is present. Bloodspot-based genetic testing for common GJB2 alleles should be considered as second tier testing for bedside newborn hearing screening.

In a case-control study of infant leukaemia, we assessed agreement between medical records and mother's self-reported pregnancy-related conditions and procedures and infant treatments. Interview and medical record data were available for 234 case and 215 control mothers. Sensitivity, specificity and predictive values for maternal report were estimated for case and control mothers separately, taking the medical record as correct. For most perinatal conditions, sensitivity and specificity were over 75%. Low sensitivity was observed for maternal protein or albumin in the urine (cases: 12% [95% exact confidence interval (CI) 8%, 18%]; controls: 11% [95% CI 7%, 17%]) and infant supplemental oxygen use (cases: 25% [95% CI 11%, 43%]; controls: 24% [95% CI 13%, 37%]). Low specificity was found for peripheral oedema (cases: 47% [95% CI 37%, 58%]; controls: 54% [95% CI 43%, 64%]). Sensitivity for maternal hypertension appeared much lower for cases (cases: 46% [95% CI 28%, 66%]; controls: 90% [95% CI 70%, 99%]; P = 0.003). We did not detect other case-control differences in recall (differentiality), even though the average time between childbirth and interview was 2.7 years for case and 3.7 years for control mothers. Many conditions exhibited notable differences between interview and records. We recommend use of multiple measurement sources to allow both cross-checking and synthesis of results into more accurate measures.

The Region 4 Genetics Collaborative has brought together metabolic clinicians and follow-up specialists from state departments of health in the region (Illinois, Indiana, Kentucky, Michigan, Minnesota, Ohio, and Wisconsin) in a workgroup to create a dynamic registry, the Inborn Errors of Metabolism Information System, to facilitate gathering information about long-term follow-up for individuals identified by newborn blood spot screening. With the concept that by developing a core series of agreed-on data elements and general treatment strategies, differences in treatment plans could yield evidence about optimal treatment choices, data elements for initial intake, and interval follow-up were selected based on a paradigm condition, medium-chain acyl-CoA dehydrogenase deficiency. Demographic elements that will be used as a common data set for all conditions were identified along with condition-specific elements and general information to be obtained at intervals. Subjects were enrolled after obtaining prospective informed consent; data entry began in January 2007. Additional conditions have had data sets defined and data entry initiated; 21 disorders as of July 2009. Web-based data entry has been employed using DocSite® as the platform for data entry. With continued collaboration among members of the workgroup, we hope to extend the intellectual questions that can be explored using this data, expand the spectrum of the registry and number of patients engaged, and integrate the registry into additional domains.

Atopic disease is hypothesized to be protective against several malignancies, including childhood/adolescent leukemia. To summarize the available epidemiologic evidence, the authors performed a meta-analysis of associations between atopy/allergies, asthma, eczema, hay fever, and hives and childhood/adolescent leukemia, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). They searched MEDLINE literature (1952–March 2009) and queried international experts to identify eligible studies. Ten case-control studies were included. Summary odds ratios and 95% confidence intervals were computed via random-effects models. Odds ratios for atopy/allergies were 1.42 (95% confidence interval (CI): 0.60, 3.35) for 3 studies of leukemia overall, 0.69 (95% CI: 0.54, 0.89) for 6 studies of ALL, and 0.87 (95% CI: 0.62, 1.22) for 2 studies of AML, with high levels of heterogeneity detected for leukemia overall and ALL. Inverse associations were observed for ALL and asthma (odds ratio (OR) = 0.79, 95% CI: 0.61, 1.02), eczema (OR = 0.74, 95% CI: 0.58, 0.96), and hay fever (OR = 0.55, 95% CI: 0.46, 0.66) examined separately. Odds ratios for ALL differed by study design, exposure data source, and latency period, indicating that these factors affect study results. These results should be interpreted cautiously given the modest number of studies, substantial heterogeneity, and potential exposure misclassification but are useful in designing future research.

The FLASH XUV-free electron laser has been used to irradiate solid samples at intensities of the order 1016 W cm-2 at a wavelength of 13.5 nm. The subsequent time integrated XUV emission was observed with a grating spectrometer. The electron temperature inferred from plasma line ratios was in the range 5-8 eV with electron density in the range 1021-1022 cm-3. These results are consistent with the saturation of absorption through bleaching of the L-edge by intense photo-absorption reported in an earlier publication. © 2009 Elsevier B.V. All rights reserved.

Up to 15% of infants with asymptomatic congenital cytomegalovirus (CMV) infection will experience some degree of sensorineural hearing loss. Many infants who fail newborn hearing screening (NHS) are likely to have congenital CMV infection, but may escape definitive virologic identification because diagnostic evaluation may not commence until several weeks or months of age, making differentiation between congenital and postnatal CMV infection difficult. Early diagnosis linking virologic identification of congenital CMV infection to infants failing NHS may improve diagnostic precision and enhance opportunities for therapeutic intervention.The goal of this study was to compare newborn dried blood spots from Minnesota infants who had failed NHS, and were designated for referral, with control infants who passed NHS, for the presence of CMV DNA by real-time PCR, using hybridization probes for the CMV gene UL54.Of 479 infants with a failed NHS (bilateral failure), 13 had CMV DNA present in the blood spot (2.7%). This compared with only 2/479 positive results from a control group of infants who passed the NHS (0.4%; P = 0.007, Fisher exact test). Comparisons of the glycoprotein B (gB) genotype as well as direct DNA sequencing of selected positives revealed that PCR positive samples represented unique clinical isolates. The mean viral load among the 15 positive samples was 1.6 x 10(3) genomes/microgram of total DNA.Newborn bloodspot CMV screening by real-time PCR may be a useful and rapid adjunct to functional NHS and may enable more rapid etiologic diagnosis of sensorineural hearing loss in newborns.

OBJECTIVE. Cerebral malaria affects >785000 African children every year. We previously documented an increased frequency of cognitive impairment in children with cerebral malaria 6 months after their initial malaria episode. This study was conducted to determine the long-term effects of cerebral malaria on the cognitive function of these children. METHODS. Children who were 5 to 12 years of age and presented to Mulago Hospital, Kampala, Uganda, with cerebral malaria (n = 44) or uncomplicated malaria (n = 54), along with healthy, asymptomatic community children (n = 89), were enrolled in a prospective cohort study of cognition. Cognitive testing was performed at enrollment and 2 years later. The primary outcome was presence of a deficit in ≥1 of 3 cognitive areas tested. RESULTS. At 2-year follow-up testing, 26.3% of children with cerebral malaria and 12.5% with uncomplicated malaria had cognitive deficits in ≥1 area, as compared with 7.6% of community children. Deficits in children with cerebral malaria were primarily in the area of attention (cerebral malaria, 18.4%, vs community children, 2.5%). After adjustment for age, gender, nutrition, home environment, and school level, children with cerebral malaria had a 3.67-fold increased risk for a cognitive deficit compared with community children. Cognitive impairment at 2-year follow-up was associated with hyporeflexia on admission and neurologic deficits 3 months after discharge. CONCLUSIONS. Cerebral malaria is associated with long-term cognitive impairments in 1 of 4 child survivors. Future studies should investigate the mechanisms involved so as to develop interventions aimed at prevention and rehabilitation.

Cerebrospinal fluid (CSF) and serum levels of 12 cytokines or chemokines important in central nervous system (CNS) infections were measured in 76 Ugandan children with cerebral malaria (CM) and 8 control children. As compared with control children, children with cerebral malaria had higher cerebrospinal fluid levels of interleukin (IL)-6, CXCL-8/IL-8, granulocyte-colony stimulating factor (G-CSF), tumor necrosis factor-alpha (TNF-alpha), and IL-1 receptor antagonist. There was no correlation between cerebrospinal and serum cytokine levels for any cytokine except G-CSF. Elevated cerebrospinal fluid but not serum TNF-alpha levels on admission were associated with an increased risk of neurologic deficits 3 months later (odds ratio 1.55, 95% CI: 1.10, 2.18, P = 0.01) and correlated negatively with age-adjusted scores for attention (Spearman rho, -0.34, P = 0.04) and working memory (Spearman rho, -0.32, P = 0.06) 6 months later. In children with cerebral malaria, central nervous system TNF-alpha production is associated with subsequent neurologic and cognitive morbidity.

A well-known heuristic in epidemiology is that non-differential exposure or disease misclassification biases the expected values of an estimator toward the null value. This heuristic works correctly only when additional conditions are met, such as independence of classification errors. We present examples to show that, even when the additional conditions are met, if the misclassification is only approximately non-differential, then bias is not guaranteed to be toward the null. In light of such examples, we advise that evaluation of misclassification should not be based on the assumption of exact non-differentiality unless the latter can be deduced logically from the facts of the situation.

Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. In the past various classification systems for HLDs have been used, based on imaging findings, clinical manifestation, and organelle-specific disorders. Here we present a molecular insight into HLDs based on a defect in specific gene engaged in myelination. We discuss recent findings on pathogenesis, clinical presentation, and imaging related to these disorders. We focus on HLDs that are in use in differential diagnostics of Pelizaeus-Merzbacher disease (PMD), with a special emphasis on Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition with delayed myelination due to thyroid transport disturbances. On the background of previously published patients we describe a proband initially considered as presenting with a severe PMD, whose diagnosis of AHDS due to a novel nonsense SLC16A2 mutation unraveled two previously undiagnosed generations of affected males who died in infancy from unexplained reasons. Since AHDS is found to be a relatively frequent cause of X-linked intellectual disability, we emphasize the need for determining the whole thyroid profile especially in hypotonic males with a delay of psychomotor development.

DYT1 primary torsion dystonia is an autosomal dominant disorder caused by deletion of a GAG triplet in exon 5 of the DYT1 gene. A significant proportion of individuals with early-onset generalized dystonia is believed to be DYT1 mutation carriers. We assessed the frequency of the GAG deletion in the DYT1 gene in a group of 61 Polish probands with clinical diagnosis of primary dystonia. The deletion was identified in four probands presenting with early-onset generalized disease (7%). Further studies in probands' families revealed two symptomatic and nine asymptomatic mutation carriers. We tested all mutation-positive individuals for the presence of some common polymorphisms within the DYT1 gene. Two of the 15 mutation-positive individuals additionally carried polymorphisms in 3'-UTR of the gene. Early onset in a limb and progression toward a generalized form, but not family history of dystonia, are indicative of DYT1 dystonia in Polish dystonic individuals.

OBJECTIVE. This study was conducted to assess prospectively the frequency of cognitive deficits in children with cerebral malaria. METHODS. Cognitive testing in the areas of working memory, attention, and learning was performed for Ugandan children 5 to 12 years of age with cerebral malaria (n = 44), children with uncomplicated malaria (n = 54), and healthy community children (n = 89) at admission and 3 and 6 months later. RESULTS. Six months after discharge, 21.4% of children with cerebral malaria had cognitive deficits, compared with 5.8% of community children. Deficits were seen in the areas of working memory (11.9% vs 2.3%) and attention (16.7% vs 2.3%). Children with cerebral malaria had a 3.7-fold increased risk of a cognitive deficit, compared with community children, after adjustment for age, gender, nutritional status, school level, and home environment. Among children with cerebral malaria, those with a cognitive deficit had more seizures before admission (mean: 4.1 vs 2.2) and a longer duration of coma (43.6 vs 30.5 hours), compared with those without a deficit. Children with uncomplicated malaria did not have an increased frequency of cognitive deficits. CONCLUSIONS. Cerebral malaria may be a major cause of cognitive impairment in children in sub-Saharan Africa. Cognitive deficits in children with cerebral malaria are more likely for those who have multiple seizures before effective treatment for cerebral malaria.

One important source of error in study results is error in measuring exposures. When interpreting study results, one should consider the impact that exposure-measurement error (EME) might have had on study results. To assess how often this consideration is made and the form it takes, journal articles were randomly sampled from original articles appearing in the American Journal of Epidemiology and Epidemiology in 2001, and the International Journal of Epidemiology between December 2000 and October 2001. Twenty-two (39%) of the 57 articles surveyed mentioned nothing about EME. Of the 35 articles that mentioned something about EME, 16 articles described qualitatively the effect EME could have had on study results. Only one study quantified the impact of EME on study results; the investigators used a sensitivity analysis. Few authors discussed the measurement error in their study in any detail. Overall, the potential impact of EME on error in epidemiologic study results appears to be ignored frequently in practice.

Background Many investigators write as if non-differential exposure misclassification inevitably leads to a reduction in the strength of an estimated exposure-disease association. Unfortunately, non-differentiality alone is insufficient to guarantee bias towards the null. Furthermore, because bias refers to the average estimate across study repetitions rather than the result of a single study, bias towards the null is insufficient to guarantee that an observed estimate will be an underestimate. Thus, as noted before, exposure misclassification can spuriously increase the observed strength of an association even when the misclassification process is non-differential and the bias it produced is towards the null. Methods We present additional results on this topic, including a simulation study of how often an observed relative risk is an overestimate of the true relative risk when the bias is towards the null. Results The frequency of overestimation depends on many factors: the value of the true relative risk, exposure prevalence, baseline (unexposed) risk, misclassification rates, and other factors that influence bias and random error. Conclusions Non-differentiality of exposure misclassification does not justify claims that the observed estimate must be an underestimate; further conditions must hold to get bias towards the null, and even when they do hold the observed estimate may by chance be an overestimate.

Since the investigations on petrified wood performed so far have not proved the assumption that the ring structure is coupled to the changes in the crystalline form of silica, attention was paid to other possible reasons. Using small angle X-ray scattering methods we determined the Porod curves and pore size distributions for five different samples of petrified wood, of different origin. We observed clear porosity differences in different samples. In addition, the normal X-ray diffractometric measurements were carried out, which gave a totally uniform image of the crystallographic structure of all the samples. All of them were made of pure α-quartz. The differentiation of rings in dark and bright zones should be put down to the changes in porosity rather than to other factors. The pores seem to be much more concentrated in those ring locations, which correspond to the original dark wood positions in living wood.

A series of mono- and dinuclear lanthanum complexes of 15,31-dimethyl-3,11,19,27,33,35-hexaazapentacyclo[27.3.1.1.(5,9)1,(13,17). 1(21,25)]hexatriaconta-5,7,9(33),13,15,17(34),21,23,25(35),29,31, 1(36)-dodecaene-34,36-diol (24RBPyBC, L) have been defined in solution. Their ability to hydrolyze bis(4-nitrophenyl) phosphate, a phosphate diester, was studied. The various metal-coordinated hydroxide nucleophiles that form in solution attack the substrate in the hydrolysis reaction. The dihydroxo dilanthanum complex, L-2La-2(OH), is the most effective catalyst. Its rate constant is 75 times larger than the rate constant for the monohydroxo dilanthanum complex, L-2La-OH. The mononuclear complexes are not as successful as the dinuclear complexes because they have fewer metal ions per complex to act as Lewis acids. They also cannot generate hydroxide nucleophiles at low pH values like the dinuclear complexes can. The reaction has an unusual third-order dependence on the catalyst concentration which is valid for the dinuclear complexes as well as the mononuclear complexes. This implies a mechanism where a metal-coordinated hydroxide nucleophile attacks the phosphorus of the substrate on the side opposite the negatively charged oxygens.

The technique of calculating the spectrum of a diatomic molecule from the spectrum of another diatomic molecule by the use of the generalized potential curve (GRPC) method is tested and demonstrated on the example of the ground state of alkali diatomic molecules, and is applied to predict the vibrational and rotational spectrum for the ground state of KRb from 69% to 90% of the depth of the potential well, D e , which had been estimated by the use of the RPC method to be 4220 cm −1 (cf. F. Jenc and B. A. Brandt, J. Mol. Spectrosc. 154, 226-228 (1992)). Lower and upper limits of the spectral energy values are also estimated. In the tests (where the potential is known up to the dissociation limit), high accuracy has been obtained.

Purpose Special care must be taken when adjusting for outcome misclassification in case-control data. Basic adjustment formulas using either sensitivity and specificity or predictive values (as with external validation data) do not account for the fact that controls are sampled from a much larger pool of potential controls. A parallel problem arises in surveys and cohort studies in which participation or loss is outcome related. Methods We review this problem and provide simple methods to adjust for outcome misclassification in case-control studies, and illustrate the methods in a case-control birth certificate study of cleft lip/palate and maternal cigarette smoking during pregnancy. Results Adjustment formulas for outcome misclassification that ignore case-control sampling can yield severely biased results. In the data we examined, the magnitude of error caused by not accounting for sampling is small when population sensitivity and specificity are high, but increases as (1) population sensitivity decreases, (2) population specificity decreases, and (3) the magnitude of the differentiality increases. Failing to account for case-control sampling can result in an odds ratio adjusted for outcome misclassification that is either too high or too low. Conclusions One needs to account for outcome-related selection (such as case-control sampling) when adjusting for outcome misclassification using external information.

Maternal diet during pregnancy may be associated with cancer in offspring. Intake of individual foods, as well as dietary patterns, can be used when examining these relations. Here, the authors examined associations between maternal dietary intake patterns and pediatric germ cell tumors (GCTs) using principal components analysis and logistic regression. Mothers of 222 GCT cases aged less than 15 years who were diagnosed at a Children's Oncology Group institution between 1993 and 2001 and those of 336 frequency-matched controls completed a self-administered food frequency questionnaire of diet during early pregnancy. Four dietary patterns were identified: “Western,” “fruits and vegetables,” “protein,” and “healthful.” With adjustment for birth weight, parity, and vitamin use, the fruits and vegetables pattern was significantly associated with a lower odds for GCTs (odds ratio (OR) = 0.83, 95% confidence interval (CI): 0.69, 0.99; 2 sided). Upon stratification, the fruits and vegetables pattern was significantly associated with a lower odds in males (OR = 0.66, 95% CI: 0.47, 0.92) but not females (OR = 0.91, 95% CI: 0.72, 1.14). A quantitative assessment of assumed nondifferential reporting error indicated no notable deviations from unadjusted odds ratio estimates. Results of this exploratory analysis suggest that maternal prenatal dietary patterns could be considered in future studies of GCTs in offspring.

Previous studies have demonstrated different levels of processing for visual stimuli dependent upon whether the objects were attended to or not. This study consisted of two manipulations to further diagnose the processing of unattended objects. First, the attended object was visually degraded on some trials to determine if this would negatively influence the processing of unattended images. Second, the number of unattended objects within a trial was varied. Previous studies used one unattended object, while this study will use both one and three unattended objects within a trial. Although the degradation of the attended object did result in significantly longer reaction times in their naming, both degradation of the attended object and the amount of unattended objects did not influence the processing of unattended objects.

Summary. To study the effect of a new direct acting reversible P2Y12 inhibitor, elinogrel (PRT060128), and the relation to cytochrome P450 (CYP) polymorphisms in patients with high platelet reactivity (HPR) on standard dual antiplatelet therapy. Methods and Results: We studied the pharmacodynamic and pharmacokinetic effects of a single 60-mg oral dose of elinogrel in 20 of 45 previously stented stable patients with HPR. We also genotyped for CYP2C19*2,3,5,17 and CYP3A5*3. Platelet reactivity fell within 4 h of dosing, the earliest time point evaluated as measured by the following assays: maximum 5 and 10 μm ADP LTA (P

Background Several interventions to improve cognition in at risk children have been suggested. Identification of key variables predicting cognition is necessary to guide these interventions. This study was conducted to identify these variables in Ugandan children and guide such interventions. Methods A cohort of 89 healthy children (45 females) aged 5 to 12 years old were followed over 24 months and had cognitive tests measuring visual spatial processing, memory, attention and spatial learning administered at baseline, 6 months and 24 months. Nutritional status, child's educational level, maternal education, socioeconomic status and quality of the home environment were also measured at baseline. A multivariate, longitudinal model was then used to identify predictors of cognition over the 24 months. Results A higher child's education level was associated with better memory (p = 0.03), attention (p = 0.005) and spatial learning scores over the 24 months (p = 0.05); higher nutrition scores predicted better visual spatial processing (p = 0.002) and spatial learning scores (p = 0.008); and a higher home environment score predicted a better memory score (p = 0.03). Conclusion Cognition in Ugandan children is predicted by child's education, nutritional status and the home environment. Community interventions to improve cognition may be effective if they target multiple socioeconomic variables.

Background: Recent studies in childhood cancer suggest that maternal vitamin supplementation may reduce the risk of leukaemia, neuroblastoma and certain types of childhood brain tumours. For example, a previous study found a significantly reduced risk of acute lymphoblastic leukaemia (ALL) but not acute myeloid leukaemia (AML) in children with Down syndrome whose mothers reported any vitamin supplement use prior to knowledge of pregnancy (ALL OR adjusted for confounders 0.51, 95% confidence limits (CL): 0.30, 0.89; AML OR adjusted for confounders 0.92, 95% CL 0.48, 1.76). Recall of exposures, including maternal vitamin supplement use, however, may be difficult and subject to error. Epidemiologists are encouraged to quantitatively adjust for systematic error in study results, but often do not. Methods: The impact that misclassification of maternal vitamin supplement use may have had on the observed ORs in this study was quantified. Uncertainty analysis was used to calculate ORs adjusted for inaccurate reporting of vitamin supplement use under assumed probability distributions for exposure misclassification parameters. Results: Given our assumptions, adjustment for exposure misclassification yielded ORs that were predominantly more protective for ALL than the crude OR. Conclusions: Uncertainty analysis can give important insights into the magnitude and direction of error in study results due to exposure misclassification.

Introduction: The ADP receptor P2Y 12 plays a central role in platelet function. Clopidogrel therapy is associated with various limitations including irreversible inhibition, a delayed antiplatelet effect, wide response variability, and non-responsiveness that has been linked to adverse ischemic event occurrence. We report the first pharmacodynamic study of a single oral dose of PRT060128 (PRT128), a novel, direct-acting reversible P2Y 12 inhibitor in patients with high platelet reactivity while on maintenance dose clopidogrel therapy(75mg/d) and aspirin. Methods: Previously stented patients (n=27) on maintenance aspirin and clopidogrel therapy were screened for high platelet reactivity (HPR) defined as upper tertile 5μ M ADP-induced aggregation (>43%) based on prior studies conducted at our Center; 7/27 had HPR and were treated with a single oral dose (60 mg) of PRT128. Platelet function was assessed at baseline, 4 hours, 6 hours, and 24 hours post-dosing by light transmittance aggregometry (LTA) stimulated by 5μ M, 20 μ M ADP, and 4μ g/ml collagen; Thrombelastography PlateletMapping (MA ADP ), Accumetrics P2Y12 assay (PRU), platelet reactivity ratio (%) by vasodilator stimulated phosphoprotein phosphorylation (VASP), and Perfusion Chamber Assay (PCA). Results: Results shown in the Table represent means ± standard deviation for the 7 patients at each time point. Conclusion: Based on results using multiple pharmacodynamic assays, PRT060128 is a potent rapid-acting inhibitor of P2Y 12 that overcomes high platelet reactivity in patients non-responsive to clopidogrel therapy. The pharmacodynamic properties of this novel P2Y 12 antagonist warrant future large scale investigations to determine clinical efficacy.

Background Tobacco use has been found to be more prevalent among lesbian, gay, bisexual, and transgender (LGBT) adults than among the general population, but there is little information about LGBT youth. This study examined tobacco use in relation to sexual identity in a community venue-based sample of youth. Methods Time–space sampling was used to select individuals aged 13–24 years visiting venues frequented by both LGBT and non-LGBT youth, including drop-in and recreational centers, cafes, bars, and a park. ORs for the association between LGBT identity and tobacco use were estimated using logistic regression models with adjustment for demographic covariates and venue selection. The two main outcomes were lifetime and last-30-day cigarette smoking. Sixteen secondary outcomes pertained to the type, initiation, frequency, and quantity of tobacco use; symptoms of dependence; and cessation. Results Seventy-seven percent (500/653) of eligible participants completed surveys by interview in 2005–2006. Sixty-three percent smoked in the last 30 days, 22% smoked more than 30 days ago, and 17% reported no prior cigarette smoking. LGBT identity predicted any prior cigarette use (OR 2.2, 95% CI=1.7, 3.2), but not recent use. Compared to non-LGBT youth, LGBT participants were less likely to use smokeless tobacco (OR 0.6, 95% CI=0.5, 0.7) and to want to quit smoking cigarettes (OR 0.6, 95% CI=0.5, 0.8). Other tobacco-related attitudes and behaviors were similar. Conclusions Few meaningful differences in tobacco use were related to sexual identity. The remarkably high levels of cigarette smoking in the sample highlights the need for prevention and cessation resources.

Cerebrospinal fluid (CSF) and serum levels of 12 cytokines or chemokines important in central nervous system (CNS) infections were measured in 76 Ugandan children with cerebral malaria (CM) and 8 control children. As compared with control children, children with cerebral malaria had higher cerebrospinal fluid levels of interleukin (IL)-6, CXCL-8/IL-8, granulocyte-colony stimulating factor (G-CSF), tumor necrosis factor-alpha (TNF-alpha), and IL-1 receptor antagonist. There was no correlation between cerebrospinal and serum cytokine levels for any cytokine except G-CSF. Elevated cerebrospinal fluid but not serum TNF-alpha levels on admission were associated with an increased risk of neurologic deficits 3 months later (odds ratio 1.55, 95% CI: 1.10, 2.18, P = 0.01) and correlated negatively with age-adjusted scores for attention (Spearman rho, -0.34, P = 0.04) and working memory (Spearman rho, -0.32, P = 0.06) 6 months later. In children with cerebral malaria, central nervous system TNF-alpha production is associated with subsequent neurologic and cognitive morbidity.