Certolizumab treatment during late pregnancy in patients with rheumatic diseases: Low drug levels in cord blood but possible risk for maternal infections. A case series of 13 patients

OBJECTIVE Due to reduction of immune-suppressive drugs, patients with rheumatic diseases can experience an increase in disease activity during pregnancy. In such cases, TNF-inhibitors may be prescribed. However, monoclonal antibodies with the Fc moiety are actively transported across the placenta, resulting in therapeutic drug levels in the newborn. As certolizumab (CZP) lacks the Fc moiety, it may bear a lower risk for the child. METHOD We report a case series of thirteen patients (5 with rheumatoid arthritis and 8 with spondyloarthritis) treated with CZP during late pregnancy to control disease activity. RESULT CZP measured in cord blood of eleven infants ranged between undetectable levels and 1μg/mL whereas the median CZP level of maternal plasma was 32.97μg/mL. Three women developed an infection during the third trimester, of whom one had a severe infection and one had an infection that resulted in a pre-term delivery. During the postpartum period, 6 patients remained on CZP while breastfeeding. CZP levels in the breast milk of two breastfeeding patients were undetectable. CONCLUSION The lack of the active transplacental transfer of CZP gives the possibility to treat inflammatory arthritis during late gestation without potential harm to the newborn. However, in pregnant women treated with TNF-inhibitors and prednisone, attention should be given to the increased susceptibility to infections, which might cause prematurity. CZP treatment can be continued while breastfeeding.

Report from the National Institute of Allergy and Infectious Diseases workshop on drug allergy

Allergic reactions to drugs are a serious public health concern. In 2013, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop on drug allergy. International experts in the field of drug allergy with backgrounds in allergy, immunology, infectious diseases, dermatology, clinical pharmacology, and pharmacogenomics discussed the current state of drug allergy research. These experts were joined by representatives from several National Institutes of Health institutes and the US Food and Drug Administration. The participants identified important advances that make new research directions feasible and made suggestions for research priorities and for development of infrastructure to advance our knowledge of the mechanisms, diagnosis, management, and prevention of drug allergy. The workshop summary and recommendations are presented herein.

Atypical variants of bovine spongiform encephalopathy: rare diseases with consequences for BSE surveillance and control

Occurring for the first time in 1986 in the United Kingdom, bovine spongiform encephalopathy (BSE), the so-called “mad-cow disease”, has had unprecedented consequences in veterinary public health. The implementation of drastic measures, including the ban of meat-and-bone-meal from livestock feed and the removal of specified risk materials from the food chain has eventually resulted in a significant decline of the epidemic. The disease was long thought to be caused by a single agent, but since the introduction of immunochemical diagnostic techniques, evidence of a phenotypic variation of BSE has emerged. Reviewing the literature available on the subject, this paper briefly summarizes the current knowledge about these atypical forms of BSE and discusses the consequences of their occurrence for disease control measures.

Delineating the molecular basis of human genetic diseases: Epigenetic and functional studies

Identifying and characterizing the genes responsible for inherited human diseases will ultimately lead to a more holistic understanding of disease pathogenesis, catalyze new diagnostic and treatment modalities, and provide insights into basic biological processes. This dissertation presents research aimed at delineating the genetic and molecular basis of human diseases through epigenetic and functional studies and can be divided into two independent areas of research. The first area of research describes the development of two high-throughput melting curve based methods to assay DNA methylation, referred to as McMSP and McCOBRA. The goal of this project was to develop DNA methylation methods that can be used to rapidly determine the DNA methylation status at a specific locus in a large number of samples. McMSP and McCOBRA provide several advantages over existing methods, as they are simple, accurate, robust, and high-throughput making them applicable to large-scale DNA methylation studies. McMSP and McCOBRA were then used in an epigenetic study of the complex disease Ankylosing spondylitis (AS). Specifically, I tested the hypothesis that aberrant patterns of DNA methylation in five AS candidate genes contribute to disease susceptibility. While no statistically significant methylation differences were observed between cases and controls, this is the first study to investigate the hypothesis that epigenetic variation contributes to AS susceptibility and therefore provides the conceptual framework for future studies. ^ In the second area of research, I performed experiments to better delimit the function of aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1), which when mutated causes various forms of inherited blindness such as Leber congenital amaurosis. A yeast two-hybrid screen was performed to identify putative AIPL1-interacting proteins. After screening 2 × 106 bovine retinal cDNA library clones, 6 unique putative AIPL1-interacting proteins were identified. While these 6 AIPL1 protein-protein interactions must be confirmed, their identification is an important step in understanding the functional role of AIPL1 within the retina and will provide insight into the molecular mechanisms underlying inherited blindness. ^

Ionotropic Glutamate Receptors Show Unique Distribution and Localization in the Dorsal Cochlear Nucleus of the Rhesus Monkey

The dorsal cochlear nucleus (DCN) receives auditory information via the auditory nerve coming from the cochlea. It is responsible for much of the integration of auditory information, and it projects this auditory information to higher auditory brain centers for further processing. This study focuses on the DCN of adult Rhesus monkeys to characterize two specific cell types, the fusiform and cartwheel cell, based on morphometric parameters and type of glutamate receptor they express. The fusiform cell is the main projection neuron, while the cartwheel cell is the main inhibitory interneuron. Expression of AMPA glutamate receptor subunits is localized to certain cell types. The activity of the CN depends on the AMPA receptor subunit composition and expression. Immunocytochemistry, using specific antibodies for AMPA glutamate receptor subunits GluR1, GluR2/3 and GluR4, was used in conjunction with morphometry to determine the location, morphological characteristics and expression of AMPA receptor subunits in fusiform and cartwheel cells in the primate DCN. Qualitative as well as quantitative data indicates that there are important morphological differences in cell location and expression of AMPA glutamate receptor subunits between the rodent DCN and that of primates. GluR2/3 is widely expressed in the primate DCN. GluR1 is also widely expressed in the primate DCN. GluR4 is diffusely expressed. Expression of GluR2/3 and GluR4 in the primate is similar to that of the rodent. However, expression of GluR1 is different. GluR1 is only expressed by cartwheel cells in the rodent DCN, but is expressed by a variety of cells, including fusiform cells, in the DCN of the primate.

The nature and treatment of diseases of the ear

by William Kramer. Transl. from the German, with the latest improvements of the author since the last German ed. by James Risdon Bennett

DNA incisions stimulate genetic instability of triplet repeat sequences related to human hereditary neurological diseases

The molecular mechanisms responsible for the expansion and deletion of trinucleotide repeat sequences (TRS) are the focus of our studies. Several hereditary neurological diseases including Huntington's disease, myotonic dystrophy, and fragile X syndrome are associated with the instability of TRS. Using the well defined and controllable model system of Escherichia coli, the influences of three types of DNA incisions on genetic instability of CTG•CAG repeats were studied: DNA double-strand breaks (DSB), single-strand nicks, and single-strand gaps. The DNA incisions were generated in pUC19 derivatives by in vitro cleavage with restriction endonucleases. The cleaved DNA was then transformed into E. coli parental and mutant strains. Double-strand breaks induced deletions throughout the TRS region in an orientation dependent manner relative to the origin of replication. The extent of instability was enhanced by the repeat length and sequence (CTG•CAG vs. CGG•CCG). Mutations in recA and recBC increased deletions, mutations in recF stabilized the TRS, whereas mutations in ruvA had no effect. DSB were repaired by intramolecular recombination, versus an intermolecular gene conversion or crossover mechanism. 30 nt gaps formed a distinct 30 nt deletion product, whereas single strand nicks and gaps of 15 nts did not induce expansions or deletions. Formation of this deletion product required the CTG•CAG repeats to be present in the single-stranded region and was stimulated by E. coli DNA ligase, but was not dependent upon the RecFOR pathway. Models are presented to explain the DSB induced instabilities and formation of the 30 nucleotide deletion product. In addition to the in vitro creation of DSBs, several attempts to generate this incision in vivo with the use of EcoR I restriction modification systems were conducted. ^

Sexually transmissible diseases, sexual factors and prostate cancer: A review of literature

A review of literature was carried out regarding sexually related factors, sexually transmissible diseases (STD's) and infections with prostate cancer (PC) development risk. The review of literature, in conjunction with the tabulation of studies, suggested that ejaculation and circumcision may play a protective role in the development of PC and that multiple sex partners and an active sex life may play a causal role in the development of PC which may negate and counteract the protective effects of ejaculation and circumcision. HIV infection may plausibly play a function in deteriorating and compromising immune controls on carcinogenesis. Because of the coexistence of a highly active sexual lifestyle and sexual promiscuity with the growing occurence of STD's, their maybe a correlation with the high incidence of prostate cancer in the United States. Potential multi-institutional studies are warranted to confirm the high incidence of this neoplasm with the increasing cases of STD's and if in fact there is a proportional association to further elucidate the factors responsible for its high incidence.^

Quality assurance plan for a vaccine preventable diseases surveillance program

Public health surveillance programs for vaccine preventable diseases (VPD) need functional quality assurance (QA) in order to operate with high quality activities to prevent preventable communicable diseases from spreading in the community. Having a functional QA plan can assure the performance and quality of a program without putting excessive stress on the resources. A functional QA plan acts as a check on the quality of day-to-day activities performed by the VPD surveillance program while also providing data that would be useful for evaluating the program. This study developed a QA plan that involves collection, collation, analysis and reporting of information based on standardized (predetermined) formats and indicators as an integral part of routine work for the vaccine preventable disease surveillance program at the City of Houston Department of Health and Human Services. The QA plan also provides sampling and analysis plans for assessing various QA indicators, as well as recommendations to the Houston Department of Health and Humans Services for implementation of the QA plan. The QA plan developed for VPD surveillance in the City of Houston is intended to be a low cost system that could serve as a template for QA plans as part of other public health programs not only in the city or the nation, but could be adapted for use anywhere across the globe. Having a QA plan for VPD surveillance in the City of Houston would serve well for the funding agencies like the CDC by assuring that the resources are being expended efficiently, while achieving the real goal of positively impacting the health and lives of the recipient/target population. ^

A systematic review of economic evaluations for interventions of cardiovascular diseases

Background. Cardiovascular disease (CVD) exhibits the most striking public health significance due to its high prevalence and mortality as well as huge economic burdens all over the world, especially in industrialized countries. Major risk factors of CVDs have been the targets of population-wide prevention in the United States. Economic evaluations provide structured information in regard to the efficiency of resource utilization which can inform decisions of resource allocation. The main purpose of this review is to investigate the pattern of study design of economic evaluations for interventions of CVDs. ^ Methods. Primary journal articles published during 2003-2008 were systematically retrieved via relevant keywords from Medline, NHS Economic Evaluation Database (NHS EED) and EBSCO Academic Search Complete. Only full economic evaluations for narrowly defined CVD interventions were included for this review. The methodological data of interest were extracted from the eligible articles and reorganized in Microsoft Access database. Chi-square tests in SPSS were used to analyze the associations between pairs of categorical data. ^ Results. One hundred and twenty eligible articles were reviewed after two steps of literature selection with explicit inclusion and exclusion criteria. Descriptive statistics were reported regarding the evaluated interventions, outcome measures, unit costing and cost reports. The chi-square test of the association between prevention level of intervention and category of time horizon showed no statistical significance. The chi-square test showed that sponsor type was significantly associated with whether new or standard intervention being concluded as more cost effective. ^ Conclusions. Tertiary prevention and medication interventions are the major interests for economic evaluators. The majority of the evaluations were claimed from either a provider’s or a payer’s perspective. Almost all evaluations adopted gross costing strategy for unit cost data rather than micro costing. EQ-5D is the most commonly used instrument for subjective outcome measurement. More than half of the evaluations used decision analytic modeling techniques. The lack of consistency in study design standards in published evaluations appears in several aspects. Prevention level of intervention is not likely to be a factor for evaluators to decide whether to design an evaluation in a lifetime horizon or not. Published evaluations sponsored by industry are more likely to conclude that new intervention is more cost effective than standard intervention.^

Systematic review of genetic risk score in coronary heart disease and other diseases

In order to better take advantage of the abundant results from large-scale genomic association studies, investigators are turning to a genetic risk score (GRS) method in order to combine the information from common modest-effect risk alleles into an efficient risk assessment statistic. The statistical properties of these GRSs are poorly understood. As a first step toward a better understanding of GRSs, a systematic analysis of recent investigations using a GRS was undertaken. GRS studies were searched in the areas of coronary heart disease (CHD), cancer, and other common diseases using bibliographic databases and by hand-searching reference lists and journals. Twenty-one independent case-control studies, cohort studies, and simulation studies (12 in CHD, 9 in other diseases) were identified. The underlying statistical assumptions of the GRS using the experience of the Framingham risk score were investigated. Improvements in the construction of a GRS guided by the concept of composite indicators are discussed. The GRS will be a promising risk assessment tool to improve prediction and diagnosis of common diseases.^

Organization of the inferotemporal cortex in the macaque monkey: Connections of areas PITv and CITvp

Visual cortex of macaque monkeys consists of a large number of cortical areas that span the occipital, parietal, temporal, and frontal lobes and occupy more than half of cortical surface. Although considerable progress has been made in understanding the contributions of many occipital areas to visual perceptual processing, much less is known concerning the specific functional contributions of higher areas in the temporal and frontal lobes. Previous behavioral and electrophysiological investigations have demonstrated that the inferotemporal cortex (IT) is essential to the animal's ability to recognize and remember visual objects. While it is generally recognized that IT consists of a number of anatomically and functionally distinct visual-processing areas, there remains considerable controversy concerning the precise number, size, and location of these areas. Therefore, the precise delineation of the cortical subdivisions of inferotemporal cortex is critical for any significant progress in the understanding of the specific contributions of inferotemporal areas to visual processing. In this study, anterograde and/or retrograde neuroanatomical tracers were injected into two visual areas in the ventral posterior and central portions of IT (areas PITv and CITvp) to elucidate the corticocortical connections of these areas with well known areas of occipital cortex and with less well understood regions of inferotemporal cortex. The locations of injection sites and the delineation of the borders of many occipital areas were aided by the pattern of interhemispheric connections, revealed following callosal transection and subsequent labeling with HRP. The resultant patterns of connections were represented on two-dimensional computational (CARET) and manual cortical maps and the laminar characteristics and density of the projection fields were quantified. The laminar and density features of these corticocortical connections demonstrate thirteen anatomically distinct subdivisions or areas distributed within the superior temporal sulcus and across the inferotemporal gyrus. These results serve to refine previous descriptions of inferotemporal areas, validate recently identified areas, and provide a new description of the hierarchical relationships among occipitotemporal cortical areas in macaques. ^