Piecemeal degranulation of mast cells in the inflammatory eyelid lesions of interleukin-4 transgenic mice. Evidence of mast cell histamine release in vivo by diamine oxidase-gold enzyme-affinity ultrastructural cytochemistry

We used light and electron microscopy to analyze the eyelid inflammation that develops in transgenic mice that overexpress interleukin-4 (IL-4; Tepper et al, Cell 62:457, 1990). Analysis of alkaline Giemsa-stained plastic sections examined by light microscopy (Dvorak et al, J Exp Med 132:558, 1970), as well as by routine transmission electron microscopy, indicated that the mast cells in the inflammatory eyelid lesions were undergoing piecemeal degranulation, a form of secretion in which the cells' cytoplasmic granules exhibit characteristic morphologic changes that are thought to be associated with the prolonged, vesicle-mediated release of the granules' constituents. Moreover, by using a newly reported enzyme affinity-gold method, which stains histamine based on binding to diamine oxidase-gold (Dvorak et al, J Histochem Cytochem 41:787, 1993), we show that these activated mast cells had released much of their histamine content. The eyelid lesions also exhibited increased numbers of mast cells; interstitial fibrosis, particularly around cutaneous nerves and blood vessels; activated fibroblasts; focal axonal damage; venules with endothelial cells containing numerous vesiculo-vacuolar organelles; and infiltrates of neutrophils and eosinophils. Our findings illustrate that overexpression of the IL-4 gene in vivo can result in eyelid lesions associated with piecemeal degranulation of mast cells, as well as tissue fibrosis and a variety of other pathologic changes. These results also represent the first direct morphologic evidence for histamine secretion by mast cells in vivo.     

Primary structure of the (1-->3,1-->4)-beta-D-glucan 4-glucohydrolase from barley aleurone

During germination of barley grains, the cell walls of the starchy endosperm are degraded by (1→3,1→4)-β-glucanases (EC 3.2.1.73) secreted from the aleurone and scutellar tissues. The complete sequence of the aleurone (1→3,1→4)-β-glucanase isoenzyme II comprises 306 amino acids and was determined by sequencing nine tryptic peptides (110 residues) and aligning them with the amino acid sequence deduced from a cDNA clone encoding the 291 NH₂-terminal residues. Although no amino acid sequence homology with a bacterial (1→3)(1→4)-β-glucanase is apparent, close to 50% homology is found with two large regions of a (1→3)-β-glucanase from tobacco pith tissue. The gene for barley (1→3,1→4)-β-glucanase isoenzyme II shares with that for the α-amylase isoenzyme 1 a strongly preferred use of codons with G and C in the wobble position (94% and 90%, respectively). Both enzymes are secreted from the aleurone cells during germination. Such one-sided codon usage is not characteristic for the gene encoding the (1→3)-β-glucanase of tobacco pith tissue or the hor2-4 gene encoding the B₁ hordein storage protein in the endosperm.     

Point-of-care testing versus standard practice for chlamydia: a new approach to assessing the public health effect of rapid testing and treatment at local level

BackgroundChlamydia trachomatis is the most commonly diagnosed bacterial sexually transmitted infection in Britain. Present standards specify treatment within 14 days of testing positive; point-of-care testing (POCT) can eliminate this delay and potentially reduce loss to follow-up; its greater convenience might increase testing. 90-min nucleic acid amplification tests are the best available POCTs for chlamydia, with alternatives under development. However, cost-effectiveness depends on cost-per-test, sensitivity and specificity, and the effect of POCT on transmission.MethodsWe developed a user-friendly web-based method, based on a transmission-dynamic model for chlamydia, to assess the epidemiological impact and cost-effectiveness of introducing POCT in different local settings. The model uses behavioural and prevalence data from the National Survey of Sexual Attitudes and Lifestyles, and Public Health England surveillance data; these data inform on local-level variation, which is represented by sampling parameter values from within their ranges of uncertainty and selecting parameter sets that reproduce local coverage and diagnosis rates. The user can select different local settings, and vary sensitivity and specificity for the tests, specify costs (fixed and unit costs, including staff time), and then assess the effect of introducing POCT in different clinical services by comparison with a situation with no POCT. In the model, presumptive treatment is represented, which we expect to be reduced with the introduction of POCT because test results would be rapidly available to guide treatment.FindingsChanges in numbers of infections and diagnoses occurring under different scenarios (including conventional testing) were estimated, with uncertainty ranges, allowing calculation of total costs, and cost per infection (and serious sequelae) averted, while accommodating the considerable variation in chlamydia testing coverage, positivity, and diagnosis rates. Potential changes in sexual behaviour between test and treatment could determine the relative contribution of increased treatment rates and reduced treatment delay to the reduction in prevalence as a consequence of POCT.InterpretationThe effect of POCT was dependent on both the test performance characteristics and the assumptions about the implementation of the test across local services. Exploration of many uncertainties surrounding chlamydia epidemiology and screening implementation is possible with this model. This method can complement local and national knowledge, and contribute to local-level management of chlamydia infection.FundingInnovate UK (Technology Strategy Board), UK Medical Research Council, and the National Institute for Health Research. The Electronic Self-Testing Instruments for Sexually Transmitted Infection (eSTI2) Consortium eSTI2 is Funded under the UKCRC Translational Infection Research (TIR) Initiative supported by the Medical Research Council (Grant Number G0901608) with contributions to the Grant from the Biotechnology and Biological Sciences Research Council, the National Institute for Health Research on behalf of the Department of Health, the Chief Scientist Office of the Scottish Government Health Directorates, and the Wellcome Trust     

Hepatitis C Seroprevalence Among Prison Inmates Since 2001: Still High but Declining

Objectives

Although the hepatitis C epidemic in the United States disproportionately affects correctional populations, the last national estimates of seroprevalence and disease burden among these populations are more than a decade old. We investigated routine hepatitis C surveillance conducted in state prison systems and updated previous estimates.

Methods

We surveyed all U.S. state correctional departments to determine which state prison systems had performed routine hepatitis C screening since 2001. Using seroprevalence data for these prison systems, we estimated the national hepatitis C seroprevalence among prisoners in 2006 and the share of the epidemic borne by correctional populations.

Results

Of at least 12 states performing routine testing from 2001 to 2012, seroprevalences of hepatitis C ranged from 9.6% to 41.1%. All but one state with multiple measurements demonstrated declining seroprevalence. We estimated the national state prisoner seroprevalence at 17.4% in 2006. Based on the estimated total U.S. correctional population size, we projected that 1,857,629 people with hepatitis C antibody were incarcerated that year. We estimated that correctional populations represented 28.5%–32.8% of the total U.S. hepatitis C cases in 2006, down from 39% in 2003.

Conclusions

Our results provide an important updated estimate of hepatitis C seroprevalence and suggest that correctional populations bear a declining but still sizable share of the epidemic. Correctional facilities remain important sites for hepatitis C case finding and therapy implementation. These results may also assist future studies in projecting the societal costs and benefits of providing new treatment options in prison systems.Hepatitis C virus (HCV) is the most common chronic bloodborne pathogen in the United States, both in the general population and among prisoners. National Health and Nutrition Examination Survey (NHANES) data from 2003–2006 suggested an overall anti-HCV serum antibody prevalence (seroprevalence) of 1.3% among household-dwelling populations.¹ Others have suggested that the national seroprevalence may be closer to 2.0% after adding prisoners, homeless people, and other populations not sampled by NHANES.² However, enrollment in NHANES requires several months of housing stability,³ so people with unstable or intermittent housing at any time during a given year are unlikely to participate. Thus, the number of infected people not in households during a period of time, rather than at a single point, should be added to the national seroprevalence estimate.Unsafe injection practices, including injection drug use, are the primary risk factors for HCV infection in the general population.⁴ National HCV prevalence is greater among men than women, and among non-Hispanic black people compared with non-Hispanic white people.¹ Prevalence peaks among individuals born between 1945 and 1965.⁵HCV infection disproportionately affects those who have been in jails and prisons. Although men (compared with women) and black people (compared with white people) are disproportionately incarcerated, the most likely cause for this infection rate disparity is injection drug use, which is both a risk factor for the disease and a criminal behavior.⁶ Hammett et al. estimated that correctional populations in 1997 accounted for 29.4%–43.2% of the total U.S. hepatitis C case burden.⁷ In 2003, the Centers for Disease Control and Prevention (CDC) reported that 16%–41% of inmates had serological evidence of prior HCV exposure, based on data derived from eight states. CDC also estimated that correctional populations bore 39% of the disease burden.⁸The 1976–1980 birth cohort currently comprises the largest proportion of state prison, federal prison, and local jail populations.⁹ As the birth cohort with peak HCV prevalence (1945–1965) ages out of crime-prone years, its contact with the criminal justice system will decline. Hence, the prevalence of HCV among correctional populations should fall. Two states included in the 2003 CDC analysis have since updated their seroprevalence estimates and both demonstrated declines. In Rhode Island, a sampling of prisoners in the mid-1990s showed an HCV seroprevalence of 37%,¹⁰ but seroprevalence dropped to 23% from 1998 to 2000.¹¹ In California, seroprevalence dropped from 41% of entering inmates in 1994¹² to 34% among a small cohort of entrants tested in 2001.¹³It has been estimated that 65%–75% of people with viral hepatitis are unaware of their status.¹⁴ Inmates are likely to be at the upper end of this range.¹⁵ Correctional facilities have represented rich sources for case finding. Once identified, new cases can be directed to treatment programs either in prison or the community. The need to initiate treatment before release for each case is contingent upon multiple factors. One determinant is whether the expected duration of incarceration is longer than the time required for treatment, which is currently one year but becoming shorter.¹⁶Prison health-care planners would benefit from up-to-date information regarding the number of hepatitis C infections in their systems. Currently, the U.S. lacks data on the prevalence of HCV among prisoners and the share of the epidemic borne by incarcerated individuals since the last national estimates were derived a decade ago.^7,8 We investigated routine HCV surveillance conducted in state prison systems to update estimates of the national prison HCV seroprevalence and the share of the epidemic borne by inmates and releasees. We hypothesized that HCV prevalence was falling nationwide among prisoners and that imprisoned populations represented a reduced share of the hepatitis C epidemic.     

Pseudopapilledema and association with idiopathic intracranial hypertension

Purpose

Diagnosing idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, can be challenging in children. Diagnosis is based on lumbar puncture, opening pressures, and appearance of the optic disk. Misdiagnosis of papilledema, a typical finding, may lead to unnecessary treatments and procedures. We report 52 children over a 6-year period to better identify the true incidence of pseudopapilledema and other factors that may confound the diagnosis of IIH.

Methods

A retrospective chart review approved by the Institutional Review Board was performed. Fifty-two children under the age of 21 referred to us based on suspected IIH or papilledema from 2007 to 2013 are included in this study. Patients were assessed by a pediatric ophthalmologist and a neurosurgeon.

Results

Fifty-two children were initially diagnosed with IIH and/or papilledema; 26 diagnoses were revised to pseudopapilledema after pediatric ophthalmological review. Out of those 26 patients with pseudopapilledema, 14 had undergone lumbar punctures, 19 had MRIs, 9 had CTs, and 12 were taking medications—these medications were discontinued upon revision of the diagnoses. The difference in the CSF opening pressure between children diagnosed with true IIH (32.7 cm H₂O) and children diagnosed with pseudopapilledema (24.7 cm H₂O) was statistically significant.

Conclusions

IIH diagnosis is heavily reliant on the appearance of the optic disk. Pediatric ophthalmological assessment is essential to carefully examine the optic disk and prevent further unnecessary investigation and treatments. Close communication between pediatricians, ophthalmologists, and neurosurgeons can avoid invasive procedures for children who do have pseudopapilledema, and not IIH or associated papilledema.     

Associations of perceived prenatal stress and adverse pregnancy outcomes with perceived stress years after delivery

Archives of Women's Mental Health - Maternal stress is a risk factor for adverse pregnancy outcomes (APOs). This study evaluates the associations of prenatal stress and APOs with maternal...     

Soy Formula Is Not Estrogenic and Does Not Result in Reproductive Toxicity in Male Piglets: Results from a Controlled Feeding Study

Soy infant formula which is fed to over half a million infants per year contains isoflavones such as genistein, which have been shown to be estrogenic at high concentrations. The developing testis is sensitive to estrogens, raising concern that the use of soy formulas may result in male reproductive toxicity. In the current study, male White-Dutch Landrace piglets received either sow milk (Sow), or were provided milk formula (Milk), soy formula (Soy), milk formula supplemented with 17-beta-estradiol (2 mg/kg/d) (M + E2) or supplemented with genistein (84 mg/L of diet; (M + G) from postnatal day 2 until day 21. E2 treatment reduced testis weight (p < 0.05) as percentage of body weight, significantly suppressed serum androgen concentrations, increased tubule area, Germ cell and Sertoli cell numbers (p < 0.05) relative to those of Sow or Milk groups. Soy formula had no such effects relative to Sow or Milk groups. mRNAseq revealed 103 differentially expressed genes in the M + E2 group compared to the Milk group related to endocrine/metabolic disorders. However, little overlap was observed between the other treatment groups. These data suggest soy formula is not estrogenic in the male neonatal piglet and that soy formula does not significantly alter male reproductive development.     

Mapping Canadian Data Assets to Generate Real-World Evidence: Lessons Learned from Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration’s RWE Data Working Group

Canadian provinces routinely collect patient-level data for administrative purposes. These real-world data (RWD) can be used to generate real-world evidence (RWE) to inform clinical care and healthcare policy. The CanREValue Collaboration is developing a framework for the use of RWE in cancer drug funding decisions. A Data Working Group (WG) was established to identify data assets across Canada for generating RWE of oncology drugs. The mapping exercise was conducted using an iterative scan with informant surveys and teleconference. Data experts from ten provinces convened for a total of three teleconferences and two in-person meetings from March 2018 to September 2019. Following each meeting, surveys were developed and shared with the data experts which focused on identifying databases and data elements, as well as a feasibility assessment of conducting RWE studies using existing data elements and resources. Survey responses were compiled into an interim data report, which was used for public stakeholder consultation. The feedback from the public consultation was used to update the interim data report. We found that databases required to conduct real-world studies are often held by multiple different data custodians. Ninety-seven databases were identified across Canada. Provinces held on average 9 distinct databases (range: 8–11). An Essential RWD Table was compiled that contains data elements that are necessary, at a minimal, to conduct an RWE study. An Expanded RWD Table that contains a more comprehensive list of potentially relevant data elements was also compiled and the availabilities of these data elements were mapped. While most provinces have data on patient demographics (e.g., age, sex) and cancer-related variables (e.g., morphology, topography), the availability and linkability of data on cancer treatment, clinical characteristics (e.g., morphology and topography), and drug costs vary among provinces. Based on current resources, data availability, and access processes, data experts in most provinces noted that more than 12 months would be required to complete an RWE study. The CanREValue Collaboration’s Data WG identified key data holdings, access considerations, as well as gaps in oncology treatment-specific data. This data catalogue can be used to facilitate future oncology-specific RWE analyses across Canada.