The effect of preexisting anti-carrier immunity on subsequent responses to CRM197 or Qb-VLP conjugate vaccines

Context: Certain antigens, such as haptens (small molecules), short peptides, and carbohydrates (e.g. bacterial polysaccharides) are non- or poorly immunogenic unless conjugated to a carrier molecule that provides a structural scaffold for antigen presentation as well as T cell help required for B-cell activation and maturation. However, the carriers themselves are immunogenic and resulting carrier-specific immune responses may impact the immunogenicity of other conjugate vaccines using the same carrier that are administered subsequently.

Objective: Herein, using two different carriers (cross-reactive material 197, CRM and Qb-VLP), we examined in mice the impact that preexisting anti-carrier antibodies (Ab) had on subsequent immune responses to conjugates with either the same or a different carrier.

Method: For this purpose, we used two nicotine hapten conjugates (NIC7-CRM or NIC-Qb), two IgE peptide conjugates (Y-CRM or Y-Qb), and a pneumococcal polysaccharide conjugate (Prevnar 13^®).

Results: Prior exposure to CRM or Qb-VLP significantly reduced subsequent responses to the conjugated antigen having the homologous carrier, with the exception of Prevnar 13® where anti-polysaccharide responses were similar to those in animals without preexisting anti-carrier Ab.

Conclusion: Collectively, the data suggest that the relative sizes of the antigen and carrier, as well as the conjugation density for a given conjugate impact the extent of anti-carrier suppression. All animals developed anti-carrier responses with repeat vaccination and the differences in Ab titer between groups with and without preexisting anti-carrier responses became less apparent; however, anti-carrier effects were more durable for Ab function.     

Primary cilia act as mechanosensors during bone healing around an implant

The primary cilium is an organelle that senses cues in a cell's local environment. Some of these cues constitute molecular signals; here, we investigate the extent to which primary cilia can also sense mechanical stimuli. We used a conditional approach to delete Kif3a in pre-osteoblasts and then employed a motion device that generated a spatial distribution of strain around an intra-osseous implant positioned in the mouse tibia. We correlated interfacial strain fields with cell behaviors ranging from proliferation through all stages of osteogenic differentiation. We found that peri-implant cells in the Col1Cre;Kif3a^fl/fl mice were unable to proliferate in response to a mechanical stimulus, failed to deposit and then orient collagen fibers to the strain fields caused by implant displacement, and failed to differentiate into bone-forming osteoblasts. Collectively, these data demonstrate that the lack of a functioning primary cilium blunts the normal response of a cell to a defined mechanical stimulus. The ability to manipulate the genetic background of peri-implant cells within the context of a whole, living tissue provides a rare opportunity to explore mechanotransduction from a multi-scale perspective.     

MICA4/HLA-DRB1*04/TNF1 haplotype is associated with mixed connective tissue disease in Swedish patients

In order to investigate major histocompatibility complex (MHC) class I chain-related gene A (MICA), tumor necrosis factor (TNFa), -308TNFA, and human leukocyte antigen (HLA-DR/DQ) polymorphisms in mixed connective tissue disease (MCTD), we analyzed 24 patients and 229 healthy controls from Sweden. MICA and TNFa typing was performed by polymerase chain reaction (PCR) and genotyping. HLA-DR and -DQ were genotyped using PCR-sequence specific primers (PCR-SSP) and PCR-sequence-specific oligonucleotide probe (PCR-SSOP), respectively. For analysis of -308TNFA polymorphisms we performed PCR with restriction endonuclease enzymes. We found that the MICA5.1-5.1 genotype was positively associated with MCTD. Shared epitope genes (DRB1*01 and DRB1*04) were also significantly positively associated with MCTD. Polymorphism of -308TNFA was not differently distributed in MCTD patients compared with controls. Furthermore, we demonstrated that frequencies of three estimated haplotypes were increased in MCTD patients compared with controls. Interestingly, the haplotype with MICA allele 4 together with DRB1*04 and TNF1 alleles gives the most specific pattern for MCTD patients compared with controls. Our study demonstrates a clear contribution of HLA loci in susceptibility to MCTD in the Swedish population. Susceptibility to MCTD may be linked to the MICA4/HLA-DRB1*04/TNF1 haplotype and MICA 5.1-5.1 genotype. Mixed connective tissue disease was also associated with shared epitope genes, which in RA has been associated with a more severe disease. Whether these genotypes affect the clinical phenotype of MCTD needs to be determined.     

Reflections on the use of mental health resilience concepts in migration and global mental health

Abstract

With the concept of resilience increasingly deployed across a range of issues in development studies—from conflict resilience to climate resilience—this paper considers the relevance of resilience concepts to current issues and concerns in global mental health. Resilience discourses can be seen as one response to the need for more holistic accounts of mental health that focus, not only on stressors and risk factors for mental ill health, but also recognize the sometimes overlooked capacities of people and communities to manage and coproduce their own mental wellbeing. For example, migration forms the backdrop to global mental health for a significant proportion of the world’s populace. And yet, thus far, most literature on migrant mental health has tended to focus on risk factors and stressors with comparatively little consideration given to potential sources or resources for positive mental health and coping with adversity. Nevertheless, while concepts of “resilience” are increasingly advocated in development studies and global mental health contexts, such concepts also have their critics. For example, resilience rhetorics can “depoliticize” by appearing to normalize otherwise unacceptable circumstances which might—from post-development and other alternative critical perspectives—be viewed as politically constituted through-and-through.     

Commercial software upgrades may significantly alter Perfusion CT parameter values in colorectal cancer

Objective

To determine how commercial software platform upgrades impact on derived parameters for colorectal cancer.

Materials and methods

Following ethical approval, 30 patients with suspected colorectal cancer underwent Perfusion CT using integrated 64 detector PET/CT before surgery. Analysis was performed using software based on modified distributed parameter analysis (Perfusion software version 4; Perfusion 4.0), then repeated using the previous version (Perfusion software version 3; Perfusion 3.0). Tumour blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability surface area product (PS) were determined for identical regions-of-interest. Slice-by-slice and ??whole tumour?? variance was assessed by Bland-Altman analysis.

Results

Mean BF, BV and PS was 20.4%, 59.5%, and 106% higher, and MTT 14.3% shorter for Perfusion 4.0 than Perfusion 3.0. The mean difference (95% limits of agreement) were +13.5 (?44.9 to 72.0), +2.61 (?0.06 to 5.28), ?1.23 (?6.83 to 4.36), and +14.2 (?4.43 to 32.8) for BF, BV, MTT and PS respectively. Within subject coefficient of variation was 36.6%, 38.0%, 27.4% and 60.6% for BF, BV, MTT and PS respectively indicating moderate to poor agreement.

Conclusion

Software version upgrades of the same software platform may result in significantly different parameter values, requiring adjustments for cross-version comparison.     

Selective frontoinsular von Economo neuron and fork cell loss in early behavioral variant frontotemporal dementia

Behavioral variant frontotemporal dementia (bvFTD) erodes complex social-emotional functions as the anterior cingulate cortex (ACC) and frontoinsula (FI) degenerate, but the early vulnerable neuron within these regions has remained uncertain. Previously, we demonstrated selective loss of ACC von Economo neurons (VENs) in bvFTD. Unlike ACC, FI contains a second conspicuous layer 5 neuronal morphotype, the fork cell, which has not been previously examined. Here, we investigated the selectivity, disease-specificity, laterality, timing, and symptom relevance of frontoinsular VEN and fork cell loss in bvFTD. Blinded, unbiased, systematic sampling was used to quantify bilateral FI VENs, fork cells, and neighboring neurons in 7 neurologically unaffected controls (NC), 5 patients with Alzheimer's disease (AD), and 9 patients with bvFTD, including 3 who died of comorbid motor neuron disease during very mild bvFTD. bvFTD showed selective FI VEN and fork cell loss compared with NC and AD, whereas in AD no significant VEN or fork cell loss was detected. Although VEN and fork cell losses in bvFTD were often asymmetric, no group-level hemispheric laterality effects were identified. Right-sided VEN and fork cell losses, however, correlated with each other and with anatomical, functional, and behavioral severity. This work identifies region-specific neuronal targets in early bvFTD.     

Diagnostic Yield of Electroencephalography in the Medical and Surgical Intensive Care Unit

Background

To determine the incidence of electrographic seizures during continuous electroencephalography (cEEG) in the medical and surgical ICU.

Methods

We retrospectively reviewed the records of all adults who underwent cEEG in our medical and surgical ICU over a 4.5 year period. Patients with acute brain injury were excluded. Our primary outcome was cEEG documentation of an electrographic seizure, defined as a rhythmic discharge or spike and wave pattern demonstrating definite evolution and lasting at least 10 s. To assess inter-rater variability in cEEG interpretation, two electrophysiologists independently reviewed all available cEEGs of subjects with electrographic seizures documented on their clinical cEEG report and those of an equal number of randomly selected subjects from the remaining cohort.

Results

Kappa analysis showed a value of 0.88, indicating excellent inter-rater agreement. Electrographic seizures were identified in 12 of 105 patients (11 %, 95 % CI 5–18 %). This rate did not change after excluding patients with a history of seizure, remote brain injury, or seizure-like events before cEEG. In an ordinal logistic regression model controlling for age, sex, and SOFA score, electrographic seizures were associated with lower odds of good outcomes on the Glasgow Outcome Scale at discharge (OR 0.3, 95 % CI 0.1–0.8).

Conclusion

In a tertiary care medical and surgical ICU, electrographic seizures were seen on 11 % of cEEGs ordered for the evaluation of encephalopathy, and were associated with worse functional outcomes at discharge. Our findings confirm the results of a prior study suggesting a substantial burden of electrographic seizures in critically ill encephalopathic patients.     

Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke

Free radicals and inflammatory mediators are involved in transient focal cerebral ischemia (FCI). Preadministration of N-acetylcysteine (NAC) has been found to attenuate the cerebral ischemia-reperfusion injury in a rat model of experimental stroke. This study was undertaken to investigate the neuroprotective potential of NAC administered after ischemic events in experimental stroke. FCI was induced for 30 min by occluding the middle cerebral artery (MCA). NAC (150 mg/kg) was administered intraperitoneally at the time of reperfusion followed by another dose 6 hr later. Animals were sacrificed after 24 hr of reperfusion. The cerebral infarct consistently involved the cortex and striatum. Infarction was assessed by staining the brain sections with 2,3,5-triphenyltetrazolium chloride. Animals treated with NAC showed a significant reduction in infarct area and infarct volume and an improvement in neurologic scores and glutathione level. Reduction in infarction was significant even when a single dose of NAC was administered at 6 hr of reperfusion. Immunohistochemical and quantitative real-time PCR studies demonstrated a reduction in the expression of proinflammatory cytokines such as tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) and inducible nitric oxide synthase (iNOS) in NAC compared to that in vehicle-treated animals. The expression of activated macrophage/microglia (ED1) and apoptotic cell death in ischemic brain was also reduced by NAC treatment. These results indicate that in a rat model of experimental stroke, administration of NAC even after ischemia onset protected the brain from free radical injury, apoptosis, and inflammation, with a wide treatment window.     

Liquid nitrogen cryotherapy in the management of oral lesions: a retrospective clinical study

Background & objectives  The purpose of this study was to evaluate effectiveness and convenience of cryosurgical procedure, to assess the events during postoperative healing and to find out the incidence of recurrence Materials and methods  This study was conducted in the Department of Oral and Maxillofacial Surgery, KLESVK Institute of Dental Sciences, Belgaum. The 40 patients selected for the study were divided into 2 groups of 20 patients each irrespective of age and sex. Group I 20 patients with Pre-Malignant Lesions Group II 20 patients with Oral Mucous Cyst Results  It was observed that all the 20 patients of mucocele were cured without any complication and recurrence, but in 20 patients of leukoplakia 5 patients had recurrence which was directly attributed to their persisting habits. Conclusion  We state that this modality of treatment is promising with good results and has certain advantage over other modalities of treatment.