Comparing the immune response to a novel intranasal nanoparticle PLGA vaccine and a commercial BPI3V vaccine in dairy calves

peer-reviewedBackground There is a need to improve vaccination against respiratory pathogens in calves by stimulation of local immunity at the site of pathogen entry at an early stage in life. Ideally such a vaccine preparation would not be inhibited by the maternally derived antibodies. Additionally, localized immune response at the site of infection is also crucial to control infection at the site of entry of virus. The present study investigated the response to an intranasal bovine parainfluenza 3 virus (BPI3V) antigen preparation encapsulated in PLGA (poly dl-lactic-co-glycolide) nanoparticles in the presence of pre-existing anti-BPI3V antibodies in young calves and comparing it to a commercially available BPI3V respiratory vaccine. Results There was a significant (P < 0.05) increase in BPI3V-specific IgA in the nasal mucus of the BPI3V nanoparticle vaccine group alone. Following administration of the nanoparticle vaccine an early immune response was induced that continued to grow until the end of study and was not observed in the other treatment groups. Virus specific serum IgG response to both the nanoparticle vaccine and commercial live attenuated vaccine showed a significant (P < 0.05) rise over the period of study. However, the cell mediated immune response observed didn’t show any significant rise in any of the treatment groups. Conclusion Calves administered the intranasal nanoparticle vaccine induced significantly greater mucosal IgA responses, compared to the other treatment groups. This suggests an enhanced, sustained mucosal-based immunological response to the BPI3V nanoparticle vaccine in the face of pre-existing antibodies to BPI3V, which are encouraging and potentially useful characteristics of a candidate vaccine. However, ability of nanoparticle vaccine in eliciting cell mediated immune response needs further investigation. More sustained local mucosal immunity induced by nanoparticle vaccine has obvious potential if it translates into enhanced protective immunity in the face of virus outbreak

What characteristics of primary care and patients are associated with early death in patients with lung cancer in the UK?

Background: The UK has poor lung cancer survival rates and high early mortality, compared to other countries. We aimed to identify factors associated with early death, and features of primary care that might contribute to late diagnosis. Methods: All cases of lung cancer diagnosed between 2000 and 2013 were extracted from The Health Improvement Network database. Patients who died within 90 days of diagnosis were compared with those who survived longer. Standardised chest X-ray (CXR) and lung cancer rates were calculated for each practice. Results: Of 20 142 people with lung cancer, those who died early consulted with primary care more frequently prediagnosis. Individual factors associated with early death were male sex (OR 1.17; 95% CI 1.10 to 1.24), current smoking (OR 1.43; 95% CI 1.28 to 1.61), increasing age (OR 1.80; 95% CI 1.62 to 1.99 for age ≥80 years compared to 65–69 years), social deprivation (OR 1.16; 95% CI 1.04 to 1.30 for Townsend quintile 5 vs 1) and rural versus urban residence (OR 1.22; 95% CI 1.06 to 1.41). CXR rates varied widely, and the odds of early death were highest in the practices which requested more CXRs. Lung cancer incidence at practice level did not affect early deaths. Conclusions: Patients who die early from lung cancer are interacting with primary care prediagnosis, suggesting potentially missed opportunities to identify them earlier. A general increase in CXR requests may not improve survival; rather, a more timely and appropriate targeting of this investigation using risk assessment tools needs further assessment

Co-prescription of medication for bipolar disorder and diabetes mellitus : a nationwide population based study with focus on gender differences

BackgroundStudies have shown a correlation between bipolar disorder and diabetes mellitus. It is unclear if this correlation is a part of common pathophysiological pathways, or if medication for bipolar disorder has negative effects on blood sugar regulation.MethodsThe Norwegian prescription database was analyzed. Prescriptions for lithium, lamotrigine, carbamazepine and valproate were used as proxies for bipolar disorder. Prescriptions for insulin and oral anti-diabetic agents were used as proxies for diabetes mellitus. We explored the association between medication for bipolar disorder and diabetes medication by logistic regressionResultsWe found a strong association between concomitant use of medication to treat diabetes mellitus and mood stabilizers for the treatment of bipolar disorder. Females had a 30% higher risk compared to men of being treated for both disorders. Persons using oral anti-diabetic agents had higher odds of receiving valproate than either lithium or lamotrigine. Use of insulin as monotherapy seemed to have lower odds than oral anti-diabetic agents of co-prescription of mood stabilizers, compared to the general population.ConclusionsThis study showed a strong association between the use of mood stabilizers and anti-diabetic agents. The association was stronger among women than men

Microwave spectroscopy of positronium atoms in free space

We report measurements of the positronium (Ps) 2 3 S 1 → 2 3 P 2 interval in which atoms traveling in free space were irradiated with microwave radiation generated using a horn antenna. Previous measurements of this transition, performed using atoms in waveguides, exhibited asymmetric and shifted line shapes. In the free-space measurements we report here, much smaller line-shape asymmetry was observed, but with large frequency shifts that varied with the orientation of the horn antenna. Our observations are supported by line-shape simulations and demonstrate that variations in the microwave radiation field distribution can perturb measured line shapes and give rise to apparent frequency shifts without necessarily causing large asymmetries; this effect can explain previous measurements in which an apparent discrepancy with predictions from quantum electrodynamics was ob- served [L. Gurung, T. J. Babij, S. D. Hogan, and D. B. Cassidy, Phys. Rev. Lett. 125, 073002 (2020)]

Male reproductive health and environmental xenoestrogens

EHP is a publication of the U.S. government. Publication of EHP lies in the public domain and is therefore without copyright. Research articles from EHP may be used freely; however, articles from the News section of EHP may contain photographs or figures copyrighted by other commercial organizations and individuals that may not be used without obtaining prior approval from both the EHP editors and the holder of the copyright. Use of any materials published in EHP should be acknowledged (for example, "Reproduced with permission from Environmental Health Perspectives") and a reference provided for the article from which the material was reproduced.Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.Supported by EU Contract BMH4-CT96-0314

Measurement of the annihilation decay rate of 2³S₁ positronium

We report a measurement of the annihilation decay rate of 2 3S1 positronium (Ps) atoms, Γexp(2 3S1). Ground state atoms optically excited to radiatively metastable 2 3S1 states were quenched via Stark mixing by the application of a time-delayed electric field. Rapid radiative decay of the Stark mixed states to the ground state, followed by self-annihilation, was observed via the annihilation radiation time spectrum, and used to determine the number of excited state atoms remaining at different times, and hence the decay rate. We obtain Γexp(2 3S1) = 843 ± 72 kHz, in broad agreement with the Zeeman-shifted theoretical value of 890 kHz

Teacher Wellbeing: The Importance of Teacher–Student Relationships

Many studies have examined the importance of teacher-student relationships for the development of children. Much less is known, however, about how these relationships impact the professional and personal lives of teachers. This review considers the importance of teacher-student relationships for the wellbeing of teachers guided by the Transactional Model of Stress and Coping of Lazarus (1991). Based on theories on interpersonal relationships, it is postulated that teachers have a basic need for relatedness with the students in their class that originates from the close proximity between teacher and student. It is discussed that teachers internalize experiences with students in representational models of relationships that guide emotional responses in daily interactions with students, and changes teacher wellbeing in the long run. In addition, the notion of mental representations of relationships at different levels of generalization could offer a window to understand how individual teacher-student relationships may affect the professional and personal self-esteem of teachers. Lastly, it is argued that the influence of student misbehavior on teacher stress may be more fully understood from a relationship perspective. The review shows that few studies have directly tested these propositions and offers suggestions for future research

Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states

Role of Interaction and Nucleoside Diphosphate Kinase B in Regulation of the Cystic Fibrosis Transmembrane Conductance Regulator Function by cAMP-Dependent Protein Kinase A

Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent protein kinase A (PKA) and ATP-regulated chloride channel. Here, we demonstrate that nucleoside diphosphate kinase B (NDPK-B, NM23-H2) forms a functional complex with CFTR. In airway epithelia forskolin/IBMX significantly increases NDPK-B co-localisation with CFTR whereas PKA inhibitors attenuate complex formation. Furthermore, an NDPK-B derived peptide (but not its NDPK-A equivalent) disrupts the NDPK-B/CFTR complex in vitro (19-mers comprising amino acids 36-54 from NDPK-B or NDPK-A). Overlay (Far-Western) and Surface Plasmon Resonance (SPR) analysis both demonstrate that NDPK-B binds CFTR within its first nucleotide binding domain (NBD1, CFTR amino acids 351-727). Analysis of chloride currents reflective of CFTR or outwardly rectifying chloride channels (ORCC, DIDS-sensitive) showed that the 19-mer NDPK-B peptide (but not its NDPK-A equivalent) reduced both chloride conductances. Additionally, the NDPK-B (but not NDPK-A) peptide also attenuated acetylcholine-induced intestinal short circuit currents. In silico analysis of the NBD1/NDPK-B complex reveals an extended interaction surface between the two proteins. This binding zone is also target of the 19-mer NDPK-B peptide, thus confirming its capability to disrupt NDPK-B/CFTR complex. We propose that NDPK-B forms part of the complex that controls chloride currents in epithelia

Synergies, tensions and challenges in HIV prevention, treatment and cure research: exploratory conversations with HIV experts in South Africa

Background: The ethical concerns associated with HIV prevention and treatment research have been widely explored in South Africa over the past 3 decades. However, HIV cure research is relatively new to the region and significant ethical and social challenges are anticipated. There has been no published empirical enquiry in Africa into key informant perspectives on HIV cure research. Consequently, this study was conducted to gain preliminary data from South African HIV clinicians, researchers and activists. Methods: In-depth interviews were conducted on a purposive sample of fourteen key informants in South Africa. Audiotaped interviews were transcribed verbatim with concurrent thematic analysis. The perspectives of HIV clinicians, researchers and activists were captured. Analyst triangulation occurred as the data were analysed by three authors independently. Results: The rapid evolution of HIV cure research agendas was prominent with participants expressing some concern that the global North was driving the cure agenda. Participants described a symbiotic relationship between cure, treatment and prevention research necessitating collaboration. Assessing and managing knowledge and expectations around HIV cure research emerged as a central theme related to challenges to constructing ‘cure’ - how patients understand the idea of cure is important in explaining the complexity of cure research especially in the South African context where understanding of science is often challenging. Managing expectations and avoiding curative misconception will have implications for consent processes. Unique strategies in cure research could include treatment interruption, which has the potential to create therapeutic and ethical conflict and will be perceived as a significant risk. Ethical challenges in cure research will impact on informed consent and community engagement. Conclusions: It was encouraging to note the desire for synergy amongst researchers and clinicians working in the fields of prevention, treatment and cure. Translation of complex HIV cure science into lay language is critical. Moving forward, RECs must be adequately constituted with scientific expertise and community representation when reviewing cure protocols. It is hoped that knowledge and resource sharing in the context of collaboration between research scientists working in cure and those working in treatment and prevention will accelerate progress towards cur