Antigen expression determines adenoviral vaccine potency independent of IFN and STING signaling

Recombinant adenoviral vectors (rAds) are lead vaccine candidates for protection against a variety of pathogens, including Ebola, HIV, tuberculosis, and malaria, due to their ability to potently induce T cell immunity in humans. However, the ability to induce protective cellular immunity varies among rAds. Here, we assessed the mechanisms that control the potency of CD8 T cell responses in murine models following vaccination with human-, chimpanzee-, and simian-derived rAds encoding SIV-Gag antigen (Ag). After rAd vaccination, we quantified Ag expression and performed expression profiling of innate immune response genes in the draining lymph node. Human-derived rAd5 and chimpanzee-derived chAd3 were the most potent rAds and induced high and persistent Ag expression with low innate gene activation, while less potent rAds induced less Ag expression and robustly induced innate immunity genes that were primarily associated with IFN signaling. Abrogation of type I IFN or stimulator of IFN genes (STING) signaling increased Ag expression and accelerated CD8 T cell response kinetics but did not alter memory responses or protection. These findings reveal that the magnitude of rAd-induced memory CD8 T cell immune responses correlates with Ag expression but is independent of IFN and STING and provide criteria for optimizing protective CD8 T cell immunity with rAd vaccines.     

Craniofacial anatomical risk factors in men with obstructive sleep apnea and heart failure: a pilot study

Purpose

Obstructive sleep apnea (OSA) is complicated with heart failure (HF); however, the reason for this is not well understood. Craniofacial anatomic risk factors may contribute to OSA pathogenesis in HF patients. However, there are no data about cephalometric findings among OSA patients with HF.

Methods

Consecutive patients with HF and OSA (defined as total apnea–hypopnea index (AHI) ≥15/h) were enrolled. As controls, OSA patients without HF but matching the test group in age, BMI, and obstructive AHI were also enrolled.

Results

Overall, 17 OSA patients with HF and 34 OSA patients without HF were compared. There are no significant differences in the characteristics or polysomnographic parameters between 2 groups. In the cephalometric findings, compared with patients without HF, patients with HF showed a significantly greater angle between the line SN to point “A” (SNA) and a longer inferior airway space and greater airway area. However, the tongue area of patients with HF was more than those without HF.

Conclusions

The craniofacial structures of OSA patients with HF were different from those without HF. OSA patients with HF had an upper airway anatomy that is more likely to collapse when sleeping while recumbent, despite having a larger airway space.     

Association of sleep‐disordered breathing with decreased cognitive function among patients with dementia

Sleep is known to be essential for proper cognitive functioning. Sleep disturbance, especially respiratory disturbance during sleep, is a risk factor for the development of dementia. However, it is not known whether hypopnoea during sleep is related to severity of cognitive function in patients already diagnosed with dementia. Considering the high prevalence of sleep problems in aged people, it is important to determine if hypopnoea during sleep contributes to dementia. In addition, it would be desirable to develop a feasible method for objectively evaluating sleep in patients with dementia. For this purpose, a simple sleep recorder that employs single or dual bioparameter recording, which is defined as a type‐4 portable monitor, is suitable. In this study, a type‐4 sleep recorder was used to evaluate respiratory function during sleep in 111 patients with dementia, and data suggesting a possible relationship with cognitive function levels were examined. Multivariate logistic regression was used to investigate the association of severity of dementia with sleep‐disordered breathing, age, diabetes, dyslipidaemia and hypertension. It was found that the respiratory disturbance index was associated with severity of cognitive dysfunction in our subjects. Furthermore, patients younger than 80 years were more susceptible to lower cognitive function associated with sleep‐disordered breathing than patients 80 years old or over, because an increase in the respiratory disturbance index was associated with deteriorated cognitive function only in the former age group. These results suggest that proper treatment of sleep apnea is important for the preservation of cognitive function, especially in patients with early‐stage dementia.     

A case of bleeding duodenal ulcer with pemphigus vulgaris during steroid therapy

We report a rare case of bleeding duodenal ulceration in the different form of pemphigus vulgaris (PV). A 52-year-old female was diagnosed with acute pharyngitis and administered methylprednisolone. After several days, melena and many blisters were noted on her body. Endoscopy revealed blood oozing from the second part of a duodeneal ulcer around the major duodenal papilla. After initial endoscopic hemostasis, we observed a large regional, shallow duodenal ulcer. The blisters were suspected to represent the Nikolsky’s sign. The histological findings of her skin were characterized by suprabasal acantholysis and mixed inflammatory cell infiltrates, including scattered eosinophils. There were no other significant findings on skin biopsy or by direct immunofluorescence. Enzyme-linked immunosorbent assay showed an elevated titer of anti-desmoglein 3 autoantibodies in her serum, and the patient was finally diagnosed with mucosal-dominant PV. Although we performed multiple biopsies from the esophagus, stomach and duodenum, the samples did not contain significant findings to enable us to distinguish from pemphigus vulgaris. Corticosteroids remain an essential component of PV treatment. When clinicians encounter PV development during steroid therapy, upper gastrointestinal complications should be considered and diagnostic endoscopy conducted.     

Enhanced Ca2+-sensing receptor function in idiopathic pulmonary arterial hypertension

Rationale: A rise in cytosolic Ca(2+) concentration ([Ca(2+)](cyt)) in pulmonary arterial smooth muscle cells (PASMC) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. Increased resting [Ca(2+)](cyt) and enhanced Ca(2+) influx have been implicated in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH). Objective: We examined whether the extracellular Ca(2+)-sensing receptor (CaSR) is involved in the enhanced Ca(2+) influx and proliferation in IPAH-PASMC and whether blockade of CaSR inhibits experimental pulmonary hypertension. Methods and Results: In normal PASMC superfused with Ca(2+)-free solution, addition of 2.2 mmol/L Ca(2+) to the perfusate had little effect on [Ca(2+)](cyt). In IPAH-PASMC, however, restoration of extracellular Ca(2+) induced a significant increase in [Ca(2+)](cyt). Extracellular application of spermine also markedly raised [Ca(2+)](cyt) in IPAH-PASMC but not in normal PASMC. The calcimimetic R568 enhanced, whereas the calcilytic NPS 2143 attenuated, the extracellular Ca(2+)-induced [Ca(2+)](cyt) rise in IPAH-PASMC. Furthermore, the protein expression level of CaSR in IPAH-PASMC was greater than in normal PASMC; knockdown of CaSR in IPAH-PASMC with siRNA attenuated the extracellular Ca(2+)-mediated [Ca(2+)](cyt) increase and inhibited IPAH-PASMC proliferation. Using animal models of pulmonary hypertension, our data showed that CaSR expression and function were both enhanced in PASMC, whereas intraperitoneal injection of the calcilytic NPS 2143 prevented the development of pulmonary hypertension and right ventricular hypertrophy in rats injected with monocrotaline and mice exposed to hypoxia. Conclusions: The extracellular Ca(2+)-induced increase in [Ca(2+)](cyt) due to upregulated CaSR is a novel pathogenic mechanism contributing to the augmented Ca(2+) influx and excessive PASMC proliferation in patients and animals with pulmonary arterial hypertension.