Inhaled phage therapy: a promising and challenging approach to treat bacterial respiratory infections

Introduction: Bacterial respiratory tract infections (RTIs) are increasingly difficult to treat due to evolving antibiotic resistance. In this context, bacteriophages (or phages) are part of the foreseen alternatives or combination therapies. Delivering phages through the airways seems more relevant to accumulate these natural antibacterial viruses in proximity to their bacterial host, within the infectious site.

Areas covered: This review addresses the potential of phage therapy to treat RTIs and discusses preclinical and clinical results of phages administration in this context. Recent phage formulation and aerosolization attempts are also reviewed, raising technical challenges to achieve efficient pulmonary deposition via inhalation.

Expert opinion: Overall, the inhalation of phages as antibacterial treatment seems both clinically relevant and technically feasible. Several crucial points still need to be investigated, such as phage product pharmacokinetics and immunogenicity. Furthermore, given phage-specific features, appropriate regulatory and manufacturing guidelines will need to be defined. Finally, randomized controlled clinical trials should be carried out to establish phage therapy’s clinical positioning in the antimicrobial arsenal against RTIs.     

Priming with an adenovirus 35-circumsporozoite protein (CS) vaccine followed by RTS,S/AS01B boosting significantly improves immunogenicity to Plasmodium falciparum CS compared to that with either malaria vaccine alone

The RTS,S/AS02A protein-based vaccine consistently demonstrates significant protection against infection with Plasmodium falciparum malaria and also against clinical malaria and severe disease in children in areas of endemicity. Here we demonstrate with rhesus macaques that priming with a replication-defective human adenovirus serotype 35 (Ad35) vector encoding circumsporozoite protein (CS) (Ad35.CS), followed by boosting with RTS,S in an improved MPL- and QS21-based adjuvant formulation, AS01B, maintains antibody responses and dramatically increases levels of T cells producing gamma interferon and other Th1 cytokines in response to CS peptides. The increased T-cell responses induced by the combination of Ad35.CS and RTS,S/AS01B are sustained for at least 6 months postvaccination and may translate to improved and more durable protection against P. falciparum infection in humans.     

Kickstand rods and correction of coronal malalignment in patients with adult spinal deformity

Purpose

Coronal malalignment (CM) is a challenging spinal deformity to treat. The kickstand rod (KR) technique is powerful for correcting truncal shift. This study tested the hypothesis that the KR technique provides superior coronal alignment correction in adult deformity compared with traditional rod techniques.

Methods

A retrospective evaluation of a prospectively collected multicenter database was performed. A 2:1 matched cohort of non-KR accessory rod and KR patients was planned based on preoperative coronal balance distance (CBD) and a vector of global shift. Patients were subgrouped according to CM classification with a 30-mm CBD threshold defining CM, and comparisons of surgical and clinical outcomes among groups was performed.

Results

Twenty-one patients with preoperative CM treated with a KR were matched to 36 controls. KR-treated patients had improved CBD compared with controls (18 vs. 35 mm, P < 0.01). The postoperative CBD did not result in clinical differences between groups in patient-reported outcomes (P ≥ 0.09). Eight (38%) of 21 KR patients and 12 (33%) of 36 control patients with preoperative CM had persistent postoperative CM (P = 0.72). CM class did not significantly affect the likelihood of treatment failure (postoperative CBD > 30 mm) in the KR cohort (P = 0.70), the control cohort (P = 0.35), or the overall population (P = 0.31).

Conclusions

Application of the KR technique to coronal spinal deformity in adults allows for successful treatment of CM. Compared to traditional rod techniques, the use of KRs did not improve clinical outcome measures 1 year after spinal deformity surgery but was associated with better postoperative coronal alignment.

     

Trabecular Bone Score (TBS) Predicts Vertebral Fractures in Japanese Women Over 10 Years Independently of Bone Density and Prevalent Vertebral Deformity: The Japanese Population‐Based Osteoporosis (JPOS) Cohort Study

Bone strength is predominantly determined by bone density, but bone microarchitecture also plays an important role. We examined whether trabecular bone score (TBS) predicts the risk of vertebral fractures in a Japanese female cohort. Of 1950 randomly selected women aged 15 to 79 years, we analyzed data from 665 women aged 50 years and older, who completed the baseline study and at least one follow‐up survey over 10 years, and who had no conditions affecting bone metabolism. Each survey included spinal imaging by dual‐energy X‐ray absorptiometry (DXA) for vertebral fracture assessment and spine areal bone mineral density (aBMD) measurement. TBS was obtained from spine DXA scans archived in the baseline study. Incident vertebral fracture was determined when vertebral height was reduced by 20% or more and satisfied McCloskey‐Kanis criteria or Genant's grade 2 fracture at follow‐up. Among eligible women (mean age 64.1 ± 8.1 years), 92 suffered incident vertebral fractures (16.7/10³ person‐years). These women were older with lower aBMD and TBS values relative to those without fractures. The unadjusted odds ratio of vertebral fractures for one standard deviation decrease in TBS was 1.98 (95% confidence interval [CI] 1.56, 2.51) and remained significant (1.64, 95% CI 1.25, 2.15) after adjusting for aBMD. The area under the receiver operating characteristic curve of TBS and aBMD combined was 0.700 for vertebral fracture prediction and was not significantly greater than that of aBMD alone (0.673). However, reclassification improvement measures indicated that TBS and aBMD combined significantly improved risk prediction accuracy compared with aBMD alone. Further inclusion of age and prevalent vertebral deformity in the model improved vertebral fracture prediction, and TBS remained significant in the model. Thus, lower TBS was associated with higher risk of vertebral fracture over 10 years independently of aBMD and clinical risk factors including prevalent vertebral deformity. TBS could effectively improve fracture risk assessment in clinical settings. © 2014 American Society for Bone and Mineral Research.     

Normal serum and lipoprotein-deficient serum give different expressions of excitability, corresponding to different stages of differentiation, in chicken cardiac cells in culture.

Monolayers of cardiac cells from 11-day-old chicken hearts have different properties when maintained in fetal calf serum or in a lipoprotein-deficient serum (LPDS). Cells in fetal calf serum have a resting potential near -60 mV; the rate of rise of the action potential is low (less than 10 V/sec); the action potential and the contraction are essentially unaffected by tetrodotoxin (TTX); and the beating properties are unaffected by muscarinic agents. Cells in LPDS have a resting potential near -75 mV, and a fast rise of the action potential (approximately equal to 100 V/sec) that is drastically decreased by TTX with a parallel abolition of contraction, and the beat is blocked by very low concentrations of muscarinic agonists. Cells that are physiologically fully responsive to TTX and to muscarinic agents have receptors that remain stable 24 hr after protein synthesis is blocked, whereas cells that are physiologically unresponsive to TTX and muscarinic agents have receptors that are rapidly degraded with half-lives between 9 hr (TTX receptor) and 14 hr (muscarinic receptor). Differences in the physiological and biochemical properties are accompanied by changes in the cholesterol contents of the cell membranes. The properties of cardiac cells cultured in normal serum are similar to those found for cells of chicken hearts in the very early embryonic stage, whereas those of cardiac cells cultured in LPDS correspond to the late embryonic stage.     

Münchausen syndrome with forgery on biologic results. A case report

Münchausen syndrome is a disorder defined by the following: acute factitious symptoms leading to inappropriate investigation and therapy, a restless journey from hospital to hospital and autobiographical falsification. We report here a 20-year-old woman who presented at our hospital consultation of internal medicine with laboratory-test results suggesting the diagnosis of leukemia. A new complete blood cells count and a medullogram by sternal puncture did not show any abnormality. Comparative examination of laboratory-test sheets lead to the diagnosis of Münchausen syndrome as some results had been falsified. With unlimited access to information through internet and word or image processing softwares, laboratory results have become easy to falsify nowadays, particularly for patients with Münchausen syndrome, who may then be quite difficult to diagnose accurately in the context of medical consultation.