Alcohol-based pressurised metered-dose inhalers for use in asthma: a descriptive study.

BACKGROUND: Chlorofluorocarbons (CFCs) have historically served as the propellants of choice in pressurised metered-dose asthma inhalers, but concern has been raised in recent decades regarding their damaging effect on the ozone layer. Among the alternative propellants being considered is alcohol, which can be used as a co-solvent in asthma inhalers. Healthcare professionals need to be aware of alcohol-containing inhalers, since certain populations may have religious and/or cultural concerns regarding the use of such preparations. OBJECTIVES: To identify pressurised metered-dose asthma inhalers which contain alcohol-based propellants. METHODS: We searched the British National Formulary to identify companies that manufacture asthma treatments and wrote to them to enquire about which of their products contained alcohol and if so in what percentage. These direct contacts were supplemented by searching medical databases and the Internet for additional information. RESULTS: We identified 11 manufacturers of asthma inhalers, seven of which produced pressurised metered-dose inhalers; of these, six were willing to disclose the requested information, and information on the seventh product was obtained from an alternative valid source of information. Most CFC preparations contain alcohol, but CFC- and alcohol-free preparations do exist. CONCLUSIONS: Clinicians need to be aware that the majority of CFC-free inhalers contain alcohol. Alcohol-free, and CFC- and alcohol-free, preparations are available for the delivery of both rescue and preventative treatment and these should be considered for use in those patients who may have concern about alcohol-based treatments.     

Changes in left ventricular diastolic performance after aortic balloon valvuloplasty: acute and late effects

To evaluate acute and follow-up changes in left ventricular diastolic performance, simultaneous digital left ventriculography and micromanometry were performed in 49 patients undergoing aortic balloon valvuloplasty. All patients improved symptomatically after valvuloplasty, and 26 returned 6.3 +/- 1.5 months later for follow-up catheterization. Immediately after valvuloplasty, aortic valve area increased (before 0.5 +/- 0.2 versus after 0.8 +/- 0.2 cm2, p less than 0.01), cardiac output (before 4.3 +/- 1.2 versus after 4.4 +/- 1.3 liters/min) and ejection fraction (before 51 +/- 18% versus after 52 +/- 17%) did not change and diastolic indexes worsened, signified by a decrease in peak filling rate (before 247 +/- 80 versus after 226 +/- 78 ml/s, p less than 0.01) and increase in the time constant of isovolumetric relaxation (tau) (before 78 +/- 29 versus after 96 +/- 40 ms, p less than 0.01) and the modulus of chamber stiffness (before 0.107 +/- 0.071 versus after 0.141 +/- 0.083, p less than 0.01). At follow-up catheterization, 16 patients continued to have symptomatic improvement (group 1) and 10 had recurrence of symptoms (group 2). Aortic valve area, cardiac output and ejection fraction at follow-up catheterization in both groups were similar and unchanged from values before valvuloplasty.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development of a mono‐specific anti‐VEGF bivalent nanobody with extended plasma half‐life for treatment of pathologic neovascularization

Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis within solid cancers. Thus, targeting VEGF might be part of a feasible therapy for treating pathological neovascularization, and nanobodies ? derived from heavy chain‐only antibodies occurring within Camelidae ? are a novel class of nanometer‐sized antibodies possessing unique properties that could be developed into a promising therapeutic. However, nanobodies have a very short half‐life in vivo due to their small size. Development of a bivalent nanobody is one way to remediate the half‐life problem of nanobodies. Two identical anti‐VEGF nanobodies were connected using the hinge region of llama IgG2c. The recombinant plasmid (pHEN6c‐bivalent nanobody) was transformed into E.coli WK6 cells and expression of the bivalent nanobody construct was induced with 1mM Isopropyl β‐D‐1‐thiogalactopyranoside (IPTG). Recombinant bivalent nanobody was purified using nickel affinity chromatography and its activity on human endothelial cells was assessed using 3‐(4,5‐Dimethylthiazol‐2‐yr)‐2,5‐diphenyltetrazolium bromide (MTT), tube formation, and cell migration assays. The pharmacokinetic study was performed after intravenous (i.v.) injection of recombinant bivalent nanobody into six‐week‐old C57BL/6 mice. Recombinant bivalent nanobody performed significantly better than monovalent nanobody in inhibiting proliferation, tube formation, and migration of human endothelial cells. Pharmacokinetic results showed a 1.8‐fold longer half‐life of bivalent nanobody in comparison with the monovalent nanobody. These results underscore the potential of recombinant anti‐VEGF bivalent nanobody as a promising tool for development of a novel therapeutic with an extended plasma half‐life for VEGF‐related diseases.     

VE1 immunohistochemistry is an adjunct tool for detection of BRAF V600E mutation: Validation in thyroid cancer patients

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy among other endocrine tumors, and BRAF ^V600E is a frequent genetic mutation occurring in the disease. Although different molecular techniques, most importantly sequencing has been widely recognized as a gold standard but molecular diagnosis remains an expensive, laborious, and time‐intensive process. Recently, immunohistochemistry (IHC) with anti‐BRAF V600E (VE1) antibody has increased practical utility and implemented clinically for the detection of BRAF ^V600E mutation. Therefore, the study aimed to evaluate diagnostic accuracy of VE1 IHC for detecting the BRAF ^V600E mutation frequency and clinical implementation in diagnostic laboratories. In this study, 72 formalin fixed paraffin‐embedded tissues (FFPE) were used to determine the BRAF ^V600E mutation status using IHC and Sanger sequencing. The mutation was found in 29% and 28% cases using IHC and Sanger sequencing, respectively. Furthermore, the results showed 100% sensitivity, 98.07% specificity, 95.2% positive predictive value, and 100% negative predictive value. Notably, significant associations were found between BRAF ^V600E status and tumor stage, tumor focality, and extrathyroidal extensions, respectively. VE1 IHC was found to be a highly sensitive, specific, and diagnostically accurate method in this cohort. Therefore, BRAF ^V600E detection through IHC has been considered as the best tailored technique for routine pathology laboratories.     

Unique features of chicken Toll-like receptors

Toll-like receptors (TLRs) are a major class of innate immune pattern recognition receptors that have a key role in immune homeostasis and the defense against infections. The research explosion that followed the discovery of TLRs more than a decade ago has boosted fundamental knowledge on the function of the immune system and the resistance against disease, providing a rational for clinical modulation of the immune response. In addition, the conserved nature of the ancient TLR system throughout the animal kingdom has enabled a comparative biology approach to understand the evolution, structural architecture, and function of TLRs. In the present review we focus on TLR biology in the avian species, and, especially, on the unique functional properties of the chicken TLR repertoire.     

Single-Domain Antibodies or Nanobodies: A Class of Next-Generation Antibodies

Nanobodies for the first time were identified in the sera of Camelidae. Single-domain antibodies or nanobodies are a class of next-generation antibodies that have specific features: small size (in nanoscale), high penetration in various tissues, high stability in hard situations and ease production process in microbial systems. In fact single-domain antibodies are the smallest fragment of the antibody with binding ability. Unique characteristics and features of nanobodies make them an appropriate candidate for further evaluation as the development of novel antibody-based therapeutics. In this regard single-domain antibodies are in the interest of many researchers as well as biopharmaceutical companies for diagnostic and therapeutic applications. Nowadays several single domain antibodies have been developed and evaluated in different clinical trials. Because of many advantages of single-domain antibodies over other formats of antibodies, they could be good replacement for other formats of antibodies in near future. Here, we review the biology, engineering platforms and application of nanobodies.     

Cardiac computed tomography in the contemporary evaluation of infective endocarditis

Increasing data have accumulated on the role of Cardiac Computed Tomography (CCT) in infective endocarditis (IE) with high accuracy for large vegetations, perivalvular complications and for exclusion of coronary artery disease to avoid invasive angiography. CCT can further help to clarify the etiology of infective prosthetic valve dysfunction (e.g. malposition, abscess, leak, vegetation or mass). Structural interventions have increased the relevance of CCT in valvular heart disease and have amplified its use. CCT may be ideally integrated into a multimodality approach that incorporates a central role of transesophageal echocardiography (TEE) with 18-FDG PET and/or cardiac magnetic resonance in individually selected cases, guided by the Heart Team. The coronavirus-19 (COVID-19) pandemic has resulted in renewed attention to CCT as a safe alternative or adjunct to TEE in selected patients. This review article provides a comprehensive, contemporary review on CCT in IE to include scan optimization, characteristics of common IE findings on CCT, published data on the diagnostic accuracy of CCT, multimodality imaging comparison, limitations and future technical advancements.     

Parasympathetic nervous system activity and children's sleep

We examined indices of children's parasympathetic nervous system activity (PNS), including respiratory sinus arrhythmia during baseline (RSAB) and RSA reactivity (RSAR), to a laboratory challenge, and importantly the interaction between RSAB and RSAR as predictors of multiple parameters of children's sleep. Lower RSAR denotes increased vagal withdrawal (reductions in RSA between baseline and task) and higher RSAR represents decreased vagal withdrawal or augmentation (increases in RSA between baseline and task). A community sample of school‐attending children (121 boys and 103 girls) participated [mean age = 10.41 years; standard deviation (SD) = 0.67]. Children's sleep parameters were examined through actigraphy for 7 consecutive nights. Findings demonstrate that RSAB and RSAR interact to predict multiple sleep quality parameters (activity, minutes awake after sleep onset and long wake episodes). The overall pattern of effects illustrates that children who exhibit more disrupted sleep (increased activity, more minutes awake after sleep onset and more frequent long wake episodes) are those with lower RSAB in conjunction with lower RSAR. This combination of low RSAB and low RSAR probably reflects increased autonomic nervous system arousal, which interferes with sleep. Results illustrate the importance of individual differences in physiological regulation indexed by interactions between PNS baseline activity and PNS reactivity for a better understanding of children's sleep quality.     

Body size miniaturization in a lineage of colubrid snakes: Implications for cranial anatomy

As body size strongly determines the biology of an organism at all levels, it can be expected that miniaturization comes with substantial structural and functional constraints. Dwarf snakes of the genus Eirenis are derived from big, surface-dwelling ancestors, considered to be similar to those of the sister genus Dolichophis. To better understand the structural implications of miniaturization on the feeding apparatus in Eirenis, the morphology of the cranial musculoskeletal system of Dolichophis schmidti was compared with that of the miniature Eirenis punctatolineatus and E. persicus using high-resolution µCT data. The gape index was compared between D. schmidti and 14 Eirenis species. Our results show a relatively increased neurocranium size and decreased maximal jaw muscle force in E. persicus, compared with the D. schmidti, and an intermediate situation in E. punctatolineatus. A significant negative allometry in gape index relative to body size is observed across the transition from the Dolichophis to Pediophis and Eirenis subgenera. However, the gape index relative to head size showed a significant negative allometry only across the transition from the Dolichophis to Pseudocyclophis subgenus. In Dolichophis–Eirenis dwarfing lineages, different structural patterns are observed through miniaturization, indicating that overcoming the challenge of miniaturization has achieved via different adaptations.