Small skeletons show size-specific scaling: an exploration of allometry in the mammalian lumbar spine.

Studies of vertebrate bone biomechanics often focus on skeletal adaptations at upper extremes of body mass, disregarding the importance of skeletal adaptations at lower extremes. Yet mammals are ancestrally small and most modern species have masses under 5 kg, so the evolution of morphology and function at small size should be prioritized for understanding how mammals subsist. We examined allometric scaling of lumbar vertebrae in the small-bodied Philippine endemic rodents known as cloud rats, which vary in mass across two orders of magnitude (15.5 g-2700 g). External vertebral dimensions scale with isometry or positive allometry, likely relating to body size and nuances in quadrupedal posture. In contrast to most mammalian trabecular bone studies, bone volume fraction and trabecular thickness scale with positive allometry and isometry, respectively. It is physiologically impossible for these trends to continue to the upper extremes of mammalian body size, and we demonstrate a fundamental difference in trabecular bone allometry between large- and small-bodied mammals. These findings have important implications for the biomechanical capabilities of mammalian bone at small body size; for the selective pressures that govern skeletal evolution in small mammals; and for the way we define 'small' and 'large' in the context of vertebrate skeletons.

Long-term corticosteroid use, adrenal insufficiency and the need for steroid-sparing treatment in adult severe asthma.

Secondary adrenal insufficiency (AI) occurs as the result of any process that disrupts normal hypothalamic and/or anterior pituitary function and causes a decrease in the secretion of steroid hormones from the adrenal cortex. The most common cause of secondary AI is exogenous corticosteroid therapy administered at supraphysiologic dosages for ≥ 1 month. AI caused by oral corticosteroids (OCS) is not well-recognized or commonly diagnosed but is often associated with reduced well-being and can be life-threatening in the event of an adrenal crisis. Corticosteroid use is common in respiratory diseases, and asthma is a representative condition that illustrates the potential challenges and opportunities related to corticosteroid-sparing therapies. For individuals with severe asthma (approximately 5%-10% of all cases), reduction or elimination of maintenance OCS without loss of control can now be accomplished with biologic therapies targeting inflammatory mediators. However, the optimal strategy to ensure early identification and treatment of AI and safe OCS withdrawal in routine clinical practice remains to be defined. Many studies with biologics have involved short evaluation periods and small sample sizes; in addition, cautious approaches to OCS tapering in studies with a placebo arm, coupled with inconsistent monitoring for AI, have contributed to the lack of clarity. If the goal is to greatly reduce and, where possible, eliminate long-term OCS use in severe asthma through the increasing adoption of biologic treatments, there is an urgent need for clinical trials that address both the speed of OCS withdrawal and how to monitor for AI.

The current and future role of biomarkers in type 2 cytokine-mediated asthma management.

Assessment and management of asthma is complicated by the heterogeneous pathophysiological mechanisms that underlie its clinical presentation, which are not necessarily reflected in standardized management paradigms and which necessitate an individualized approach to treatment. This is particularly important with the emerging availability of a variety of targeted forms of therapy that may only be appropriate for use in particular patient subgroups. The identification of biomarkers can potentially aid diagnosis and inform prognosis, help guide treatment decisions and allow clinicians to predict and monitor response to treatment. Biomarkers for asthma have been identified from a variety of sources, including airway, exhaled breath and blood. Biomarkers from exhaled breath include fractional exhaled nitric oxide, measurement of which can help identify patients most likely to benefit from inhaled corticosteroids and targeted anti-immunoglobulin E therapy. Biomarkers measured in blood are relatively non-invasive and technically more straightforward than those measured from exhaled breath or directly from the airway. The most well established of these are the blood eosinophil count and serum periostin, both of which have demonstrated utility in identifying patients most likely to benefit from targeted anti-interleukin and anti-immunoglobulin E therapies, and in monitoring subsequent treatment response. For example, serum periostin appears to be a biomarker for responsiveness to inhaled corticosteroid therapy and may help identify patients as suitable candidates for anti-IL-13 treatment. The use of biomarkers can therefore potentially help avoid unnecessary morbidity from high-dose corticosteroid therapy and allow the most appropriate and cost-effective use of targeted therapies. Ongoing clinical trials are helping to further elucidate the role of established biomarkers in routine clinical practice, and a range of other circulating novel potential biomarkers are currently being investigated in the research setting.

The cost of systemic corticosteroid-induced morbidity in severe asthma: a health economic analysis.

BACKGROUND: Treatment of severe asthma may include high dose systemic-steroid therapy which is associated with substantial additional morbidity. This study estimates the additional healthcare costs associated with steroid-induced morbidity by comparing three patients groups: those with severe asthma, moderate asthma and no asthma. METHODS: Patients with severe asthma (n = 808, GINA step 5 treatment) were matched by age and gender with patients with mild/moderate asthma (n = 3,975, GINA step 2 and 3 treatment) and a non-asthma control cohort (with a diagnosis of rhinitis; n = 2,412) from the Optimum Patient Care Research Database (OPCRD), a nationally representative primary care database. Prescribed drugs and publicly funded healthcare activity were monetised and annual costs per patient estimated. Regression analyses were used to estimate the additional healthcare cost associated with steroid-induced morbidity. RESULTS: Average healthcare costs per person per year range from £2603 - £4533 for the severe asthma cohort, to £978 - £2072 for the mild/moderate asthma cohort, to £560 - £1324 for the non-asthma control cohort, depending on the costing scenario. Differences in induced morbidity costs were evident between patients with asthma differentiated by steroid exposure. In relation to prescription drugs used to treat steroid-induced co-morbidities, females with severe asthma and high steroid exposure cost approximately £789 more per year than a corresponding female with no asthma, while males cost approximately £744 more than their counterparts with no asthma. Estimates were extrapolated to all healthcare costs. CONCLUSIONS: This study provides the first robust estimates of the additional cost of healthcare related to steroid-induced morbidity relative to patients with no steroid exposure. The study will help inform use of steroid-sparing strategies in this patient group.

Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity.

BACKGROUND: The mechanism underlying respiratory virus-induced cough hypersensitivity is unknown. Upregulation of airway neuronal receptors responsible for sensing physical and chemical stimuli is one possibility, and the transient receptor potential (TRP) channel family are potential candidates. We have used an in vitro model of sensory neurons and human rhinovirus (HRV-16) to study the effect of virus infection on TRP expression. METHODS: IMR-32 neuroblastoma cells were differentiated in culture to express three TRP channels: TRPV1, TRPA1 and TRPM8. Flow cytometry and qRT-PCR were used to measure TRP channel protein and mRNA levels following inoculation with live virus, inactivated virus, virus-induced soluble factors or pelleted virus particles. Multiplex bioassay was used to determine nerve growth factor (NGF), interleukin (IL)-1ß, IL-6 and IL-8 levels in response to infection. RESULTS: Early upregulation of TRPA1 and TRPV1 expression occurred 2-4 h post infection. This was independent of replicating virus as virus-induced soluble factors alone were sufficient to increase channel expression 50-fold and 15-fold, respectively. NGF, IL-6 and IL-8 levels, increased in infected cell supernatants, represent possible candidates. In contrast, TRPM8 expression was maximal at 48 h (9.6-fold) and required virus replication rather than soluble factors. CONCLUSIONS: We show for the first time that rhinovirus can infect neuronal cells. Furthermore, infection causes upregulation of TRP channels by channel-specific mechanisms. The increase in TRPA1 and TRPV1 levels can be mediated by soluble factors induced by infection whereas TRPM8 requires replicating virus. TRP channels may be novel therapeutic targets for controlling virus-induced cough.

Extracting quantum work statistics and fluctuation theorems by single-qubit interferometry.

We propose an experimental scheme to verify the quantum nonequilibrium fluctuation relations using current technology. Specifically, we show that the characteristic function of the work distribution for a nonequilibrium quench of a general quantum system can be extracted by Ramsey interferometry of a single probe qubit. Our scheme paves the way for the full characterization of nonequilibrium processes in a variety of quantum systems, ranging from single particles to many-body atomic systems and spin chains. We demonstrate our idea using a time-dependent quench of the motional state of a trapped ion, where the internal pseudospin provides a convenient probe qubit.

A gutsy performance: the potential for supplementation of short-chain fatty acids to benefit athletic health, exercise performance, and recovery.

The gut microbiome is known to play an important role in the day-to-day physiology and health of the human host. It is, therefore, not surprising that there is interest surrounding the gut microbiome and its potential to benefit athletic health and performance. This has, in part, been driven by the consideration that gut bacterial by-products (i.e. metabolic waste) could be harnessed by the host and utilised for a beneficial outcome. The concept of harnessing bacterial metabolites as beneficial health modulators has developed the theory of leveraging short-chain fatty acids (SCFAs) as novel supplements for enhancing athletic performance. This review discusses the current literature investigating SCFA administration in cellular, animal, and human models, with the aim of linking the demonstrated physiological/biochemical mechanisms to potential exercise/athletic benefit. In addition, practical implications and factors relating to SCFA-supplementation in athletic populations are considered. The literature demonstrates a tangible rationale that SCFAs can have a positive impact on human physiology to afford benefits to the athletic population. These advantages include the capacity to improve respiratory immunity to combat elevated levels/severity of upper respiratory tract infections often reported in athletes; the blunting of pro-inflammatory and pro-fibrotic pathways to aid in exercise recovery; and the role of SCFAs as usable energy sources and metabolism modulators to fuel exercise and improve performance and/or endurance capacity. However, there is currently minimal research completed in human participants and thus further investigations into the direct benefit of SCFAs in exercise performance and/or recovery-based studies are required.

EUFOREA summit in Brussels 2023: inspiring the future of allergy & respiratory care.

In March 2023, the European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual Summit in Brussels with expert panel members of EUFOREA, representatives of the EUFOREA patient advisory board, and the EUFOREA board and management teams. Its aim was to define the research, educational and advocacy initiatives to be developed by EUFOREA over the next 2 years until the 10th anniversary in 2025. EUFOREA is an international non-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic allergic and respiratory diseases via research, education, and advocacy. Based on its medical scientific core competency, EUFOREA offers an evidence-supported platform to introduce innovation and education in healthcare leading to optimal patient care, bridging the gap between latest scientific evidence and daily practice. Aligned with the mission of improving health care, the expert panels of asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS) & European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS), allergen immunotherapy (AIT) and paediatrics have proposed and elaborated a variety of activities that correspond to major unmet needs in the allergy and respiratory field. The current report provides a concise overview of the achievements, ambitions, and action plan of EUFOREA for the future, allowing all stakeholders in the allergy and respiratory field to be up-dated and inspired to join forces in Europe and beyond.

Genome-wide association study to identify genetic determinants of severe asthma.

BACKGROUND: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. OBJECTIVE: To identify common genetic variants affecting susceptibility to severe asthma. METHODS: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. RESULTS: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10((-8)) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10((-8)) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. CONCLUSIONS: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

Stress-related health depreciation: Using allostatic load to predict self-rated health.

Approximately one quarter of UK adults are currently diagnosed with two or more chronic conditions, often referred to as multimorbidity. Chronic stress has been implicated in the development of many diseases common to multimorbidity. Policymakers and clinicians have acknowledged the need for more preventative approaches to deal with the rise of multimorbidity and "early ageing". However divergence may occur between an individual's self-rated health and objectively measured health that may preclude preventative action. The use of biomarkers which look 'under the skin' provide crucial information on an individual's underlying health to facilitate lifestyle change or healthcare utilisation. The UK's Understanding Society dataset, was used to examine whether baseline variation in biomarkers measuring stress-related "wear and tear" - Allostatic Load (AL) - predict changes in future self-rated health (SRH) while adjusting for baseline SRH, socioeconomic and lifestyle factors, and healthcare inputs. An interaction between baseline AL and baseline SRH was included to test for differential rates of SRH change. We examined SRH using the SF6D instrument, measuring health-related-quality of life (HRQoL), as well as its physical and mental health components separately. We found that HRQoL and physical health decline faster for those with higher baseline AL (indicating greater "wear and tear") however the same pattern was not observed for mental health. These findings provide novel insights for clinicians and policymakers on the usefulness of AL in capturing health trajectories of which individual's may not be aware and its importance in targeting resilience enhancing measures earlier in the lifecourse to delay physical health decline.

Respiratory viral infection in lower airways of asymptomatic children.

AIM: The aim of this study was to determine if asthmatic children have viruses more commonly detected in lower airways during asymptomatic periods than normal children. METHODS: Fifty-five asymptomatic children attending elective surgical procedures (14 with stable asthma, 41 normal controls) underwent non-bronchoscopic bronchoalveolar lavage. Differential cell count and PCR for 13 common viruses were performed. RESULTS: Nineteen (35%) children were positive for at least one virus, with adenovirus being most common. No differences in the proportion of viruses detected were seen between asthmatic and normal 'control' children. Viruses other than adenovirus were associated with higher neutrophil counts, suggesting that they caused an inflammatory response in both asthmatics and controls (median BAL neutrophil count, 6.9% for virus detected vs. 1.5% for virus not detected, p = 0.03). CONCLUSIONS: Over one-third of asymptomatic children have a detectable virus (most commonly adenovirus) in the lower airway; however, this was not more common in asthmatics. Viruses other than adenovirus were associated with elevated neutrophils suggesting that viral infection can be present during relatively asymptomatic periods in asthmatic children.

Avian (chicken) parathyroid hormone: synthesis and comparative biological evaluation of the 1-34 fragment.

The full-length amino acid sequence of the avian (chicken) form of parathyroid hormone (cPTH) has recently been elucidated. We have chemically synthesized, purified to a high degree, and analytically and biologically characterized the N-terminal 1-34 fragment of the avian hormone. The biological properties of cPTH-(1-34)NH2 were evaluated and compared to the bovine fragment bPTH-(1-34) in several assays. The potency of cPTH-(1-34)NH2 in binding to PTH receptors, in stimulating adenylate cyclase activity and in relaxing smooth muscle tissue was approximately one-tenth that of bPTH-(1-34). Comparison of the avian sequence to other native PTH related sequences suggests that changes in the binding domain of the 1-34 active fragment may account for the decline in potency.

Hypercapnic alteration of visual evoked responses in acute cerebral infarction.

To determine the effect of inhaled carbon dioxide on acute ischemic cerebral injury, we have compared occipital visual evoked responses (VER) at baseline and during hypercapnia in 20 patients with acute unilateral cerebral infarction (ten with and ten without homonymous hemianopsia) and in ten normal controls. Visual evoked responses were judged on the basis of interhemispheral symmetry. In eight of ten controls and six of 20 patients, baseline VERs were symmetrical and remained unchanged during hypercapnia. In 14 patients with asymmetrical baseline VERs, hypercapnia caused improvement of symmetry in five, worsening in three, and no change in six. Hypercapnic vasodilation may be either beneficial or deleterious to cerebral function in patients with acute cerebral infarction.

Altered cerebral inhibition of respiratory and cardiac responses to hypercapnia in acute stroke.

Ventilatory and heart-rate responses to hypercapnia were evaluated by a CO2 rebreathing technique in 56 patients with acute ischemic stroke and 14 normal controls. Both ventilatory and heart-rate responses were increased in patients with hemispheral lesions, but not in patients with brainstem lesions. In patients with hemispheral infarct, there was a decrease in CO2 sensitivity 1 to 3 weeks later. Acute hemisphere lesions may result in a transient decrease of cerebral inhibition of brainstem-mediated autonomic responses to a chemical stimulus.

Is there an association between angiotensin-converting enzyme gene variants and chronic nonproductive cough?

BACKGROUND: It is unclear why some patients develop a chronic nonproductive cough. Angiotensin-converting enzyme (ACE) inactivates tussive peptides in the airways such as bradykinin and tachykinins. An insertion/deletion polymorphism in the ACE gene accounts for variation in ACE levels, and patients with the II genotype have lowest serum ACE levels compared with ID and DD genotypes. We hypothesized that the II genotype would be associated with increased risk of developing a chronic cough. MATERIALS AND METHODS: We recruited 47 patients (33 women), referred for evaluation of cough (median cough duration, 24 months; range, 2 to 240 months). Cough patients were evaluated using a comprehensive diagnostic protocol, and cough reflex sensitivity was measured using a capsaicin inhalation challenge. ACE genotyping was performed on DNA samples from patients using the polymerase chain reaction followed by agarose gel electrophoresis. ACE genotypes in patients with chronic cough were compared with those in 199 healthy control subjects. Serum ACE levels were determined using a colorimetric assay. RESULTS: Genotype frequencies for the ACE gene were similar between patients and control subjects. There was no correlation between capsaicin sensitivity and ACE genotypes or serum ACE levels. CONCLUSION: Susceptibility to develop chronic cough is not associated with ACE genotype.

Simple liquid chromatography method for the rapid simultaneous determination of prednisolone and cortisol in plasma and urine using hydrophilic lipophilic balanced solid phase extraction cartridges.

This article describes the development and validation of a simple solid phase extraction (SPE) and HPLC method for the extraction and the specific determination of prednisolone and hydrocortisone (cortisol) in both plasma and urine using one washing step with Oasis hydrophilic lipophilic balanced (HLB) cartridges (1 ml/30 mg, 30 microm). Recoveries of prednisolone and cortisol from plasma and urine exceeded 82%. The limit of quantification (LOQ) in plasma and urine was 9.9 and 6.7 ng/ml for cortisol, respectively, and 11.6 and 8.0 ng/ml for prednisolone, respectively. The intraday and interday precision (measured by CV%) for both prednisolone and cortisol in both plasma and urine was always less than 7%. The accuracy (measured by relative error %) for both prednisolone and cortisol in both plasma and urine was always less than 8%. The advantages of the developed method are the use of a one step washing SPE utilising HLB cartridges which do not suffer the drying out problems of conventional SPE cartridges and the time saving when compared with solvent extraction (SE), in addition to the simultaneous determination of prednisolone and cortisol in both plasma and urine.

Cardiac and respiratory monitoring of acute stroke patients.

This study evaluates physiologic monitoring as a tool for improved nursing observation of acute stroke patients. Forty-four patients admitted within 48 hours of onset of stroke were monitored using an automated arrhythmia detection system and impedance pneumography. Cardiac arrhythmias were observed in 25 of 44 patients. Three patients with episodes of atrial fibrillation were digitalized and converted to normal sinus rhythm. Respiratory patterns were intermittently abnormal in 39 of 44 patients. The presence of intermittent Cheyne-Strokes respirations or tachypnea was associated with an increased mortality rate. Cardiac monitoring appears to be a useful tool for prompt detection of potentially serious arrhythmias in stroke patients. Respiratory monitoring is useful for detection of abnormalities of respiratory rate and pattern; these abnormalities may serve as an early indicator of change in neurologic status.

Managing heart failure: update from Michael Reese's special program.

Heart failure is a major health problem, particularly among the elderly who experience the long term consequence of coronary artery disease. Over the past several years, the heart failure program at Michael Reese Hospital has seen a large number of elderly patients with heart failure. Two-thirds of these patients had a previous myocardial infarction, while 20% had an idiopathic (dilated) cardiomyopathy. Herein, we review that experience, focusing particularly on clinical presentation, our non-invasive approach to objectively determining their functional capacity and the severity of their failure, and, finally, a consideration of the various aspects of their medical management.

Cost minimisation analysis of provision of oxygen at home: are the drug tariff guidelines cost effective?

OBJECTIVES: To determine the level of oxygen cylinder use at which it becomes more cost effective to provide oxygen by concentrator at home in Northern Ireland, and to examine potential cost savings if cylinder use above this level had been replaced by concentrator in 1996. DESIGN: Cost minimisation analysis. SETTING: Area health boards in Northern Ireland. MAIN OUTCOME MEASURES: Cost effective cut off point for switch to provision of oxygen from cylinder to concentrator. Potential maximum and minimum savings in Northern Ireland (sensitivity analysis) owing to switch to more cost effective strategy on the basis of provision of cylinders in 1996. RESULTS: In Northern Ireland it is currently cost effective to provide oxygen by concentrator when the patient is using three or more cylinders per month independent of the duration of the prescription. More widespread use of concentrators at this level of provision is likely to lead to a cost saving. CONCLUSIONS: The Drug Tariff prescribing guidelines, advocating that provision of oxygen by concentrator becomes cheaper when 21 cylinders are being used per month-are currently inaccurate in Northern Ireland. Regional health authorities should review their current arrangements for provision of oxygen at home and perform a cost analysis to determine at what level it becomes more cost effective to provide oxygen by concentrator.