Accuracy and economic evaluation of screening tests for undiagnosed COPD among hypertensive individuals in Brazil.

In Brazil, prevalence of diagnosed COPD among adults aged 40 years and over is 16% although over 70% of cases remain undiagnosed. Hypertension is common and well-recorded in primary care, and frequently co-exists with COPD because of common causes such as tobacco smoking, therefore we conducted a cross-sectional screening test accuracy study in nine Basic Health Units in Brazil, among hypertensive patients aged ≥40 years to identify the optimum screening test/combinations to detect undiagnosed COPD. We compared six index tests (four screening questionnaires, microspirometer and peak flow) against the reference test defined as those below the lower limit of normal (LLN-GLI) on quality diagnostic spirometry, with confirmed COPD at clinical review. Of 1162 participants, 6.8% (n = 79) had clinically confirmed COPD. Peak flow had a higher specificity but lower sensitivity than microspirometry (sensitivity 44.3% [95% CI 33.1, 55.9], specificity 95.5% [95% CI 94.1, 96.6]). SBQ performed well compared to the other questionnaires (sensitivity 75.9% [95% CI 65.0, 84.9], specificity 59.2% [95% CI 56.2, 62.1]). A strategy requiring both SBQ and peak flow to be positive yielded sensitivity of 39.2% (95% CI 28.4, 50.9) and specificity of 97.0% (95% CI 95.7, 97.9). The use of simple screening tests was feasible within the Brazilian primary care setting. The combination of SBQ and peak flow appeared most efficient, when considering performance of the test, cost and ease of use (costing £1690 (5554 R$) with 26.7 cases detected per 1,000 patients). However, the choice of screening tests depends on the clinical setting and availability of resources.ISRCTN registration number: 11377960.

Intraventricular murine Aß infusion elicits hippocampal inflammation and disrupts the consolidation, but not retrieval, of conditioned fear in C57BL6/J mice.

Although one of the defining characteristics of Alzheimer's disease is the presence of amyloid-beta (Aß) plaques, the early accumulation of soluble Aß oligomers (AßOs) may disrupt synaptic function and trigger cognitive impairments long before the appearance of plaques. Furthermore, murine models aimed at understanding how AßOs alter formation and retrieval of associative memories are conducted using human Aß species, which are more neurotoxic in the mouse brain than the native murine species. Unfortunately, there is currently a lack of attention in the literature as to what the murine version of the peptide (mAß) does to synaptic function and how it impacts the consolidation and retrieval of associative memories. In the current study, adult mice were infused with mAß 0, 2, 6, or 46 h after contextual-fear conditioning, and were tested 2-48 h later. Interestingly, only mAß infusions within 2 h of training reduced freezing behavior at test, indicating that mAß disrupted the consolidation, but not retrieval of fear memory. This consolidation deficit coincided with increased IL-1ß and reduced synaptophysin mRNA levels, without disrupting other synaptic signaling-related genes here examined. Despite differences between murine and human Aß, the deleterious functional outcomes of early-stage synaptic oligomer presence are similar. Thus, models utilizing or inducing the production of mAß in non-transgenic animals are useful in exploring the role of dysregulated synaptic plasticity and resultant learning deficits induced by Aß oligomers.

Mini review shows that structured light plethysmography provides a non-contact method for evaluating breathing patterns in children.

AIM: Structured light plethysmography (SLP) is a novel light-based method that captures chest wall movements to evaluate tidal breathing. We carried out a narrative mini review of the clinical use of SLP in paediatrics. METHODS: PubMed and Google Scholar were searched for papers published in English up to December 2018. This identified a methodology paper published in 2010 and eight full papers, including three paediatric studies and one paediatric case report. We also included data from ten conference abstracts and one clinical case study. RESULTS: We found data that validated the ability of SLP to differentiate airway obstruction from tidal breathing parameters and bronchodilator responsiveness for children aged two years and over. Non-contact measurement of regional chest wall movement was a unique feature. Feasibility data were scarce and more studies are needed, especially in infants. Preliminary studies suggest that SLP has the potential to be used in cases of dysfunctional breathing and neuromuscular diseases and as a follow-up tool after lung infections or surgery. CONCLUSION: Structured light plethysmography has been validated to demonstrate lung function abnormality in paediatric asthma, but further studies are needed to demonstrate its benefits over current practice and how it can be used for other conditions.

Functional effects of an interpenetrating polymer network on articular cartilage mechanical properties.

OBJECTIVE: Depletion of glycosaminoglycans (GAGs) and degradation of collagen network are early hallmarks of osteoarthritis (OA). Currently, there are no chondroprotective therapies that mitigate the loss of GAGs or effectively restore the collagen network. Recently, a novel polymeric cartilage supplement was described that forms a charged interpenetrating polymer network (IPN) reconstituting the hydrophilic properties of the extracellular matrix (ECM). To investigate the mechanism by which this hydrophilic IPN improves articular cartilage material properties, a finite element (FE) model is used to evaluate the IPN's effect on the fibrillar collagen network, nonfibrillar matrix, and interstitial fluid flow. METHODS: Bovine osteochondral plugs were degraded with chondroitinase ABC to selectively decrease GAG content. Samples were mechanically tested before and after IPN treatment using unconfined testing geometry and stress-relaxation protocol. Every measurement was modeled separately using a fibril-reinforced poroviscoelastic FE model. Measurement replication was achieved by optimizing the following model parameters: initial and strain-dependent fibril network modulus (Ef0, Efε, respectively), nonfibrillar matrix modulus (Enf), initial permeability (k0) and strain-dependent permeability factor (M). RESULTS: Based on the FE model results, treatment of native and GAG depleted cartilage with the hydrophilic IPN increases the ECM stiffness and impedes fluid flow. The IPN did not alter the stiffness of fibrillary network. Cartilage permeability and the strain-dependent permeability factor decreased with increasing IPN w/v%. CONCLUSIONS: The IPN reconstitutes cartilage material properties primarily by augmenting the hydrophilic ECM. This reinforcement of the solid phase also affects the fluid phase reestablishing low permeability.

Reinforcement of articular cartilage with a tissue-interpenetrating polymer network reduces friction and modulates interstitial fluid load support.

OBJECTIVE: Osteoarthritis (OA) is associated with increased articular cartilage hydraulic permeability and decreased maintenance of high interstitial fluid load support (IFLS) during articulation, resulting in increased friction on the cartilage solid matrix. This study assesses frictional response following in situ synthesis of an interpenetrating polymer network (IPN) designed to mimic glycosaminoglycans (GAGs) depleted during OA. METHODS: Cylindrical osteochondral explants containing various interpenetrating polymer concentrations were subjected to a torsional friction test under unconfined creep compression. Time-varying coefficient of friction, compressive engineering strain, and normalized strain values (ε/εeq) were calculated and analyzed. RESULTS: The polymer network reduced friction coefficient over the duration of the friction test, with statistically significantly reduced friction coefficients (95% confidence interval 14-34% reduced) at equilibrium compressive strain upon completion of the test (P = 0.015). A positive trend was observed relating polymer network concentration with magnitude of friction reduction compared to non-treated tissue. CONCLUSION: The cartilage-interpenetrating polymer treatment improves lubrication by augmenting the biphasic tissue's interstitial fluid phase, and additionally improves the friction dissipation of the tissue's solid matrix. This technique demonstrates potential as a therapy to augment tribological function of articular cartilage.

Fibre architecture and song activation rates of syringeal muscles are not lateralized in the European starling.

The songbird vocal organ, the syrinx, is composed of two sound generators, which are independently controlled by sets of two extrinsic and four intrinsic muscles. These muscles rank among the fastest vertebrate muscles, but the molecular and morphological foundations of this rapid physiological performance are unknown. Here we show that the four intrinsic muscles in the syrinx of male European starlings (Sturnus vulgaris) are composed of fast oxidative and superfast fibres. Dorsal and ventral tracheobronchialis muscles contain slightly more superfast fibres relative to the number of fast oxidative fibres than dorsal and ventral syringealis muscles. This morphological difference is not reflected in the highest, burst-like activation rate of the two muscle groups during song as assessed with electromyographic recordings. No difference in fibre type ratio was found between the corresponding muscles of the left and right sound generators. Airflow and electromyographic measurements during song indicate that maximal activation rate and speed of airflow regulation do not differ between the two sound sources. Whereas the potential for high-speed muscular control exists on both sides, the two sound generators are used differentially for modulation of acoustic parameters. These results show that large numbers of superfast fibre types are present in intrinsic syringeal muscles of a songbird, providing further confirmation of rapid contraction kinetics. However, syringeal muscles are composed of two fibre types which raises questions about the neuromuscular control of this heterogeneous muscle architecture.

Is it necessary to use a noseclip in the performance of spirometry using a wedge bellows device?

There is no current consensus among published guidelines on whether noseclips are required during spirometry testing. This study investigated the effect of noseclips on spirometric measurements in patients with a range of disease. Fifty-two patients (30 male; mean age 58.0 years, range 19-78; mean FEV1 82.6% predicted, range 23.8-128.3%) performed measurements of VC, FVC and FEV1 according to ARTP/BTS guidelines (1994) using a wedge bellows spirometer (Vitalograph Model S, Bucks, U.K.). All patients performed two sets of measurements (with and without noseclips) in random order (Group 1 = noseclips first; n=30; Group 2 (without noseclips first, n=22). Tests were conducted by qualified physiologists. Measurements obtained with and without the use of noseclips were similar (mean differences FEV1 -0.030 L SD 0.210 and -0.005 L SD 0.093 for Groups 1 and 2 respectively; FVC -0.007 L SD 0.109 and -0.040 L SD 0.117; VC 0.036L SD 0.137 and -0.040 L SD 0.150) and were not dependent on patient group or previous test experience. Four patients had differences outside the 95% confidence limits for each parameter. There were no significant correlations between the differences with and without noseclips and severity of lung disease, age, smoking history, BMI or lung volume (all P > 0.100). The within patient coefficient of variation did not depend on the testing method. Use of noseclips during spirometry does not systematically affect the results obtained or the within-subject repeatability. Marked individual differences highlight the importance of maintaining consistency in the method adopted for a particular patient.

Finding your way in the dark: the retrosplenial cortex contributes to spatial memory and navigation without visual cues.

Path integration is presumed to rely on self-motion cues to identify locations in space and is subject to cumulative error. The authors tested the hypothesis that rats use memory to reduce such errors and that the retrosplenial cortex contributes to this process. Rats were trained for 1 week to hoard food in an arena after beginning a trial from a fixed starting location; probe trials were then conducted in which they began a trial from a novel place in light or darkness. After control injections, rats searched around the training location, showing normal spatial memory. Inactivation of the retrosplenial cortex disrupted this search preference. To assess accuracy during navigation, rats were then trained to perform multiple trials daily, with a fixed or a different starting location in light or darkness. Retrosplenial cortex inactivation impaired accuracy in darkness. The retrosplenial cortex may provide mnemonic information, which decreases errors when navigating in the dark.

Temporary inactivation of the retrosplenial cortex causes a transient reorganization of spatial coding in the hippocampus.

The ability to navigate accurately is dependent on the integration of visual and movement-related cues. Navigation based on metrics derived from movement is referred to as path integration. Recent theories of navigation have suggested that posterior cortical areas, the retrosplenial and posterior parietal cortex, are involved in path integration during navigation. In support of this hypothesis, we have found previously that temporary inactivation of retrosplenial cortex results in dark-selective impairments on the radial maze (Cooper and Mizumori, 1999). To understand further the role of the retrosplenial cortex in navigation, we combined temporary inactivation of retrosplenial cortex with recording of complex spike cells in the hippocampus. Thus, behavioral performance during spatial memory testing could be compared with place-field responses before, and during, inactivation of retrosplenial cortex. In the first experiment, behavioral results confirmed that inactivation of retrosplenial cortex only impairs radial maze performance in darkness when animals are at asymptote levels of performance. A second experiment revealed that retrosplenial cortex inactivation impaired spatial learning during initial light training. In both experiments, the normal location of hippocampal "place fields" was changed by temporary inactivation of retrosplenial cortex, whereas other electrophysiological properties of the cells were not affected. The changes in place coding occurred in the presence, and absence, of behavioral impairments. We suggest that the retrosplenial cortex provides mnemonic spatial information for updating location codes in the hippocampus, thereby facilitating accurate path integration. In this way, the retrosplenial cortex and hippocampus may be part of an interactive neural system that mediates navigation.

A neural systems analysis of adaptive navigation.

In the field of the neurobiology of learning, significant emphasis has been placed on understanding neural plasticity within a single structure (or synapse type) as it relates to a particular type of learning mediated by a particular brain area. To appreciate fully the breadth of the plasticity responsible for complex learning phenomena, it is imperative that we also examine the neural mechanisms of the behavioral instantiation of learned information, how motivational systems interact, and how past memories affect the learning process. To address this issue, we describe a model of complex learning (rodent adaptive navigation) that could be used to study dynamically interactive neural systems. Adaptive navigation depends on the efficient integration of external and internal sensory information with motivational systems to arrive at the most effective cognitive and/or behavioral strategies. We present evidence consistent with the view that during navigation: 1) the limbic thalamus and limbic cortex is primarily responsible for the integration of current and expected sensory information, 2) the hippocampal-septal-hypothalamic system provides a mechanism whereby motivational perspectives bias sensory processing, and 3) the amygdala-prefrontal-striatal circuit allows animals to evaluate the expected reinforcement consequences of context-dependent behavioral responses. Although much remains to be determined regarding the nature of the interactions among neural systems, new insights have emerged regarding the mechanisms that underlie flexible and adaptive behavioral responses.

Hippocampal representational organization and spatial context.

The hippocampus appears to undergo continual representational reorganization as animals navigate their environments. This reorganization is postulated to be reflected spatially in terms of changes in the ensemble of place cells activated, as well as changes in place field specificity and reliability for cells recorded in both hilar/CA3 and CA1 regions. The specific contribution of the hilar/CA3 region is suggested to be to compare the expected spatial context with that currently being experienced, then relay discrepancies to CA1. The properties of CA1 place fields in part reflect the spatial comparisons made in the hilar/CA3 area. In addition, CA1 organizes the input received from the hilar/CA3 place cells according to different temporal algorithms that are unique to different tasks. In this way, hippocampus helps to distinguish temporally one spatial context from another, thereby contributing to episodic memories.

Prospective audit of a respiratory sleep disorders service at District General Hospital level.

This study was designed to examine the organisation and outcomes of a District General Hospital respiratory sleep service, since data are lacking on the management of sleep-disordered breathing at this level. Questionnaires and case-notes review were used to assess the management of 119 consecutive patients referred with suspected sleep-disordered breathing. Patients diagnosed with sleep-disordered breathing were assigned nasal continuous positive airway pressure (nCPAP), ear/nose/throat (ENT) surgery or simple measures (e.g., weight loss). There were six non-attenders. At 12 months follow-up, 33 patients had been assigned to nCPAP, 25 to ENT surgery, and 37 to simple measures. Of the remainder, nine had alternative diagnoses, two were still being assessed and seven were lost to follow-up. Patients prescribed nCPAP (81% compliance) had significant symptomatic improvements with low dissatisfaction rates (20%); patients on simple measures did not improve (33% dissatisfied); only half assigned surgery had it performed, with 42% awaiting surgery and dissatisfied. Interspecialty referral resulted in major delays (mean 16 weeks). Referral letters were generally unhelpful in deciding on the appropriateness of initial referral (respiratory physician vs ENT). nCPAP was generally effective in improving symptoms, with a high level of patient satisfaction, while simple measures did not improve symptoms and were associated with lower satisfaction levels. Waiting times to ENT surgery can be long and patients express significant dissatisfaction. Referral letters are not useful in directing initial referral. Services should be co-ordinated between respiratory and ENT specialties to reduce waiting times and improve patient satisfaction.

Evaluation of phenylalanine and tyrosine metabolism in late human pregnancy.

The [2H5]-phenylalanine method for measurement of protein metabolism requires the phenylalanine hydroxylation to tyrosine to be calculated from the tyrosine flux. Although this can be estimated, for pregnancy, we made a direct measurement of the molar ratio of the fluxes of tyrosine and phenylalanine from protein breakdown (Pt/Pp) using [2H2]-tyrosine infusion. Six normal pregnant women were studied at 37 weeks' gestation. While fasting, they were administered a 3-hour primed-constant infusion with [13C]-leucine, [2H5]-phenylalanine, and [2H2]-tyrosine. Leucine (alpha-ketoisocaproic acid [KIC]) flux was 136.2+/-15.1 micromol/kg/h (mean +/- SD), phenylalanine flux 41.2+/-5.6, and tyrosine flux 25.0+/-6.0, and phenylalanine hydroxylation was 3.3+/-2.1 micromol/kg/h. The mean tyrosine to phenylalanine molar flux ratio (Pt/Pp) was 0.52+/-0.10, lower than the ratio of 0.65 to 0.85 reported in normal nonpregnant subjects and 0.73 estimated from animal studies. We studied protein metabolism in six additional pregnant women and six nonpregnant women using [13C]-leucine and [2H5]-phenylalanine infusions only and applied the lower Pt/Pp ratio to the former group. Tyrosine flux (42.0+/-7.2 micromol/kg/h) and phenylalanine hydroxylation (9.2+/-4.2 micromol/kg/h) were significantly higher in nonpregnant subjects than in both groups of pregnant subjects. The percent contribution of phenylalanine hydroxylation to total tyrosine flux was reduced from 20% to 14%. When using [2H5]-phenylalanine to study whole-body protein metabolism in pregnancy and tyrosine flux is not measured directly by infusion of [2H2]-tyrosine, the lower Pt/Pp ratio is required. The phenylalanine model shows that tyrosine flux derived from protein breakdown and phenylalanine hydroxylation are both reduced in pregnancy.

Retrosplenial cortex inactivation selectively impairs navigation in darkness.

There is an emerging consensus that retrosplenial and posterior parietal cortex importantly contribute to navigation. Several theories of navigation have argued that these cortical areas, particularly retrosplenial cortex, are involved in path integration. In an effort to characterize the role of retrosplenial cortex in active navigation, the effects of temporary inactivation of retrosplenial cortex on spatial memory performance were evaluated in light and dark testing conditions. Inactivation of retrosplenial cortex selectively resulted in behavioral impairments when animals were tested in darkness. These data support the hypothesis that retrosplenial cortex contributes to navigation in darkness, perhaps by providing mnemonic associations of the visual and nonvisual environment that can be used to correct for cumulative errors that occur during path integration.