Midhurst Community Hospital

RATIONALE: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell-derived cytokine IL-33 plays a central role in exacerbation pathogenesis through augmentation of type 2 inflammation. OBJECTIVES: To assess whether rhinovirus induces a type 2 inflammatory response in asthma in vivo and to define a role for IL-33 in this pathway. METHODS: We used a human experimental model of rhinovirus infection and novel airway sampling techniques to measure IL-4, IL-5, IL-13, and IL-33 levels in the asthmatic and healthy airways during a rhinovirus infection. Additionally, we cultured human T cells and type 2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirus-infected bronchial epithelial cells (BECs) to assess type 2 cytokine production in the presence or absence of IL-33 receptor blockade. MEASUREMENTS AND MAIN RESULTS: IL-4, IL-5, IL-13, and IL-33 are all induced by rhinovirus in the asthmatic airway in vivo and relate to exacerbation severity. Further, induction of IL-33 correlates with viral load and IL-5 and IL-13 levels. Rhinovirus infection of human primary BECs induced IL-33, and culture of human T cells and ILC2s with supernatants of rhinovirus-infected BECs strongly induced type 2 cytokines. This induction was entirely dependent on IL-33. CONCLUSIONS: IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo. Virus-induced IL-33 and IL-33-responsive T cells and ILC2s are key mechanistic links between viral infection and exacerbation of asthma. IL-33 inhibition is a novel therapeutic approach for asthma exacerbations.

Pollinators are fundamental to maintaining both biodiversity and agricultural productivity, but habitat destruction, loss of flower resources, and increased use of pesticides are causing declines in their abundance and diversity. Using historical records, we assessed the rate of extinction of bee and flower-visiting wasp species in Britain from the mid-19th century to the present. The most rapid phase of extinction appears to be related to changes in agricultural policy and practice beginning in the 1920s, before the agricultural intensification prompted by the Second World War, often cited as the most important driver of biodiversity loss in Britain. Slowing of the extinction rate from the 1960s onward may be due to prior loss of the most sensitive species and/or effective conservation programs.

Abstract The history of the British Isles and Ireland is characterized by multiple periods of major cultural change, including the influential transformation after the end of Roman rule, which precipitated shifts in language, settlement patterns and material culture 1 . The extent to which migration from continental Europe mediated these transitions is a matter of long-standing debate 2–4 . Here we study genome-wide ancient DNA from 460 medieval northwestern Europeans—including 278 individuals from England—alongside archaeological data, to infer contemporary population dynamics. We identify a substantial increase of continental northern European ancestry in early medieval England, which is closely related to the early medieval and present-day inhabitants of Germany and Denmark, implying large-scale substantial migration across the North Sea into Britain during the Early Middle Ages. As a result, the individuals who we analysed from eastern England derived up to 76% of their ancestry from the continental North Sea zone, albeit with substantial regional variation and heterogeneity within sites. We show that women with immigrant ancestry were more often furnished with grave goods than women with local ancestry, whereas men with weapons were as likely not to be of immigrant ancestry. A comparison with present-day Britain indicates that subsequent demographic events reduced the fraction of continental northern European ancestry while introducing further ancestry components into the English gene pool, including substantial southwestern European ancestry most closely related to that seen in Iron Age France 5,6 .

This study was undertaken to investigate whether the normal dog heart would switch to lactate as the preferred substrate when the arterial lactate level was raised. Sodium L-Lactate (pH adjusted to 7.0) was infused intravenously in sufficient quantity to raise the arterial lactate levels to those found in moderate to severe exercise (over 4.5 mmol . litre-1). The dogs were studied under chloralose anaesthesia breathing spontaneously. Blood samples were obtained from a branch of the femoral artery and the coronary sinus, and analysed for lactate, glucose, fatty free acids (FFA) and oxygen content. The ratio of lactate consumption to oxygen consumption was used to express the amount of lactate oxidised as a percentage of total substrate. This ratio was found to be a function of arterial lactate and reached a maximum at an arterial lactate concentration of 4.5 mmol . litre-1; this was uninfluenced by raised arterial glucose or FFA--the myocardium preferred lactate to glucose or FFA. A direct measurement of lactate oxidised as a percentage of total fuel was obtained in experiments with L-Lactate-[14C(U)], these showed that when the arterial lactate concentration was above 4.5 mmol . litre-1, even in the presence of high glucose or FFA, 87% of the total substrate oxidised was lactate. These results show that when the normal dog heart is presented with a choice of substrates, lactate is the preferred substrate for energy production.

A multicentre study of survivors of an anterior myocardial infarction is reported. The trial consisted of 720 patients and was a double-blind, placebo-controlled study with propranolol 40 mg three times a day. Trial entry was at two to 14 days (mean 8.5 days) and follow-up at one, three, and in most centres, six and nine months. The trial was designed to detect a 50 per cent reduction in mortality and this was not shown. The non-fatal reinfarction rate was similar in both groups. Subgroup analysis identified several prognostic risk factors for death, none of which interacted with treatment.

1. Three independent methods were used to investigate population structure in the butterfly Plebejus argus . First, migration and dispersal ability were measured by mark–release–recapture in seven adjacent habitat patches, and by release of butterflies in unoccupied habitat. Secondly, colonization of newly created habitat was observed over 7 years. Finally, genetic differentiation of local populations within a metapopulation was investigated. Sampled local populations included parts of the mark–release–recapture study area. 2. Plebejus argus is relatively sedentary: the maximum movement detected was 395 m, and only 2% of individuals moved further than 100 m between recaptures on different days. None the less, adjacent local populations in the mark–release–recapture study area were linked by occasional migration, with ≈ 1.4% of individuals moving between patches separated by 13–200 m. 3. Despite low mobility, observed colonizations occurred rapidly over distances of 1 km. Because P. argus occurs at high population densities, 1.4% migration can generate enough migrants to colonize newly suitable habitat quickly at this spatial scale. 4. Mark–release–recapture data were used to predict that there would be limited genetic differentiation through drift between local populations at this spatial scale. The prediction was supported by allele frequency data for the same local populations. 5. Genetic differentiation often indicates higher levels of migration than are revealed by the movements of marked individuals. This study shows that when experimental releases and extensive marking are undertaken in areas that are large relative to most movements, indirect measures of gene flow and direct measures of dispersal can concur. 6. Evidence from the three different approaches was complementary, indicating that P. argus occurs as metapopulations within the study area.

An immunocytochemical unlabelled antibody method using rabbit antihuman lysozyme, antirabbit immunoglobulin, and soluble rabbit antihorseradish peroxidase/horseradish peroxidase complexes was used to study the fine structural distribution of lysozyme in human bronchial glands. None was identified in mucous cells but there was heavy staining of the serous cell granules. The serous cell granules were not stained uniformly, suggesting the presence of other secretory products but lysozyme secretion appears to be a major function of these cells. The pathological implications of this are discussed.

The cross-sectional shapes of the chest and its contained structures have been assessed in post-mortem anatomical sections and from computerised tomographic scans in living subjects. These shapes are described by simple equations that can be used to increase the accuracy of measuring lung volumes from chest radiographs. Radiographic estimates of total lung capacity, using the equations, were compared with plethysmographic and single-breath helium dilution measurements in 35 normal subjects. The postures commonly used for taking chest radiographs were found, on average, to decrease total lung capacity (TLC) and to increase residual volume by about 200 ml when compared with the sitting positions used for the other two measurements (studies made in 18 of the subjects). After correction for this effect, the radiographic estimates of TLC, which measure the displacement volume of the lung, exceeded the plethysmographic estimates of contained gas volume by a mean of 720 ml, which was taken as the volume of tissue, blood, and water in the lungs. The single-breath dilution estimates of TLC fell short of the plethysmographic values by a mean of 480 ml, taken as the volume of contained gas that was inaccessible to helium in 10 seconds. The tomographic studies suggested that the radiographic technique of measuring lung displacement volumes has an accuracy of +/- 210 ml. The method is rapid and simple to use and has intra- and inter-observer variabilities of less than 1% and less than 5% respectively.

The distribution of lactoferrin and glycoprotein in human bronchial glands has been studied by electron microscopy using an immunoperoxidase method to stain the former and a periodic acid-chromic acid-silver methenamine sequence for the latter, each applied to ultrathin Epon sections. The distribution of lactoferrin corresponds to that of lysozyme. Lactoferrin and lysozyme are both confined to serous acini where the granules show a variable pattern of staining. Some serous granules are filled uniformly with lactoferrin, some lack lactoferrin in a small central core or a thin peripheral rim, and some are completely devoid of lactoferrin. Glycoprotein is present in all mucous granules but only certain serous granules. The latter may be filled uniformly with glycoprotein or glycoprotein may form a thin peripheral coat about centrally located lactoferrin and lysozyme. An electron-dense central core found in some serous granules contains neither glycoprotein, lactoferrin, nor lysozyme.

Journal Article Left ventricular load, arterial impedance and their interrelationship Get access MARK I. M. NOBLE MARK I. M. NOBLE The Midhurst Medical Research Institute, Midhurst, Sussex GU29 0BL Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 13, Issue 4, April 1979, Pages 183–198, https://doi.org/10.1093/cvr/13.4.183 Published: 01 April 1979

1. Simultaneous measurements were made in anaesthetized dogs of monophasic action potentials from the right ventricle and of the maximum rate of rise of left ventricular pressure (dP(lv)/dt(max)). Atrio-ventricular dissociation was induced and the heart paced via right ventricular electrodes.2. A control period of steady pacing was followed by a test stimulus after a variable interval called the ;test-pulse interval'. The duration of the action potential of the test beat (measured at 70% repolarization) increased with test-pulse interval and reached an approximately steady value at intervals of 1.0-1.5 sec. This constitutes the ;electrical restitution curve'.3. An increase in the frequency of stimulation prior to the introduction of the test pulses caused a downward displacement of the electrical restitution curve.4. Stimulation at 2 Hz and paired pulse stimulation at 1 Hz (same number of stimuli per min) were introduced prior to the test pulses and produced very similar electrical restitution curves.5. For a constant frequency of stimulation in the control period, adrenaline produced downward displacement of the restitution curve.6. It is concluded that there is no obvious relationship between the restitution of the action potential duration and of the contractile response. We suggest therefore that electrical and mechanical restitution occur through separate processes, the former through time-dependent recovery in membrane conductances and the latter through time-dependent increase in availability of intracellular calcium for release.7. Contractions were introduced with a test-pulse interval shorter than the optimum, and were followed by a second test pulse fixed at the optimum interval of 0.8-1.0 sec. The second test beats were potentiated (post-extrasystolic potentiation). In isolated ejecting cat hearts, there was an optimum interval for the first test pulse to produce the greatest potentiation of the second test beat. This interval was 0.2-0.3 sec, and was shortened by an increase in frequency of stimulation prior to the first test beat.8. The interval preceding the first test pulse was then varied within a range (0.8-2.0 sec) which did not produce potentiation. These first test pulses were sometimes preceded by one extrasystole. The timing of this extrasystole was altered to vary the post-extrastolic potentiation of the first test pulse.9. Multiple regression analysis, carried out between dP(lv)/dt(max) of the second test pulse (DP(2), the dependent variable) and the action potential duration (AP(1)) and dP(lv)/dt(max) (DP(1)) of the first test pulse (independent variables) yielded correlation coefficients between 0.88 and 0.99. Each determination of the coefficient included data from beats with and without post-extrasystolic potentiation.10. It is postulated that the coefficient relating DP(2) to DP(1) in the multiple regression analysis (mean value 0.75) is an index of the proportion of calcium stored during relaxation which is released again on the next beat.11. When the decay of post-extrasystolic potentiation was examined in consecutive beats at the optimum interval, the action potential durations of these beats were found to be nearly constant. A plot of dP(lv)/dt(max) of each beat against dP(lv)/dt(max) of the previous beat yielded a curvilinear relationship which was less steep than that relating DP(2) to DP(1) in the two test pulse analysis; this was attributed to inconstancy of calcium ion entry during the action potential.

Other| January 01 1978 The Frank—Starling Curve M. I. M. Noble M. I. M. Noble 1Midhurst Medical Research Institute, Midhurst, Sussex, U.K. Search for other works by this author on: This Site PubMed Google Scholar Clin Sci Mol Med (1978) 54 (1): 1–7. https://doi.org/10.1042/cs0540001 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation M. I. M. Noble; The Frank—Starling Curve. Clin Sci Mol Med 1 January 1978; 54 (1): 1–7. doi: https://doi.org/10.1042/cs0540001 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 1978 The Biochemical Society and the Medical Research Society1978 Article PDF first page preview Close Modal You do not currently have access to this content.

29 single frog skeletal muscle fibers were stretched during fused tetanic contractions. The force increase during stretch exhibited a breakpoint at a critical length change (average: 16.6 nm per one-half sarcomere) that was independent of velocity of stretch and of sarcomere length between 1.8 and 2.8 microns. After stretch there was an early decaying force component with a force-extension curve similar to that during stretch, which disappeared over approximately 2 s. This component was removed by a small, quick release, leaving a longer-lasting component. The critical amplitude of release required to produce this result was found by clamping the fiber to a load at which there was zero velocity of shortening. This amplitude increased with time up to the angle in the force record during stretch, was constant for the remainder of the stretch, and decreased with time after the end of stretch; it was consistently less than the critical amplitude of stretch required to reach the breakpoint of force enhancement during stretch but was also independent of sarcomere length. The force drop accompanying the critical release showed a small increase up to an optimum magnitude at 2.4--2.7 microns sarcomere length, with a decrease at longer lengths.

1. The lung nitrogen from ten normal nonsmoking subjects and ten patients with chronic respiratory disease was washed out by inspiration of 21% oxygen and 79% argon, whilst expired nitrogen concentration was measured with a mass spectrometer and flow with a box-bag system, and the quantity of nitrogen in each expirate calculated with a Varian 73 digital computer and plotted against expired volume. 2. The resulting curve from each breath was handled either as a linear or a polynomial regression, the intercept on the abscissa being designated the series dead space volume (VDS). This dead space has also been measured by the Fowler method and by the mathematical differentiation of phase II. 3. The nitrogen recovered from the first breath varied between 190 ml and 584 ml and this has been expressed as a percentage of that volume predicted assuming perfect alveolar mixing; this has been called the alveolar gas mixing efficiency for nitrogen. The mean values for alveolar mixing efficiency computed from the four different series dead space volumes were 89.8%, 90.8%, 89.0% and 85.7%. This suggests that the value of series dead space used in computing mixing efficiency is not of great importance, and any of the four methods gives satisfactory results. 4. The data from multi-breath washout were also similarly expressed as a percentage efficiency, making the results from the two methods directly comparable. The median value for alveolar gas mixing efficiency by the single breath test was 89%, and for the multi-breath test about 76%. The latter was apparently more discriminating for ventilatory defect. In patients the values were respectively 73% and 40%.

Measurements of the myocardial content of ATP, creatine phosphate and glycogen provide a sensitive marker of the effect of inevitably global ischemia on myocardial tissue during aorto-coronary bypass surgery and give insight in the efficacy of various cardioprotective techniques. Continuous aortic cross clamping for performance of the distal anastomoses with multidose St. Thomas cardioplegia did not result in significant changes in the myocardial ATP, creatine phosphate and glycogen content. In contrast, hypothermic intermittent crossclamping resulted in a significant reduced tissue content of these markers of myocardial ischemia.

There is increasing evidence that farmers in many areas are achieving below maximum yields due to insufficient pollination. Practical and effective approaches are needed to maintain wild pollinator populations within agroecosystems so they can deliver critical pollination services that underpin crop production. We established nesting and wildflower habitat interventions in 24 UK apple orchards and measured effects on flower-visiting insects and the pollination they provide, exploring how this was affected by landscape context. We quantified the extent of pollination deficits and assessed whether the management of wild pollinators can reduce deficits and deliver improved outcomes for growers over 3 years. Wildflower interventions increased solitary bee numbers visiting apple flowers by over 20%, but there was no effect of nesting interventions. Other pollinator groups were influenced by both local and landscape-scale factors, with bumblebees and hoverflies responding to the relative proportion of semi-natural habitat at larger spatial scales (1000 m), while honeybees and other flies responded at 500 m or less. By improving fruit number and quality, pollinators contributed more than £16 k per hectare. However, deficits (where maximum potential was not being reached due to a lack of pollination) were recorded and the extent of these varied across orchards, and from year to year, with a 22% deficit in output in the worst (equivalent to ~£14 k/ha) compared to less than 3% (equivalent to ~£2 k/ha) in the best year. Although no direct effect of our habitat interventions on deficits in gross output was observed, initial fruit set and seed set deficits were reduced by abundant bumblebees, and orchards with a greater abundance of solitary bees saw lower deficits in fruit size. The abundance of pollinators in apple orchards is influenced by different local and landscape factors that interact and vary between years. Consequently, pollination, and the extent of economic output deficits, also vary between orchards and years. We highlight how approaches, including establishing wildflower areas and optimizing the ratio of cropped and non-cropped habitats can increase the abundance of key apple pollinators and improve outcomes for growers.

Left ventricular blood flow was measured in dogs with radioactive microspheres at a fixed heart rate for each dog, achieved by right atrial pacing. Blood samples were taken from an artery and from the coronary sinus, into which a catheter had been introduced under fluoroscopic control. These were analysed for oxygen content, lactate, glucose, and free fatty acids. The coronary A-V differences for these variables were used together with the flow to calculate left ventricular oxygen consumption and left ventricular uptake of the three substances. Each dog was then subjected to cardiac denervation and after three weeks, to allow for endogenous catecholamines to be depleted, a second measurement of the left ventricular blood flow was made using microspheres with a different radioactive label, together with second measurements of coronary A-V differences for oxygen content, lactate, glucose, and free fatty acids. These measurements were made with the same heart rate, arterial pressure, and anaesthetic as in the first study in each dog. Left ventricular oxygen consumptions in the innervated control study were 109.6 ± 15.9 (1 SD) mm3 O2 · min−1·g−1, and after denervation were 141.8 ± 35.7 mm3 O2 ·min−1·g−l respectively. This increase in left ventricular oxygen consumption was accompanied by concomitant increases in lactate consumption from 277.4 ± 156.7 nmol·min−1·g−1 to 917 ± 213.3 nmol·min−1·g−1 respectively, but no consistent changes in glucose and free fatty acid uptake. External left ventricular work per cm3 of oxygen consumed fell from 4.38 ± 0.63 to 2.77 ± 0.92 J (P <0.05) and for each μmol of lactate consumed fell from 2.004 ± 0.949 to 0.433 ± 0.151 J (0.05>P>0.025). This implies that tonic release of noradrenaline from nerve terminals controls the conversion of substrate and oxygen into mechanical energy.

Nine established cigarette smokers were each studied four times, smoking two identical cigarettes on each occasion. After an acclimatization study, they smoked one of three types of cigarettes, either their usual brand or one of two types of special low tar cigarettes. These latter both had tar yields of about 8 mg with nicotine yields of 0.55 (LN) and 0.90 (MN) mg respectively. The test order was randomized between individuals and before using the special cigarettes the subjects were given a pack to accustomize themselves. While smoking each cigarette, magnetic tape recordings were made of puff rate, ventilation measured by respiratory inductive plethysmography (RIP) and nasal airflow measured with a modified oxygen cannula. The data were then processed digitally off-line. Salivary nicotine and alveolar carbon monoxide levels were measured before and after smoking each cigarette, and the cigarette butt was analysed for nicotine. While smoking behaviour varied considerably between the various subjects only small differences were seen between the different cigarette types in puff volume and duration and shape of the puff profile. Some changes in smoking behaviour occurred during the course of smoking a single cigarette. Ventilatory patterns showed consistent inter-subject differences but there were no apparent variations due to the various cigarettes. Most subjects puffed during an expiration with the buccal cavity closed off, and then took a slower, deeper inspiration breathing through the mouth. Others, however, took puffs at any point in the respiratory cycle. The different nicotine yields of the cigarettes produced marked changes in the butt and salivary nicotine measurements, but neither these, nor the changes in alveolar carbon monoxide, were closely related to ventilatory measurements. Possible explanations for these discrepancies are discussed.

1. The potential value of right vagotomy for the relief of breathlessness has been explored in five patients with emphysema. Two patients had symptomatic improvement, two had minor symptomatic improvement, and one was unchanged. 2. Exercise ventilation was not noticeably depressed by unilateral right vagotomy in the two patients investigated fully, but the pattern of breathing was altered. After vagotomy, breathing was deeper, and the rise in the frequency of breathing with exercise was depressed. 3. After right vagotomy the response to rebreathing carbon dioxide also consisted of slower deeper breaths. 4. Right vagotomy sometimes appears to remove an influence preventing slow deep breathing and exacerbating dyspnoea. 5. Results of bilateral pulmonary denervation, attempted in one patient, were complicated by the need for left thoracotomy, which removed any possible beneficial effects.

This study describes a simple whole cell agglutination test for tuberculosis in which phenol-killed Mycobacterium tuberculosis H37Ra is used as the antigen. The test gave positive results in 59 of 63 culture-positive cases of tuberculosis due to M. tuberculosis, and in 4 of 11 culture-positive cases due to other mycobacteria. Negative results were recorded in 168 of 171 control subjects. A positive result was one in which a titre of 1/125 or more was recorded.