Whole blood pumping with a microthrottle pump.

We have previously reported that microthrottle pumps (MTPs) display the capacity to pump solid phase suspensions such as polystyrene beads which prove challenging to most microfluidic pumps. In this paper we report employing a linear microthrottle pump (LMTP) to pump whole, undiluted, anticoagulated, human venous blood at 200 µl min(-1) with minimal erythrocyte lysis and no observed pump blockage. LMTPs are particularly well suited to particle suspension transport by virtue of their relatively unimpeded internal flow-path. Micropumping of whole blood represents a rigorous real-world test of cell suspension transport given blood's high cell content by volume and erythrocytes' relative fragility. A modification of the standard Drabkin method and its validation to spectrophotometrically quantify low levels of erythrocyte lysis by hemoglobin release is also reported. Erythrocyte lysis rates resulting from transport via LMTP are determined to be below one cell in 500 at a pumping rate of 102 µl min(-1).

Cryptogenic fibrosing alveolitis and lung cancer: the BTS study.

BACKGROUND: The risk of lung cancer is often reported to be increased for patients with cryptogenic fibrosing alveolitis (CFA). METHODS: Vital status was sought for all 588 members of the British Thoracic Society (BTS) cryptogenic fibrosing alveolitis (CFA) study 11 years after entry to the cohort. Observed deaths due to lung cancer were compared with expected deaths using age-, sex- and period-adjusted national rates. The roles of reported asbestos exposure and smoking were also investigated. RESULTS: 488 cohort members (83%) had died; 46 (9%) were certified to lung cancer (ICD9 162). The standardised mortality ratio (SMR) was 7.4 (95% CI 5.4 to 9.9). Stratified analysis showed increased lung cancer mortality among younger subjects, men and ever smokers. Using an independent expert panel, 25 cohort members (4%) were considered to have at least moderate exposure to asbestos; the risk of lung cancer was increased for these subjects (SMR 13.1 (95% CI 3.6 to 33.6)) vs 7.2 (95% CI 5.2 to 9.7) for those with less or no asbestos exposure). Ever smoking was reported by 448 (73%) of the cohort and was considerably higher in men than in women (92% vs 49%; p<0.001). Most persons who died from lung cancer were male (87%), and all but two (96%) had ever smoked. Ever smokers presented at a younger age (mean 67 vs 70 years; p<0.001) and with less breathlessness (12% smokers reported no breathlessness vs 5% never smokers; p = 0.02). CONCLUSIONS: These findings confirm an association between CFA and lung cancer although this relationship may not be causal. The high rate of smoking and evidence that smokers present for medical attention earlier than non-smokers suggest that smoking could be confounding this association.

Microfluidic solid phase suspension transport with an elastomer-based, single piezo-actuator, micro throttle pump.

We report a Micro Throttle Pump (MTP) which has been shown to pump 5 microm diameter polystyrene beads at a concentration of 4.5 x 10(7) beads ml(-1). This new MTP design is constructed in a straightforward manner and actuated by a single piezoelectric (PZT) element. Maximum flow rates at 800 Hz drive frequency of 132 microl min(-1) with water and 108 microl min(-1) with a bead suspension were obtained. Maximum back-pressures of 6 kPa were observed in both cases. The reported MTP employs specific location of distinct internal microfluid structures cast in a single compliant elastomeric substrate to exploit the opposing directions of flexure of regions of a piezoelectric-glass composite bonded to the elastomer. By this novel means, distinct flexural regions, exhibiting compressive and tensile stresses respectively, allow both the pump's integrated input and output throttles and its pump chamber to be actuated concurrently by a single PZT. To support MTP design we also report the characterisation of an individual throttle's resistance as a function of actuator deflection and discuss the underlying mechanism of the throttling effect.

Elastomer-glass micropump employing active throttles.

We report a reciprocating microfluidic pump, the Micro Throttle Pump (MTP), constructed in a relatively uncomplicated manner from glass and microstructured poly(dimethylsiloxane)(PDMS). Unconventionally, the MTP employs throttling of fluid flow as distinct from fully-closing valve structures. Accordingly, this technique offers the prospect of solid-phase suspension tolerance. The reported MTP employs piezoelectrically (PZT) actuated deformation of flow constrictions (throttles) fabricated from PDMS at the two ports of a central, PZT actuated pump chamber. By appropriate time-sequencing of the individual PZTs' actuation, pumping can be induced in either direction. PDMS' elasticity further facilitates throttle operation by virtue of allowing significant PZT flexure that is substantially independent of the underlying PDMS microstructure. In contrast, in a rigid substrate such as silicon, deformation is constrained to where underlying microstructured cavities exist and this restricts design options. We describe the construction and performance of a prototype MTP capable of pumping 300 microl min(-1) or alternatively generating a back-pressure of 5.5 kPa. Preliminary modelling of MTP operation is also presented.

Effects of exposure to gas cooking in childhood and adulthood on respiratory symptoms, allergic sensitization and lung function in young British adults.

BACKGROUND: There is evidence that people who use gas for cooking have reduced lung function and experience more respiratory symptoms than those who use other fuels for cooking. OBJECTIVES: To study the effect of the presence of a gas cooker in the home, during both childhood and adulthood, on respiratory symptoms, allergic sensitization and ventilatory function among young adults. METHODS: A sample of 1449 young adults born in Britain 3-9 March 1958, who have been followed from birth to ages 7, 11, 16, 23 and 33 years, were examined at home at age 34-35 years. FEV1 and FVC were measured before and 20 min after inhalation of 400 microg salbutamol, and skin prick tests performed with three allergen extracts (grass, Der p 1 and cat). An interview on respiratory symptoms and indoor environmental exposures was included. RESULTS: No association was found between gas cooking in childhood or adulthood and incidence or prognosis of asthma/wheeze, allergic sensitization or current severity of respiratory symptoms. Subjects who currently used gas for cooking had a significantly reduced FEV1 (- 70 mL, 95% CI +/- 56) but not FVC (- 35 mL, 95% CI +/- 61) compared with those who used electricity for cooking. This reduction in FEV1 was concentrated among men and current asthmatics. CONCLUSION: The use of gas for cooking is unlikely to be a major influence on respiratory morbidity in young adults.

Effect of pneumonia in childhood on adult lung function.

Chronic obstructive pulmonary disease is a major health burden. Evidence that childhood lower respiratory tract infection (LRTI) is associated with reduced adult lung function and thereby with chronic obstructive pulmonary disease comes from 3 sources. First, studies of children hospitalized with specific LRTIs, for example, as a result of respiratory syncytial virus, show reduced lung function 7 to 10 years later, but many have diagnostic and referral biases. Second, population studies show that adults reporting childhood LRTI have reduced lung function, but retrospective ascertainment of LRTI is unreliable. Finally, in the largest study of adults with independent ascertainment of childhood LRTI, those with pneumonia before age 7 years had a 6% to 7% lower unadjusted mean forced expiratory volume in 1 second and forced vital capacity. The deficits in adjusted lung function persisted after albuterol was administered and were neither due to wheezing illness nor diminished after results were controlled for confounders. Loss of lung function was no greater in those with pneumonia at age <2 years than in those with pneumonia at age 2 to 7 years. This and similar studies strongly support an association between childhood pneumonia and a reduction in adult lung volume, whereas follow-up studies of children with specific LRTIs show an obstructive defect. Ongoing studies that have ascertained premorbid lung function should help determine whether pneumonia causes this deficit or is commoner in those with poorer premorbid lung function.

Reducing waiting times in lung cancer.

BACKGROUND: Concern exists over delays in the management of lung cancer patients. Maximum waiting times and a multidisciplinary team (MDT) approach have been recommended in several recent national reports. OBJECTIVE: Having implemented a MDT approach, we wished to assess whether national recommendations were achievable and to identify the major factors causing delays. METHODS: Prospective survey over five months of all new referrals with suspected lung cancer, documenting waiting times at all stages from referral to definitive treatment. RESULTS: Of the total of 92 patients, 57 were outpatients (67% seen within one week, 89% within two weeks of receipt of referral) and 35 were inpatients (all seen within two working days). Patient age did not influence waiting times to first being seen or to investigation. The result of the initial diagnostic test was received within two weeks of first being seen in 86% of patients. All patients received definitive treatment within recommended times from diagnosis. Delays in the early part of the care pathway were largely due to potentially remediable service factors, but unavoidable patient related factors were important in some prolonged diagnostic delays. CONCLUSIONS: National recommendations on waiting times are achievable in a high proportion of cases. The probable importance of the MDT approach is discussed.

Improving communication between hospital and primary care increases follow-up rates for asthmatic patients following casualty attendance.

Despite adequate access to primary care facilities, there is a group of patients who habitually present to hospital accident and emergency (A&E) departments when their asthma deteriorates. In Nottingham 50% of these patients are discharged from the A&E department without admission to hospital and are advised to inform and see their general practitioner (GP), but many fail to do so. We instituted a system of identifying all patients seen and discharged from our A&E department with asthma and informing their GPs and practice nurses within one working day of the event by fax. To determine whether any action had been taken following receipt of our fax, we contacted each general practice 1 month after the A&E attendance in 100 consecutive cases. Full data were available for 66 patients. Our faxes increased the notification of A&E attendances to GPs from 47 to 89%. This resulted in an increase in the number of follow-up appointments initiated by the practice, from 15 to 31. However, 29% of patients were not asked to attend for follow-up, in spite of the practice being aware of a recent A&E visit. Improving communication between hospital and general practice increases the rate of follow-up by GPs for patients with asthma who have been discharged from A&E. This has the potential to improve asthma management for this group of patients.

Effect of pneumonia and whooping cough in childhood on adult lung function.

BACKGROUND: Previous studies have suggested that respiratory infection during childhood is associated with respiratory disease in adulthood, but the link is unclear because of retrospective ascertainment of childhood infection, selection bias, and confounding factors. METHODS: We studied the effects of childhood pneumonia and whooping cough in 1392 British adults followed from birth in 1958. Of these, 193 had a history of pneumonia and 215 a history of whooping cough by the age of seven years. When the subjects were 34 or 35 years old, their forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were measured before and after they inhaled albuterol. RESULTS: A history of pneumonia was associated with deficits (+/-95 percent confidence limits) in both FEV1 (102+/-73 ml, P=0.006) and FVC (173+/-70 ml, P=0.001) when the analysis was adjusted for sex, height, and smoking, with no change in the ratio of FEV1 to FVC. These deficits persisted after inhalation of albuterol. In subjects with no history of wheezing, the deficit in FEV1 was 155+/-122 ml (P=0.01), in those with past wheezing it was 41+/-128 ml (P=0.53), and in those with current wheezing it was 119+/-133 ml (P=0.08). The effect was no greater for the subjects who had pneumonia at less than two years of age than for those who had it between the ages of two and seven years and was not diminished after control for multiple confounding factors. The deficits associated with whooping cough were smaller (FEV1, 41+/-70 ml; P=0.25; FVC, 81+/-76 ml; P=0.04). CONCLUSIONS: Childhood pneumonia is associated with reduced ventilatory function in adults. This reduction is independent of a history of wheezing and is not explained by other confounding factors.

A novel instrument for studying the flow behaviour of erythrocytes through microchannels simulating human blood capillaries.

A novel instrument has been developed to study the microrheology of erythrocytes as they flow through channels of dimensions similar to human blood capillaries. The channels are produced in silicon substrates using microengineering technology. Accurately defined, physiological driving pressures and temperatures are employed whilst precise, real-time image processing allows individual cells to be monitored continuously during their transit. The instrument characterises each cell in a sample of ca. 1000 in terms of its volume and flow velocity profile during its transit through a channel. The unique representation of the data in volume/velocity space provides new insight into the microrheological behaviour of blood. The image processing and subsequent data analysis enable the system to reject anomalous events such as multiple cell transits, thereby ensuring integrity of the resulting data. By employing an array of microfluidic flow channels we can integrate a number of different but precise and highly reproducible channel sizes and geometries within one array, thereby allowing multiple, concurrent isobaric measurements on one sample. As an illustration of the performance of the system, volume/velocity data sets recorded in a microfluidic device incorporating multiple channels of 100 microns length and individual widths ranging between 3.0 and 4.0 microns are presented.

British Thoracic Society study of cryptogenic fibrosing alveolitis: current presentation and initial management. Fibrosing Alveolitis Subcommittee of the Research Committee of the British Thoracic Society.

BACKGROUND: Mortality due to cryptogenic fibrosing alveolitis (CFA) is increasing, particularly in the elderly. Optimum management remains uncertain and previous studies of the disease have largely been from specialist centres. A national study was carried out of the presentation and initial management of CFA in the UK. METHODS: All respiratory physicians in England, Scotland and Wales were invited to enter patients with newly diagnosed CFA over a two year period. CFA was diagnosed on histological grounds or according to clinical criteria which included the absence of a defined connective tissue disorder or pneumoconiosis. Participating physicians (n = 150) completed a questionnaire at patient entry and at all subsequent follow up visits and death. RESULTS: A total of 588 patients (373 men, 63%) were studied of whom 441 (75%) were referrals from primary care. Their mean (SD) age was 67.4 (10.0) years and median duration of symptoms at presentation was 9.0 months. Clubbing was more common in men (203/373; 54%) than in women (86/ 215; 40%); 209 patients (36%) were graded as severely breathless at presentation. A history of dust exposure (organic or inorganic) was present in 274 patients (47%) of whom 87 had had some exposure to asbestos. Subjects exposed to dust were more likely to have smoked and had slightly higher mean lung volumes, but were otherwise indistinguishable from those not exposed in terms of clinical presentation, management, and outcome. Transbronchial biopsy specimens were taken in 164 patients (28%) and open lung biopsy specimens in 73 (12%), but 60% had no histological diagnostic procedure. Biopsy procedures were more likely to be performed in younger patients, those with better lung function, and those with a history of asbestos exposure. At presentation a decision not to initiate specific treatment was made in 284 cases (48%). The decision to initiate treatment was made predominantly on symptomatic grounds. Two years after the close of entry to the study 266 patients (45%) had died. CONCLUSIONS: CFA is predominantly a disease of elderly patients and has a poor prognosis. Physicians generally considered CFA to be a clinical diagnosis and did not initiate treatment in up to half of patients at presentation.

Childhood antecedents of allergic sensitization in young British adults.

OBJECTIVE: This study was designed to investigate whether associations of self-reported hay fever with sibship size, birth order, infant feeding, and childhood socioeconomic status reflect variations in sensitization to common aeroallergens. METHODS: One thousand three hundred sixty-nine persons born throughout Britain in 1958 were followed up to age 34 to 35 years. The cohort included 1050 subjects with a history of asthma, wheezy bronchitis, wheezing, or pneumonia and 319 with no history of wheezing illness at ages 7, 11, 16, 23, or 33 years. Skin prick tests with extracts of mixed grass pollen, house dust mite (Der p 1), and cat fur were performed; and wheal diameters were measured. RESULTS: The prevalence of positive skin test results (> or = 3 mm wheal) was independently related (p < 0.01) to male sex, reduced numbers of older siblings (but not younger siblings), and higher socioeconomic status in childhood. Current cigarette smoking and maternal smoking during pregnancy were independently associated (p < 0.01) with a reduced prevalence of skin prick test positivity. No significant independent effects (p > 0.10) were found for adult social class, maternal age, birth weight, gestation, breast feeding, preschool nursery attendance, urban birthplace, or gas stove exposure. CONCLUSION: Factors related to small families and relative affluence in childhood promote atopic sensitization to a variety of aeroallergens in later life. These observations are consistent with the suggestion that early infection may protect against subsequent allergic disease.

Pulmonary Mycobacterium kansasii infection: comparison of radiological appearances with pulmonary tuberculosis.

BACKGROUND: A study was undertaken to determine if there are differences in the radiological appearances at presentation between pulmonary infections caused by Mycobacterium kansasii and Mycobacterium tuberculosis. Correct recognition of the organism has important implications with regard to initial therapy and contact tracing. METHODS: The initial chest radiographs of 28 patients with pulmonary M kansasii infection were compared with those of 56 age, sex, and race matched patients with M tuberculosis infection. All patients in both groups were culture positive and none was known to be HIV positive. The radiographs were analysed independently by two radiologists who were unaware of the causative organism. RESULTS: Radiographic abnormalities in patients with M kansasii infection were more frequently unilateral and right side predominant, while those with tuberculosis more frequently involved a lower lobe. Air space shadowing involving more than one bronchopulmonary segment and pleural effusions were seen less frequently in M kansasii infection (four of 28 (14%) versus 30 of 56 (54%) and none of 28 versus 15 of 56 (27%)). Cavitation (21 of 28 (75%) versus 34 of 56 (61%) was seen to a similar extent in patients with M kansasii infection and in those with tuberculosis. Cavities tended to be smaller in patients with M kansasii infection (p < 0.01). CONCLUSIONS: Differences are seen in the radiographic appearances of pulmonary infection caused by M kansasii and M tuberculosis. These differences are not sufficient to allow a positive diagnosis on the basis of radiographic findings alone, but the presence of a pleural effusion or lower lobe involvement makes M kansasii infection very unlikely.

Pulmonary Mycobacterium kansasii infection: comparison of the clinical features, treatment and outcome with pulmonary tuberculosis.

BACKGROUND: In the United Kingdom Mycobacterium kansasii is the most common pulmonary non-tuberculous mycobacteria to cause disease in the non-HIV positive population. METHODS: The clinical features, treatment, and outcome of 47 patients (13 women) of mean (SD) age 58 (17) years with culture positive pulmonary M kansasii infection were compared with those of 87 patients (23 women) of mean (SD) age 57 (16) years with culture positive pulmonary M tuberculosis infection by review of their clinical and laboratory records. Each patient with M kansasii infection was matched for age, sex, race and, where possible, year of diagnosis with two patients with M tuberculosis infection. RESULTS: All those with M kansasii infection were of white race. Haemoptysis was more common in patients infected with M kansasii but they were less likely to present as a result of an incidental chest radiograph or symptoms other than those due to mycobacterial infection. Patients with M kansasii were also less likely to have a history of diabetes, but the frequency of previous chest disease and tuberculosis was similar. An alcohol intake of > 14 units/week was less frequent in those with M kansasii, but there were no significant differences in drug history, past and present smoking habit, occupational exposures, social class, or marital status. Patients with M kansasii received a longer total course of antimycobacterial therapy and, in particular, extended treatment with ethambutol and rifampicin was given. There was no significant difference in outcome between pulmonary M kansasii or M tuberculosis infection. CONCLUSIONS: There are group differences between the clinical features of the two infections but, with the possible exception of diabetes and alcohol intake, these features are unlikely to be diagnostically helpful. Treatment of M kansasii infection with ethambutol, isoniazid, and rifampicin in these patients was as effective as standard regimens given to patients infected with M tuberculosis.

Ventilatory function in British adults after asthma or wheezing illness at ages 0-35.

The impact of past and current asthma on ventilatory function was assessed among young adults born in Britain March 3-9, 1958 who had been followed from birth to ages 7, 11, 16, 23, and 33 yr. We compared 1,060 subjects with a history of asthma, wheezy bronchitis, or wheezing with 275 control subjects with no history of chest illness. Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were measured at 34-35 yr of age before and 20 min after inhalation of 400 micrograms salbutamol, and adjusted for sex, height, and smoking by multiple regression. Among 551 cases reporting no wheeze in the year before examination, ventilatory function after salbutamol did not differ significantly from the controls, except for FEV1 in 192 subjects with transient wheezing before age 7 (p < 0.05). Among 509 cases reporting wheeze in the past year, FEV1 and FEV1/FVC ratio were reduced to a greater extent in those with an earlier age of onset of wheeze (p < 0.001 for trend in each case). These relative reductions were greater if wheezing had persisted through childhood and adolescence, and were only partially reversed by inhalation of salbutamol. Progressive pulmonary changes related to chronic asthma may be an important mechanism underlying the association between childhood chest illnesses and chronic respiratory disease in adult life.

Breathlessness and exercise capacity in heart failure: the role of bronchial obstruction and responsiveness.

The cause of the breathlessness and reduced exercise capacity that occur in patients with chronic heart failure remains obscure. We examined the hypothesis that airway obstruction and bronchial hyper-responsiveness, which are recognised features of chronic heart failure, might contribute to the breathlessness and reduced exercise capacity in this condition. We studied 37 patients (7 female) with chronic heart failure, of mean age 61 years. Each patient underwent: (i) lung function testing with spirometry and expiratory flow volume loops. (ii) Measurement of bronchial responsiveness to methacholine. (iii) Symptom-limited treadmill exercise capacity using both incremental and fixed workload protocols, with measurement of Borg scores for breathlessness. Lung function was not significantly related to either exercise time, or Borg symptom scores in either exercise protocol. Bronchial hyper-responsiveness to methacholine was demonstrated in 12 patients. Exercise time did not correlate with the degree of bronchial hyper-responsiveness in these 12 patients. Group mean exercise time and Borg scores were not significantly different in these 12 patients when compared to the 25 patients in whom bronchial hyper-responsiveness was not found. We conclude that airway obstruction and bronchial hyper-responsiveness are not likely to be important determinants of reduced exercise capacity and breathlessness in chronic heart failure.