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Biomedical subjects

Richard Harding

Publications and source records attributed to Richard Harding.

At least 37 records · Page 2Linked to original sources
PubMed2005

Effect of lung hypoplasia on birth-related changes in the pulmonary circulation in sheep.

Lung hypoplasia (LH) is a serious cause of neonatal compromise, but little is known of its functional effects on the pulmonary circulation. Our aim was to characterize birth-related changes in the pulmonary circulation of newborn lambs with LH and to compare them with alterations in respiratory function. LH was induced in six ovine fetuses by the creation of a tracheo-amniotic shunt as well as amniotic fluid drainage starting at 105.6+/-1.5 (mean+/-SEM) days of gestation (term approximately 147 d). At 139.9+/-0.3 d, fetuses were exteriorized under anesthesia to implant vascular catheters and an ultrasonic flow probe around the left pulmonary artery. The lambs then were delivered and ventilated for 2 h, during which systemic and pulmonary artery pressures, left pulmonary blood flow, and measures of respiratory function were recorded. At autopsy, lungs were weighed and volume was measured at 20 cm H2O. In LH lambs, lung weight was 25% lower and respiratory system compliance was 30% lower than in controls. Mean pulmonary blood flow in LH lambs was 42% lower and pulmonary vascular resistance was 138% higher than in controls. Morphometry showed that volume density of pulmonary arteries in LH was 30% lower than in controls. We conclude that, in this LH model, changes in ventilatory indices were proportional to the change in lung size, whereas changes in the pulmonary circulation were greater than the change in lung size and were associated with reduced density of pulmonary arteries. LH severely impairs normal adaptation of the pulmonary circulation in the perinatal period.

Animals↗
PubMed2005

Pulmonary function and structure following mild preterm birth in lambs.

Our objective was to determine whether postnatal respiratory function, lung growth, and lung structure are affected by preterm birth which did not require neonatal respiratory support. Two groups of preterm (P) lambs were delivered 2 weeks before term, at 133 days of gestational age (GA). Tissue was collected at term equivalent age (TEA, 147 days GA) in one P group and at 6 weeks post-TEA in the other. Tissue was also collected from control (C) lambs soon after term birth (TEA) and at 6 weeks post-TEA. Lung function was assessed at TEA and 6 weeks post-TEA. Respiratory system compliance (Crs/kg BWT) was not different between P and C groups at TEA, but was higher (P = 0.02) in P lambs at 6 weeks post-TEA. Pulmonary resistance was 62% higher in P lambs than controls (P = 0.07) at TEA, and remained higher at 6 weeks post-TEA. Lung weights (wet and dry) were greater (P < 0.05) in preterm animals at both ages; when adjusted for body weight, only dry lung weight remained higher at 6 weeks post-TEA. Alveoli were more numerous (P = 0.05) and smaller (P = 0.05) in preterm lambs compared to controls at both ages. Alveolar septa were 33% thicker and the blood-air barrier was 26% thicker in P lambs than in controls at TEA, and remained thicker at 6 weeks post-TEA. In P lambs, the airway epithelium was thicker at TEA and 6 weeks post-TEA. At TEA, pulmonary tropoelastin expression was 27% lower in P lambs. At 6 weeks post-TEA, dry lung weight and lung protein content were approximately 50% greater in preterm lambs than in controls (P < 0.05), whereas lung DNA, elastin, and collagen contents were similar in the two groups. We conclude that mild preterm birth per se leads to both transient and persistent changes in lung development. Persistent increases in lung protein content and in the thickness of the airway epithelium, and a greater number of smaller alveolar, may alter later lung function.

Animals↗
PubMed2005

Effects into adulthood of single or repeated antenatal corticosteroids in sheep.

OBJECTIVE: To determine effects of maternal or fetal injections of betamethasone on postnatal growth and arterial pressure. STUDY DESIGN: We measured body weight, arterial pressure, and heart rate serially in sheep born after single or repeated maternal or fetal betamethasone injections. At approximately 3.5 years, organ weights were measured. RESULTS: Repeated maternal betamethasone injections caused intrauterine growth restriction, and low body weight and blood pressure at 3 months. From 6 months to 3 years, body weight, blood pressure, and heart rate were not affected by treatment. At approximately 3.5 years, brain weight was reduced after single or repeated maternal betamethasone by 13% and 18%, respectively (P = .001). Fetal betamethasone reduced brain weight by 7% to 8% (P = .018). Weights of other organs were not affected by treatment. Brain weight was unrelated to body weight at approximately 3.5 years (P = .649) but was related to birth weight (P = .029). CONCLUSION: Prenatal betamethasone does not have long-term effects on blood pressure but causes a persistent deficit in brain weight.

Animals↗
PubMed2005

Heart rate responses to non-arousing trigeminal stimulation in infants: effects of sleep position, sleep state and postnatal age.

AIMS: The aim of this study was to examine the effects of maternal smoking, sleeping position, sleep state and postnatal age on heart rate changes following non-arousing trigeminal stimulation in infants. SUBJECTS: We studied healthy term infants, 13 of whom were born to mothers who did not smoke and 11 to mothers who smoked during pregnancy. Each infant was studied using daytime polysomnography on 3 occasions: (a) 2-3 weeks, (b) 2-3 months and (c) 5-6 months after birth. Nasal air-jet stimulation was presented in both active sleep (AS) and quiet sleep (QS) when infants slept both prone and supine. RESULTS: We found no difference between infants of smoking and non-smoking mothers in any of the parameters measured. Minimum HR (MinHR) following non-arousing trigeminal stimulation was significantly lower in the supine compared to the prone sleeping position at 2-3 weeks and 2-3 months of age (p<0.05) in AS, and at all 3 ages in QS (p<0.01). MinHR was significantly lower in QS compared to AS at 2-3 months when infants slept prone and at 5-6 months when sleeping supine (p<0.01). In QS, MinHR became lower with increasing postnatal age in both sleep positions (p<0.01). In AS, there was no maturational effect. The normalized bradycardia (DeltaHR%) was significantly greater in AS than in QS at 2-3 weeks of age (p<0.05) when infants slept supine. CONCLUSION: Our study has shown that there was a decrease in heart rate (MinHR) following trigeminal stimulation in infants up to 6 months of age and this was affected by sleep position and sleep state, being larger in the supine sleeping position and the QS state.

Age Factors↗
PubMed2005

Early developmental origins of impaired lung structure and function.

Epidemiological studies show that exposure to factors that restrict fetal growth or lead to low birthweight can alter lung development and have later adverse effects on lung function and respiratory health. The major causal factors include reduced nutrient and oxygen availability, nicotine exposure via maternal tobacco smoking and preterm birth, each of which can affect critical stages of lung development. Experimental studies show that these environmental insults can permanently alter lung structure and hence lung function, increasing the risk of respiratory illness and accelerating the rate of lung aging. Further studies are required that address the molecular and cellular mechanisms by which these factors adversely affect lung development and whether such effects can be blocked or reversed. Ultimately however, a major goal should be to prevent prenatal compromises through clinical monitoring, and in the case of smoking through education, thereby ensuring that each fetus has the best possible environment in which to develop.

Adult↗
PubMed2005

Comparison of postnatal development of heart rate responses to trigeminal stimulation in sleeping preterm and term infants.

Autonomic dysfunction has been regarded as a possible cause of the sudden infant death syndrome (SIDS) and it has been suggested that preterm infants, who are at a greater risk of SIDS than term infants, may have immature autonomic control. Our aim was to compare the maturation of cardiac autonomic control during sleep in preterm and term infants by examining heart rate responses to arousing and non-arousing trigeminal stimuli. Preterm infants (n = 15) and term infants (n = 24) were studied longitudinally with daytime polysomnography. Air-jet stimulation of the nares was delivered in both active sleep (AS) and quiet sleep (QS), and heart rate (HR) changes recorded for both arousal and non-arousal responses. Changes in HR (DeltaHR%) were calculated as the relative differences between baseline HR (BHR) and either MaxHR (arousal) or MinHR (non-arousal). Comparisons of HR changes between sleep states and postnatal ages were made with two-way anova for repeated measures and between groups with two-way anova. The increase in HR (DeltaHR%) was greater in term than preterm infants (P < 0.05), but only at 2-3 weeks corrected postnatal age (CPA). In preterm infants, there were no differences in BHR between sleep states, whereas in term infants, BHR was higher in AS than in QS at 2-3 weeks and 2-3 months of age. The smaller DeltaHR% to arousing stimuli in preterm infants compared with term infants at 2-3 weeks suggests that cardiac sympathetic activity in preterm infants may be lower than in term infants. This mechanism may account for the increased risk for SIDS of preterm infants.

Age Factors↗
PubMed2005

Effects of tidal volume and positive end-expiratory pressure during resuscitation of very premature lambs.

BACKGROUND: Guidelines recommend neonatal resuscitation without controlling tidal volume or positive end-expiratory pressure (PEEP). However, these may improve gas exchange, lung volume and outcome. AIM: To investigate resuscitation of very premature lambs with a Laerdal bag without PEEP versus volume guarantee ventilation with PEEP. METHODS: Anaesthetized lambs (n=20) delivered at 125 d gestation were randomized to three groups receiving 15 min resuscitation: (1) Laerdal bag and no PEEP; (2) ventilation with a tidal volume of 5 ml/kg and 8 cm H(2)O PEEP; (3) ventilation with 10 ml/kg and 8 cm H(2)O PEEP. They were then all ventilated for 2 h with tidal volumes of 5 or 10 ml/kg, and 8 cm H(2)O PEEP. Ventilation parameters and blood gases were recorded. RESULTS: Different tidal volumes affected PaCO(2) within minutes, with 10 ml/kg causing severe hypocarbia. PEEP had little effect on PaCO(2). Oxygenation improved significantly with PEEP of 8 cm H(2)O, irrespective of tidal volume. CONCLUSION: Very premature lambs can be resuscitated effectively using volume-guarantee ventilation and PEEP. Tidal volumes affected PaCO(2) within minutes but had little effect on oxygenation. PEEP halved the oxygen requirement compared with no PEEP. Resuscitating premature babies with controlled tidal volumes and PEEP might improve their outcome.

Animals↗
PubMed2005

Fetal growth restriction induced by chronic placental insufficiency has long-term effects on the retina but not the optic nerve.

PURPOSE: Reduced birth weight is associated with an increased risk of visual impairments. This study was undertaken to determine whether prenatal exposure to a chronic compromise sufficient to cause fetal growth restriction (FGR) results in long-term alterations to the retina and optic nerve. METHODS: FGR was induced by umbilicoplacental embolization (UPE) in two cohorts of pregnant ewes from (1) 120 days of gestation (dg) until 140 dg and (2) 120 dg until term ( approximately 147 dg). Control fetuses were not subjected to UPE. The structure and neurochemistry of the retina and number and structure of ganglion cell axons were assessed in near-term (140 dg) and adult animals (2.3 years). RESULTS: In near-term FGR fetuses compared with control fetuses there were significant reductions (P < 0.05) in the outer plexiform layer (OPL), the photoreceptor inner and outer segment layers, the inner nuclear layer (INL) in the central retina and the outer nuclear layer (ONL) in the peripheral retina, and the diameter of ganglion cell axons in the optic nerve, with a proportional reduction in the thickness of myelin sheaths. In FGR animals compared with the control at 2.3 years, there were significant reductions (P < 0.05) in the total thickness of the retina, the thickness of the photoreceptor outer segment layer and the INL and the number of tyrosine hydroxylase-immunoreactive (TH-IR) dopaminergic amacrine cells. Axonal diameter and myelin sheath thickness in the optic nerve were not different (P > 0.05) between groups. CONCLUSIONS: Chronic placental insufficiency in late gestation results in long-lasting effects on specific retinal components, including photoreceptor outer segments and TH-IR amacrine cells. Other alterations observed at term, including reductions in growth and myelination of optic nerve axons, do not persist, suggesting delayed rather than permanently compromised development. Alterations persisting into adulthood could affect visual function.

Amacrine Cells↗
PubMed2005

Access and equity in HIV/AIDS palliative care: a review of the evidence and responses.

The high prevalence of pain and other symptoms throughout the HIV disease trajectory, the need for management of side effects related to antiretroviral therapy, the continuing incidence of cancers and new emerging co-morbidities as a result of extended life expectancy under new therapeutic regimes, and the ongoing need for terminal care all prove the curative versus palliative dichotomy to be inappropriate. Although there is evidence for both need and effectiveness of palliative care in HIV patient care, access is often poor and care less than optimal. This review aimed to identify evidence of barriers and inequalities in HIV palliative care in order to inform policy and service development. Biomedical databases were searched using a specific strategy, and evidence extracted into the barrier and inequity categories of patient, clinician, service and disease factors. A model of the barriers and inequalities is presented from the evidence. Recommendations are made from the evidence for promoting access and outcomes through integrated palliative care from diagnosis to end-of-life, alongside antiretroviral therapy when initiated. Service responses that have attempted to increase access to palliative care are presented.

Antiretroviral Therapy, Highly Active↗
PubMed2005

Clinical notes for informal carers in palliative care: recommendations from a random patient file audit.

Although palliative care aims to support family members and informal carers, current evidence suggests that high levels of unmet need persist, and that this population is challenging to work with. This study aimed to 1) measure the proportion of patients that have an informal carer, 2) describe the clinical notes data on existing needs and coping, 3) measure the completeness of assessment data recording, 4) appraise the utility of existing informal carers' sections in the patient files, and 5) make recommendations for improvement. An audit was conducted reviewing 145 closed patient files. Of these, 100 had identifiable informal carers (69.9%). Although patient data was complete, data was severely lacking on their informal carer. Diverse coping strategies were described, and the primary need was for finance and advice about state welfare payments (n=64). The findings suggest a need for files to identify and record informal carers as potentially distinct from family members, promote assessment data completion for informal carers on a par with that of patients, and to develop systematic approaches to systems that maximize utility and incorporate multiprofessional input into the development of clinical notes.

Adult↗
PubMed2005

Long term consequences of low birthweight on postnatal growth, adiposity and brain weight at maturity in sheep.

Low birth weight (LBW) as a result of restricted fetal growth increases the risk for later metabolic diseases and adiposity. However the relationship between LBW and postnatal growth and adult body composition has not been fully investigated. We have used sheep to determine the effects of LBW on postnatal growth and body composition at maturity. LBW was induced by twinning and placental embolization. At birth, LBW lambs were 38% lighter than controls (2.8 +/- 0.2 vs 4.4 +/- 0.3 kg, P<0.05), but had caught up in bodyweight by 8 weeks after birth. At approximately 2.3 years, bodyweights were not different between groups, but there were reductions in absolute (-8%) and relative (-17%) brain weights of LBW sheep (P<0.05) compared to controls. X-ray absorptiometry showed that the mature LBW sheep, compared to controls, had greater amounts of lean muscle (38.1 +/- 1.3 vs 35.3 +/- 0.5 kg, P<0.05) and tended to have more body fat (12.2 +/- 1.2 vs 9.6 +/- 0.9 kg; P=0.1); at autopsy abdominal fat mass was greater in LBW sheep (3.06 +/- 0.26 vs 2.20 +/- 0.25 kg, P<0.05). Plasma leptin concentrations were not different between groups. We conclude that, in sheep, LBW is associated with early postnatal catch-up in body weight, but body composition is permanently altered such that, relative to controls, adiposity is increased and brain weight is decreased.

Absorptiometry, Photon↗
PubMed2004

Neurotrophin expression in the hippocampus and cerebellum is affected by chronic placental insufficiency in the late gestational ovine fetus.

Our aim was to determine the effects of chronic placental insufficiency (CPI) during late gestation on the expression of neurotrophic factors and their receptors in the hippocampus and cerebellum in the near-term fetus. Structural alterations were also assessed in these brain regions. CPI was induced in eight fetal sheep by umbilicoplacental embolization (UPE) from 120 to 140 days of gestation (term approximately 147d) such that fetal arterial O2 saturation (SaO2) was maintained at approximately 50% of pre-UPE values. Five non-UPE fetuses served as controls. UPE resulted in fetal hypoxemia, hypoglycaemia, and growth restriction. In hippocampi from UPE fetuses, there were reductions in the optical density (OD) of the immunoreactivity (IR) of brain-derived neurotrophic factor (BDNF) protein within the mossy fibre collaterals of the polymorphic layer and in stratum lucidum (p<0.05); there was no consistent effect on tyrosine-related kinase (Trk) B receptor or neurotrophin-3 (NT-3) expression. Within the cerebellum, there was an increase in BDNF-IR (p<0.05) in the molecular layer; however, Trk B-IR and NT-3-IR were unaltered. There were no significant alterations to the structural parameters measured in the hippocampus. We conclude that CPI in late gestation affects the expression of BDNF in the fetal hippocampus and cerebellum, but these changes do not have a well-defined relationship to structural outcome.

Animals↗
PubMed2004

Targeting smoking cessation to high prevalence communities: outcomes from a pilot intervention for gay men.

BACKGROUND: Cigarette smoking prevalence among gay men is twice that of population levels. A pilot community-level intervention was developed and evaluated aiming to meet UK Government cessation and cancer prevention targets. METHODS: Four 7-week withdrawal-oriented treatment groups combined nicotine replacement therapy with peer support. Self-report and carbon monoxide register data were collected at baseline and 7 weeks. N = 98 gay men were recruited through community newspapers and organisations in London UK. RESULTS: At 7 weeks, n = 44 (76%) were confirmed as quit using standard UK Government National Health Service monitoring forms. In multivariate analysis the single significant baseline variable associated with cessation was previous number of attempts at quitting (OR 1.48, p = 0.04). CONCLUSIONS: This tailored community-level intervention successfully recruited a high-prevalence group, and the outcome data compares very favourably to national monitoring data (which reports an average of 53% success). Implications for national targeted services are considered.

Adult↗
PubMed2004

Regulation of alveolar epithelial cell phenotypes in fetal sheep: roles of cortisol and lung expansion.

Our aim was to determine whether cortisol's effect on alveolar epithelial cell (AEC) phenotypes in the fetus is mediated via a sustained alteration in lung expansion. Chronically catheterized fetal sheep were exposed to 1) saline infusion, 2) cortisol infusion (122-131 days' gestation, 1.5-4.0 mg/day), 3) saline infusion plus reduced lung expansion, or 4) cortisol infusion plus reduced lung expansion. The proportions of type I and II AECs were determined by electron microscopy, and surfactant protein (SP)-A, -B, and -C mRNA levels were determined by Northern blot analysis. Cortisol infusions significantly increased type II AEC proportions (to 38.2 +/- 2.2%), compared with saline-infused fetuses (23.8 +/- 2.4%), and reduced type I AEC proportions (to 59.0 +/- 2.2%), compared with saline-infused fetuses (70.4 +/- 2.4%). Reduced lung expansion also increased type II AEC proportions (to 52.9 +/- 3.5%) and decreased type I AEC proportions (to 34.2 +/- 3.7%), compared with control, saline-infused fetuses. The infusion of cortisol into fetuses exposed to reduced lung expansion tended to further increase type II (to 60.3 +/- 2.1%, P = 0.066) and reduce type I AEC (to 26.6 +/- 2.3%, P = 0.07) proportions. SP-A, -B, and -C mRNA levels changed in parallel with the changes in type II AEC proportions. These results indicate that cortisol alters the proportion of type I and type II AECs via a mechanism unrelated to the degree of fetal lung expansion. However, reductions in fetal lung expansion appear to have a greater impact on the proportion of AECs than cortisol.

Animals↗
PubMed2004

Positive end expiratory pressure during resuscitation of premature lambs rapidly improves blood gases without adversely affecting arterial pressure.

Positive end expiratory pressure (PEEP) is important for neonatal ventilation but is not considered in guidelines for resuscitation. Our aim was to investigate the effects of PEEP on cardiorespiratory parameters during resuscitation of very premature lambs delivered by hysterotomy at approximately 125 d gestation (term approximately 147 d). Before delivery, they were intubated and lung fluid was drained. Immediately after delivery, they were ventilated with a Dräger Babylog plus ventilator in volume guarantee mode with a tidal volume of 5 mL/kg. Lambs were randomized to receive 0, 4, 8, or 12 cm H(2)O of PEEP. They were ventilated for a 15-min resuscitation period followed by 2 h of stabilization at the same PEEP. Tidal volume, peak inspiratory pressure, PEEP, arterial pressure, oxygen saturation, and blood gases were measured regularly, and respiratory system compliance and alveolar/arterial oxygen differences were calculated. Lambs that received 12 cm H(2)O of PEEP died from pneumothoraces; all others survived without pneumothoraces. Oxygenation was significantly improved by 8 and 12 cm H(2)O of PEEP compared with 0 and 4 cm H(2)O of PEEP. Lambs with 0 PEEP did not oxygenate adequately. The compliance of the respiratory system was significantly higher at 4 and 8 cm H(2)O of PEEP than at 0 PEEP. There were no significant differences in partial pressure of carbon dioxide in arterial blood between groups. Arterial pressure was highest with 8 cm H(2)O of PEEP, and there was no cardiorespiratory compromise at any level of PEEP. Applying PEEP during resuscitation of very premature infants might be advantageous and merits further investigation.

Animals↗
PubMed2004

Brain development during fetal life: influences of the intra-uterine environment.

The intrauterine environment can significantly affect fetal brain development. Here we review our recent findings using animal models that mimic adverse intrauterine conditions which could exist during human pregnancy. We have focused on effects of both acute and chronic hypoxic and inflammatory insults. Relatively brief periods of hypoxemic compromise can have significant effects on the fetal brain causing neuronal loss and cerebral white matter damage. Subtle brain injury can occur, for example to a particular class of neuron, and this can have a significant effect on the function of a specific system. Chronic mild placental insufficiency can result in long term deficits in neuronal connectivity affecting function postnatally as demonstrated in the auditory and visual systems. Repeated acute exposure to an inflammatory agent results in diffuse subcortical white matter damage and in some cases periventricular necrosis. We have demonstrated that the timing and severity of these prenatal insults are determinants of the outcomes, in terms of the severity of the damage and the regions of the brain affected.

Animals↗
PubMed2004

Arousal and ventilatory responses to hypoxia in sleeping infants: effects of maternal smoking.

Our aim was to determine whether maternal cigarette smoking affects arousal and ventilatory responses to hypoxia in infants. Infants born to non-smoking (NS, n = 15) and smoking mothers (SM, n= 9) were studied at 2-5 weeks, 2-3 and 5-6 months. Ventilatory responses to 15% O(2) were determined preceding arousal. At each age and in both groups, infants aroused more frequently and earlier to hypoxia in active sleep (AS) than quiet sleep (QS). Arousal latency was longer in SM infants (in QS) at 5-6 months (P < 0.05). Baseline respiratory parameters were not different between groups, except that, at 2-3 months, SM infants had higher SP(O2) during AS than NS infants. Maternal smoking did not affect ventilatory responses preceding hypoxia-induced arousal in either sleep-state at any age. We conclude that mild hypoxia stimulates ventilation and arousal in infants up to 6 months and that arousability is depressed in SM infants at 5-6 months; however, ventilatory responses preceding arousal are not adversely affected by smoking.

Arousal↗