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Biomedical subjects

Richard Harding

Publications and source records attributed to Richard Harding.

At least 55 records · Page 3Linked to original sources
PubMed2004

Nephron endowment and filtration surface area in the kidney after growth restriction of fetal sheep.

Low birth weight is associated with adult-onset diseases including hypertension and renal disease; altered renal development after intrauterine growth restriction (IUGR) may underlie such prenatal programming. Our aim was to investigate nephron endowment and renal filtration surface area in fetal sheep in which IUGR resulted from late gestational umbilico-placental embolization (UPE) or natural twinning. UPE was performed between 120 and 140 d of gestation (term approximately 147 d). At autopsy (140 d), body weights of UPE and twin fetuses were, respectively, 34% and 28% lower than controls. Kidneys were sampled using a smooth fractionator approach and glomerular number was estimated using a physical disector/fractionator technique. Glomerular capillary length and filtration surface area were estimated using unbiased stereological techniques. Although relative kidney weights (grams per kilogram body weight) were not different between groups, nephron endowment was 40% lower in twin fetuses compared with controls (34.3 +/- 10.6 x 10(4) and 55.9 +/- 19.8 x 10(4), respectively; p < 0.05); UPE did not alter nephron number (50.7 +/- 13.2 x 10(4)). There was no difference in the glomerular capillary length or surface area between the UPE and control fetuses. IUGR due to twinning leads to reduced nephron endowment whereas late gestational IUGR does not, suggesting that reduced nephron endowment is dependent on the timing of the growth restriction. Our findings demonstrate that reduced birth weight per se does not necessarily imply reduced nephron endowment.

Animals↗
PubMed2004

Of sleep state and postnatal age on arousal responses induced by mild hypoxia in infants.

STUDY OBJECTIVES: It has been suggested that mild hypoxia may not be a potent stimulus for arousal during sleep in infants because infants frequently fail to arouse from quiet sleep (QS). Our aim was to characterize arousal responses of sleeping infants in both active sleep (AS) and QS under normoxic and mildly hypoxic (15% O2) conditions over the first 6 months of life. PARTICIPANTS: Five healthy term and 6 healthy preterm infants were each studied at 2 to 5 weeks, 2 to 3 months, and 5 to 6 months postterm. All infants underwent daytime polysomnography during which nasal airflow was monitored using a purpose-built pneumotachograph. All infants were studied under both normoxic (21% O2) and hypoxic (15% O2, balance N2) conditions (presentation order randomized) in each sleep state at each study age. Tests were terminated at arousal, O2 saturation falling below 85%, or 5 minutes (failure to arouse). MEASUREMENTS: Probability of failure to arouse and mean arousal latency were compared between each experimental condition, with each infant serving as its own control. RESULTS: Infants aroused more frequently under hypoxic conditions than under normoxic conditions. Overall, arousal latencies were shorter during hypoxia compared to normoxia in both sleep states at each age. Arousal latencies were longer in QS compared to AS in both hypoxic and normoxic conditions. CONCLUSION: In sleeping infants, mild hypoxia serves as a stimulus for arousal in both AS and QS. Of particular significance is our finding that arousal from AS is readily elicited by mild hypoxia.

Arousal↗
PubMed2004

Influence of maternal tobacco smoking during pregnancy on uterine, umbilical and fetal cerebral artery blood flows.

BACKGROUND: Cigarette smoking during pregnancy is a major cause of adverse perinatal outcome but effects on critical fetal and maternal circulations remain unclear. AIMS: To determine (1) the influence of habitual maternal cigarette smoking on blood flow velocities in uterine, umbilical and fetal middle cerebral arteries, and (2) the time-course of changes in these flows after smoking a cigarette. SUBJECTS AND METHODS: In 74 women who smoked and 69 non-smoking controls we measured Doppler blood flow velocity waveforms in the uterine, umbilical and fetal middle cerebral (MCA) arteries; smokers were divided into light (<10 cigarettes/day, n=28) and heavy smokers (>10 cigarettes/day, n=45). RESULTS: In the uterine artery there was no significant difference between the systolic/diastolic (S/D) ratio in smoking and non-smoking women; however, in smokers, a diastolic notch was more frequently observed in the uterine artery waveform than in controls (p<0.05), suggestive of a greater resistance in the uterine vasculature. In the umbilical artery, the S/D ratio was significantly greater in smokers than in non-smokers. In the fetal MCA, the S/D ratio was higher in heavy smokers than in light smokers (p<0.05) indicative of greater cerebrovascular resistance. There were no significant correlations between the interval between smoking the last cigarette and making the Doppler measurements and the S/D ratios in any of the vessels. CONCLUSION: Maternal cigarette smoking is associated with evidence of chronically increased resistances in the uterine, umbilical and fetal middle cerebral arteries.

Adult↗
PubMed2004

Evaluation of a short-term group intervention for informal carers of patients attending a home palliative care service.

Despite evidence of high psychological distress and unmet needs, evaluated interventions for informal caregivers in palliative care are few. This study involved an observational outcome evaluation of attendees, and a comparison group, in specialist home palliative care. The measures included carer psychological status and patient physical status at baseline, 8 weeks, and 20 weeks. Qualitative data were collected regarding content, satisfaction with, and impact of intervention. Process data described the uptake, resources, and group activity. The intervention combined informal multiprofessional teaching with facilitated peer exchange and support, and was delivered over 6 sessions of 90 minutes per week. The uptake rate was 25%; carers were less likely to accept if they were in paid employment (OR=0.26, P=0.06), and more likely to accept if they utilized avoidance coping (OR=1.13, P=0.04) or their patient had worse physical status (OR=2.1, P=0.03). Attendees described significant support and knowledge gains from the multiprofessional input and peer group. Most relied on social comparison processes to appraise their situation. Potential detection of significant effects on global psychological scores (i.e. anxiety, depression, and burden) using multivariate analysis was disallowed due to attrition. This acceptable and accessible intervention provided information and support; further outcome studies are needed for a range of interventions. Short-term interventions are unlikely to affect global psychological scores, and future evaluations should include additional time points of data collection to demonstrate support during attendance.

Adaptation, Psychological↗
PubMed2004

Effects of umbilical cord occlusion in late gestation on the ovine fetal brain and retina.

OBJECTIVE: Previous studies on the effects of umbilical cord occlusion (UCO) on the fetal brain have focused on short-term alterations, and in most cases have used only subjective techniques to evaluate brain injury. Our aim was to assess quantitatively the persistent consequences of UCO on the developing brain; we also examined the retina. METHODS: We subjected fetal sheep to a single episode of UCO at 126 days of gestation (term approximately 147 days) to induce at least 10 minutes of isoelectric fetal electrocorticogram (ECoG). RESULTS: UCO resulted in fetal asphyxia and transient mild alterations in fetal mean arterial pressure (MAP). UCO did not result in significant injury to the developing brain or retina when assessed 15 days after the insult. There was no change in the endogenous expression of brain-derived neurotrophic factor (BDNF) protein in the hippocampus, nor was there a significant loss of CA1 hippocampal pyramidal cells. However, this insult did result in subtle neuropathologic alterations in the brain, including a reduction in the weight of the cerebral hemispheres, an increase in the areal density of cerebellar Purkinje cells, and enlarged perivascular spaces around blood vessels and inflammatory cells in the cerebral white matter. UCO did not affect the thickness of the central or peripheral retina or the numbers of retinal dopaminergic, cholinergic, and nitrergic amacrine cells. CONCLUSIONS: Thus, while 10 minutes of UCO did not result in overt injury to the fetal brain or retina, the observed changes in the fetal brain suggest altered growth of neural processes, which may contribute to neurologic deficits postnatally or to increased vulnerability of the brain to later insults during either the remainder of gestation or after birth.

Animals↗
PubMed2004

Morphologic alterations in ovine placenta and fetal liver following induced severe placental insufficiency.

OBJECTIVES: Umbilical-placental embolization with microspheres has been used as a model of placental insufficiency and intrauterine growth restriction (IUGR). However, the effects of embolization on placental structure and organ morphology of the resulting IUGR fetus are relatively unexplored. In this study using ovine fetuses, we determined the location and distribution of microspheres within the placenta and explored the extent of placental and fetal organ morphologic changes induced by placental embolization. We hypothesized that microspheres administered into the umbilical circulation over 4 days would cause placental damage without significant morphologic alterations in fetal kidney or liver. METHODS: Eleven pregnant sheep at 118 +/- 1 (SE) days' gestation were studied. In six fetuses, embolization was induced by injections of 15-microm diameter microspheres on 4 successive days into the fetal descending aorta proximal to the umbilical arteries. Five fetuses served as time controls. RESULTS: In embolized fetuses, microspheres were detected in the placenta embedded in the fetal cytotrophoblastic layer or maternal parenchyma adjacent to villous cytotrophoblasts. Fetal cytotrophoblasts appeared normal except for loss of distinct separation between fetal and maternal cell layers. Microspheres were also detected in the fetal membranes within capillaries. The body weights of embolized fetuses were lower than controls, as were the body weight-normalized liver but not kidney weights. In the liver of the embolized fetuses, the number of hematopoietic cell clusters was markedly reduced, whereas the fetal kidneys appeared normal. CONCLUSIONS: We conclude that after 4 days of umbilical-placental embolization, microspheres were concentrated at the fetal villi proximal to the apical maternal-fetal interface and in the fetal membranes. There were noticeable morphologic changes in the embolized placentas, with no apparent gross damage to the placenta. The reduction in fetal liver weight and liver extramedullary hematopoietic cell abundance associated with embolization may predispose the fetus to alterations in liver function that could persist after birth.

Animals↗
PubMed2004

Respiratory control and arousal in sleeping infants.

Control of the cardiovascular and respiratory systems undergoes rapid maturation during infancy. Sleep is at a lifetime maximum during this period and has a marked influence on cardiorespiratory function. The mechanisms leading to sudden infant death syndrome (SIDS) may include a failure in the neural integration of the cardiovascular and respiratory systems, with a concomitant failure to arouse from sleep. Studies have shown that sleep states exert a marked influence on respiratory control and arousability. Infants are more arousable in active sleep compared with quiet sleep from both somatosensory and respiratory stimuli. Post-natal and gestational age at birth also have a marked influence on arousability. Arousability is depressed by the major risk factors for SIDS (prone sleeping, maternal smoking, prematurity and recent infection) and is increased by factors that decrease the risk for SIDS (e.g. use of dummies, breastfeeding).

Arousal↗
PubMed2004

Effects of exposure to chronic placental insufficiency on the postnatal brain and retina in sheep.

Chronic placental insufficiency (CPI) has the potential to affect fetal brain development and to cause brain injury. Our aim was to determine the effects of exposure to CPI during late gestation on brain and retinal structure and brain neurotrophin expression 8 weeks after birth. Six fetal sheep were exposed to CPI, induced by umbilico-placental embolization, from 120 days of gestation until term (approximately 147 days) such that fetal arterial oxygen saturation (SaO2) was reduced by approximately 50%. Nine untreated animals served as controls. During CPI, fetal arterial PO2, SaO2, pH, and growth were reduced (p < 0.05); these animals remained small at 8 weeks after birth. Structural abnormalities were present in the brains and retinae of all CPI-exposed lambs. There was a reduction in retinal width and in the number of retinal tyrosine hydroxylase-immunoreactive dopaminergic amacrine cells (p < 0.05). In the dorsal hippocampus the combined width of strata oriens and pyramidale was significantly reduced (p < 0.05). In the cerebellum there was a significant reduction (p = 0.05) in cerebellar cross-sectional area, most notably in the inner granule cell layer, and a reduction (p < 0.05) in immunoreactivity for the cytoskeletal protein neurofilament-200 in the white matter. Gliosis was present in either the cerebral white matter or cerebellum in all animals and degeneration was seen around blood vessels in 4/6 umbilico-placental embolization animals. There were reductions in brain-derived neurotrophic factor immunoreactivity in the hippocampus (p < 0.05) and tyrosine kinase B immunoreactivity in the cerebellum (p < 0.05). This study shows that late gestational CPI affects morphology and neurotrophin expression of the postnatal brain. These alterations in the brain can apparently persist from fetal life or become established after birth; some changes that were present in the fetus at term did not persist into postnatal life.

Animals↗
PubMed2003

Fetal growth restriction has long-term effects on postnatal lung structure in sheep.

We have previously shown that fetal growth restriction (FGR) during late gestation in sheep affects lung development in the near-term fetus and at 8 wk after birth. In the present study, our aim was to determine the effects of FGR on the structure of the lungs at 2 y after birth; our hypothesis was that changes observed at 8 wk after birth would persist until maturity. FGR was induced in sheep by umbilicoplacental embolization, which was maintained from 120 d until delivery at term (approximately 147 d); birth weights of FGR lambs were 41% lower than in controls. At 2 y after birth, body and lung weights were not different, but there were 28% fewer alveoli and alveoli were significantly larger than in controls; hence there was a 10% reduction in the internal surface area relative to lung volume in FGR sheep compared with controls. The lungs of FGR sheep, compared with controls, had thicker interalveolar septa as a result of increased extracellular matrix deposition; the alveolar blood-air barrier was also thicker, largely because of an 82% increase in basement membrane thickness. These changes are qualitatively similar to those observed at 8 wk. Our data show that structural alterations in the lungs induced by FGR that were apparent at 8 wk were still evident at 2 y after birth, indicating that FGR may result in permanent changes in the structure of the lungs of the offspring and may affect respiratory health and lung aging later in life.

Age Factors↗
PubMed2003

Cortisol enhances structural maturation of the hypoplastic fetal lung in sheep.

Although exogenous corticosteroids advance structural maturation of the fetal lung, they can adversely affect fetal lung and body growth. Our aim was to determine whether cortisol, at physiological doses, can enhance structural maturation of the hypoplastic fetal lung without affecting fetal lung growth. Fetal sheep were divided into four groups (n= 5 for each) and lung hypoplasia (LH) was induced in two groups. Increasing doses of cortisol (1.5-4.0 mg) were infused into one group of fetuses with LH and one group without LH; the other two groups received saline. LH retarded structural development, reduced tropoelastin mRNA levels, reduced hydroxyproline and elastin contents, and increased active matrix metalloproteinase-2 (MMP-2) levels in the fetal lung. Cortisol infusions had no effect on fetal lung growth or body weights. In fetuses with LH, cortisol increased the percentage airspace, reduced the interalveolar wall thickness, increased alveolar number and reduced the increase in active MMP-2 levels. Thus, relatively low doses of cortisol can enhance structural maturation of the fetal lung without adversely affecting fetal lung growth. However, cortisol did not correct the abnormal deposition of elastin within the alveolar parenchyma associated with LH, indicating that secondary septal crest formation remained abnormal.

Animals↗
PubMed2003

Current HIV/AIDS end-of-life care in sub-Saharan Africa: a survey of models, services, challenges and priorities.

BACKGROUND: In response to increased global public health funding initiatives to HIV/AIDS care in Africa, this study aimed to describe practice models, strategies and challenges to delivering end-of-life care in sub-Saharan Africa. METHODS: A survey end-of-life care programs was conducted, addressing the domains of service aims and configuration, barriers to pain control, governmental endorsement and strategies, funding, monitoring and evaluation, and research. Both closed and qualitative responses were sought. RESULTS: Despite great structural challenges, data from 48 programs in 14 countries with a mean annual funding of US 374,884 dollars demonstrated integrated care delivery across diverse settings. Care was commonly integrated with all advanced disease care (67%) and disease stages (65% offering care from diagnosis). The majority (98%) provided home-based care for a mean of 301 patients. Ninety-four percent reported challenges in pain control (including availability, lack of trained providers, stigma and legal restrictions), and 77% addressed the effects of poverty on disease progression and management. Although 85% of programs reported Government endorsement, end-of-life and palliative care National strategies were largely absent. CONCLUSIONS: The interdependent tasks of expanding pain control, balancing quality and coverage of care, providing technical assistance in monitoring and evaluation, collaborating between donor agencies and governments, and educating policy makers and program directors of end-of-life care are all necessary if resources are to reach their goals.

Acquired Immunodeficiency Syndrome↗
PubMed2003

pH as a trigger of peptide beta-sheet self-assembly and reversible switching between nematic and isotropic phases.

The hierarchical self-assembly of rationally designed synthetic peptides into beta-sheet tapes, ribbons, fibrils, and fibers opens up potentially useful routes to soft-solidlike materials such as hydrogels, organogels, or liquid crystals. Here, it is shown how incorporation of Glu (-CH(2)CH(2)COOH) or Orn (-CH(2)CH(2)CH(2)NH(2)) into the primary structure of an 11 amino acid peptide enables self-assembly to be rapidly (seconds) and reversibly controlled by simply changing pH. Solutions of monomeric peptide, typically at concentrations in excess of 0.003 v/v, can be switched within seconds to, for example, nematic gel states comprised of interconnected orientationally ordered arrays of fibrils or vice versa. This is to be compared with the lyophilized peptide dissolution route to nematic fluids and gels which is impracticably long, taking many hours or even days. An important design principle, that stabilization of fibrillar dispersions requires of the order of one unit of net positive or negative charge per peptide molecule, is first demonstrated and then used to design an 11 amino acid peptide P(11)-3 (CH(3)CO-Gln-Gln-Arg-Phe-Gln-Trp-Gln-Phe-Gln-Gln-Gln-NH(2)) whose self-assembly behavior is independent of pH (1 < pH < 10). pH control is then incorporated by appropriately positioning Glu or Orn side chains so that the peptide-peptide free energy of interaction in the tapelike substructure is strongly influenced by direct electrostatic forces between gamma-COO(-) in Glu(-) or delta-NH(3)(+) in Orn(+), respectively. This design principle is illustrated by the behavior of two peptides: P(11)-4 (CH(3)CO-Gln-Gln-Arg-Phe-Glu-Trp-Glu-Phe-Glu-Gln-Gln-NH(2)) which can be switched from its nematic to its isotropic fluid state by increasing pH and P(11)-5 (CH(3)CO-Gln-Gln-Orn-Phe-Orn-Trp-Orn-Phe-Gln-Gln-Gln-NH(2)) designed to exhibit the converse behavior. Acid-base titrations of fibrillar dispersions reveal deprotonation of the gamma-COOH of Glu or of the delta-NH(3)(+) of Orn(+) occurs over wide bands of up to 5 pH units, a feature of polyelectrolytes. The values of the energy parameters controlling self-assembly can therefore be smoothly and continuously varied by changing pH. This enables isotropic fluid-to-nematic transitions to be triggered by relatively small additions of acid or base, typically 1 part in 10(3) by volume of 1 M HCl or NaOH.

Gels↗
PubMed2003

The relationship between patient characteristics and carer psychological status in home palliative cancer care.

GOALS: Despite being both providers and intended recipients of care, informal carers in cancer palliative care report high levels of distress and unmet needs. In order to develop supportive care strategies, this analysis aimed to identify which patient characteristics contribute to carer psychological distress and which coping strategies carers employ. PATIENTS AND METHODS: Informal carers attending two home palliative care services gave cross-sectional data regarding patient characteristics and their own psychological status using standardised measures. Multivariate analyses were performed for each dependent carer psychological measure, with patient characteristics as independent variables (adjusted for carer age and gender). MAIN RESULTS: Forty-three carers participated. Greater patient distress was associated with carer anxiety (b value: magnitude of the effect) (b=0.31, p=0.07), and both patient psychological status (b=0.37, p=0.02) and pain (b=0.29, p=0.09) were associated with carer psychological morbidity. Carer burden was associated with patient psychological distress (b=0.35, p=0.03) and pain (b=0.29, p=0.08). Carer avoidance/emotion-focused cognitive coping strategies were associated with patient physical function (b=0.34, p=0.04), and cognitive problem-focused coping was associated with patient symptoms (b=0.28, p=0.06) and physical function (b=0.29, p=0.05). CONCLUSIONS: Adequate provision of patient psychological interventions and effective pain education and control are needed in order to improve carers' psychological health. Patient characteristics are associated with apparently opposing forms of carers' coping (i.e. both avoidance and engagement), demonstrating the importance of interventions addressing a range of coping responses. Further research is needed to understand why carers employ problem-focused coping in response to symptoms but not to pain. Evidence-based interventions for informal carers are urgently needed but must be delivered in the context of optimal patient pain and symptom control.

Adult↗
PubMed2003

Ventilatory responses preceding hypoxia-induced arousal in infants: effects of sleep-state.

Augmented ventilation and/or arousal in response to hypoxia are important protective mechanisms during sleep. We aimed to quantify ventilatory responses preceding hypoxia-induced arousal in infants and determine the effects of sleep-state. Fifteen term infants were studied at 2-4 weeks, 2-3 and 5-6 months of age. Ventilatory responses to 15% oxygen inhalation were expressed as breath-by-breath changes from normoxic levels and averaged over 5, 10 and 15 breaths preceding arousal. Minute ventilation preceding arousal significantly increased above normoxic levels only in AS at 5-6 months. There were no sleep-state related differences in minute ventilation, oxygen saturation or carbon dioxide levels (expressed as changes from normoxic values) at 5, 10 or 15 breaths preceding arousal. However, the rate of oxygen desaturation during hypoxia in AS was two to four times faster than in QS at each age. We conclude that the ventilatory responses preceding hypoxia-induced arousal do not differ between sleep-states and that arousal occurs at similar levels of desaturation in both states.

Aging↗
PubMed2003

The fetal brainstem is relatively spared from injury following intrauterine hypoxemia.

Our aim was to test the hypothesis that the fetal brainstem is relatively spared, compared to other brain regions, from hypoxia-induced damage. We have used established experimental models of acute and chronic intrauterine compromise in sheep to mimic conditions that can arise in human pregnancy. The acute insult was 12 h of placental insufficiency induced by restricted utero-placental blood flow at 90 days of gestation (term approximately 147 days). Five weeks after this insult (n=7 fetuses) there was no overt damage to the brainstem nor were there alterations to the blood vessel morphology, volume of the medulla or of medullary nuclei compared to controls (n=8). This regimen is known to have significant effects on the forebrain and cerebellum. The chronic insult was induced in five fetuses via embolisation of the umbilico-placental circulation from 120 to 140 days of gestation. An additional three fetuses were found to be spontaneously hypoxemic (SH) immediately after surgery. At 140 days, in brainstems of all chronically hypoxemic fetuses compared to controls (n=8), there was an increase (P<0.05) in the percentage of neuropil occupied by blood vessels and abnormal myelin in the most severely SH fetus but no other morphological or neurochemical alterations. This regimen is known to cause marked damage to the cerebral hemispheres and to a lesser extent to the cerebellum. We suggest that the absence of marked structural or neurochemical alterations in the brainstem is most likely due to the maintenance of oxygen delivery to the brainstem during fetal hypoxemia.

Animals↗
PubMed2003

Pharmacokinetics of betamethasone after maternal or fetal intramuscular administration.

OBJECTIVE: The purpose of this study was to determine the pharmacokinetics of betamethasone in maternal and fetal circulations after maternal or fetal intramuscular administration. STUDY DESIGN: Ewes that bore single fetuses underwent surgery at approximately 96 days of pregnancy for the implantation of fetal and maternal vascular catheters. At approximately 103 days, five ewes were injected intramuscularly with betamethasone (0.5 mg/kg body weight) or five fetuses received ultrasound-guided intramuscular injections of betamethasone (0.5 mg/kg estimated fetal weight). Maternal and fetal blood samples were collected serially for the measurement of plasma betamethasone concentrations. RESULTS: Fetal injection caused higher peak fetal betamethasone concentrations (341.2+/-23.7 nmol/L) than maternal injection (37.6+/-3.7 nmol/L; P<.001) and greater cumulative betamethasone exposure. The half-life of betamethasone in the fetal circulation was shorter after fetal injection (1.1+/-0.3 hours) than after maternal injection (8.5+/-2.0 hours; P=.006). CONCLUSION: The duration of fetal and maternal exposure to betamethasone can be minimized by direct fetal intramuscular administration that, in sheep, affords lung maturation without adverse effects on fetal growth.

Analysis of Variance↗